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Volume 12
Issue 3
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Metabolites, Volume 12, Issue 3 (March 2022) – 77 articles

Cover Story (view full-size image): Multisite musculoskeletal pain (MSMP) is the most common complaint in the general population and the leading cause of disability. Endogenous lipid species as mediators have essential roles in pain severity and response. However, longitudinal data on lipid metabolites and persistent MSMP are lacking. In this study, lipidomic profiling of 807 lipid species was performed on serum samples of 536 participants from a cohort study. HexCer(d18:1/22:0 and d18:1/24:0) and LPC(15-MHDA [sn1] [104_sn1]) were significantly associated with persistent MSMP. Two lipid classes—HexCer and LPC—were negatively associated with persistent MSMP. This study identified three novel lipid signatures of persistent MSMP, suggesting that lipid metabolism is involved in the pathogenesis of persistent pain. View this paper
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16 pages, 1896 KiB  
Article
Fast and Sensitive Quantification of AccQ-Tag Derivatized Amino Acids and Biogenic Amines by UHPLC-UV Analysis from Complex Biological Samples
by Andrea Guba, Orsolya Bába, József Tőzsér, Éva Csősz and Gergő Kalló
Metabolites 2022, 12(3), 272; https://doi.org/10.3390/metabo12030272 - 21 Mar 2022
Cited by 12 | Viewed by 3904
Abstract
Metabolomic analysis of different body fluids bears high importance in medical sciences. Our aim was to develop and validate a fast UHPLC-UV method for the analysis of 33 amino acids and biogenic amines from complex biological samples. AccQ-Tag derivatization was conducted on target [...] Read more.
Metabolomic analysis of different body fluids bears high importance in medical sciences. Our aim was to develop and validate a fast UHPLC-UV method for the analysis of 33 amino acids and biogenic amines from complex biological samples. AccQ-Tag derivatization was conducted on target molecules and the derivatized targets were analyzed by UHPLC-UV. The detection of the analytes was carried out with UV analysis and by Selected Reaction Monitoring (SRM)-based targeted mass spectrometry. The method was validated according to the FDA guidelines. Serum and non-stimulated tear samples were collected from five healthy individuals and the samples were analyzed by the method. The method was successfully validated with appropriate accuracy and precision for all 33 biomolecules. A total of 29 analytes were detected in serum samples and 26 of them were quantified. In the tears, 30 amino acids and biogenic amines were identified and 20 of them were quantified. The developed and validated UHPLC-UV method enables the fast and precise analysis of amino acids and biogenic amines from complex biological samples. Full article
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17 pages, 341 KiB  
Article
A Comparative and Comprehensive Characterization of Polyphenols of Selected Fruits from the Rosaceae Family
by Ahsan Hameed, Ziyao Liu, Hanjing Wu, Biming Zhong, Michal Ciborowski and Hafiz Ansar Rasul Suleria
Metabolites 2022, 12(3), 271; https://doi.org/10.3390/metabo12030271 - 21 Mar 2022
Cited by 12 | Viewed by 2748
Abstract
The present research presents a comprehensive characterization of polyphenols from peach, pear, and plum using liquid chromatography coupled with electrospray ionization quadrupole-time-of-flight-mass spectrometry (LC-ESI-QTOF-MS/MS), followed by the determination of their antioxidant potential. Plums showed the highest total phenolic content (TPC; 0.62 mg GAE/g), [...] Read more.
The present research presents a comprehensive characterization of polyphenols from peach, pear, and plum using liquid chromatography coupled with electrospray ionization quadrupole-time-of-flight-mass spectrometry (LC-ESI-QTOF-MS/MS), followed by the determination of their antioxidant potential. Plums showed the highest total phenolic content (TPC; 0.62 mg GAE/g), while peaches showed the highest total flavonoid content (TFC; 0.29 mg QE/g), also corresponding to their high scavenging activities (i.e., DPPH, ABTS, FRAP, and TAC). In all three fruit samples, a total of 51 polyphenolic compounds were tentatively identified and were mainly characterized from hydroxybenzoic acids, hydroxycinnamic acids, hydroxyphenylpentanoic acids, flavanols, flavonols, and isoflavonoids subclasses. Twenty targeted phenolic compounds were quantified using high-performance liquid chromatography with photodiode array detection (HPLC-PDA). The plum cultivar showed the highest content of phenolic acids (chlorogenic acid, 11.86 mg/100 g), whereas peach samples showed the highest concentration of flavonoids (catechin, 7.31 mg/100 g), as compared to pear. Based on these findings, the present research contributes and complements the current characterization data of these fruits presented in the literature, as well as ensures and encourages the utilization of these fruits in different food, feed, and nutraceutical industries. Full article
(This article belongs to the Section Plant Metabolism)
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13 pages, 3100 KiB  
Article
Mitochondrial Respiration in Response to Iron Deficiency Anemia: Comparison of Peripheral Blood Mononuclear Cells and Liver
by Christine Fischer, Lara Valente de Souza, Timea Komlódi, Luiz F. Garcia-Souza, Chiara Volani, Piotr Tymoszuk, Egon Demetz, Markus Seifert, Kristina Auer, Richard Hilbe, Natascha Brigo, Verena Petzer, Malte Asshoff, Erich Gnaiger and Günter Weiss
Metabolites 2022, 12(3), 270; https://doi.org/10.3390/metabo12030270 - 21 Mar 2022
Cited by 4 | Viewed by 3305
Abstract
Iron is an essential component for metabolic processes, including oxygen transport within hemoglobin, tricarboxylic acid (TCA) cycle activity, and mitochondrial energy transformation. Iron deficiency can thus lead to metabolic dysfunction and eventually result in iron deficiency anemia (IDA), which affects approximately 1.5 billion [...] Read more.
Iron is an essential component for metabolic processes, including oxygen transport within hemoglobin, tricarboxylic acid (TCA) cycle activity, and mitochondrial energy transformation. Iron deficiency can thus lead to metabolic dysfunction and eventually result in iron deficiency anemia (IDA), which affects approximately 1.5 billion people worldwide. Using a rat model of IDA induced by phlebotomy, we studied the effects of IDA on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and the liver. Furthermore, we evaluated whether the mitochondrial function evaluated by high-resolution respirometry in PBMCs reflects corresponding alterations in the liver. Surprisingly, mitochondrial respiratory capacity was increased in PBMCs from rats with IDA compared to the controls. In contrast, mitochondrial respiration remained unaffected in livers from IDA rats. Of note, citrate synthase activity indicated an increased mitochondrial density in PBMCs, whereas it remained unchanged in the liver, partly explaining the different responses of mitochondrial respiration in PBMCs and the liver. Taken together, these results indicate that mitochondrial function determined in PBMCs cannot serve as a valid surrogate for respiration in the liver. Metabolic adaptions to iron deficiency resulted in different metabolic reprogramming in the blood cells and liver tissue. Full article
(This article belongs to the Special Issue Frontiers in the Study of Metabolic Diseases Using Rodent Models)
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14 pages, 538 KiB  
Article
Bioaccumulation of Blood Long-Chain Fatty Acids during Hemodialysis
by Tong Liu, Inci Dogan, Michael Rothe, Jana Reichardt, Felix Knauf, Maik Gollasch, Friedrich C. Luft and Benjamin Gollasch
Metabolites 2022, 12(3), 269; https://doi.org/10.3390/metabo12030269 - 21 Mar 2022
Cited by 4 | Viewed by 2381
Abstract
Long-chain fatty acids (LCFAs) serve as energy sources, components of cell membranes, and precursors for signaling molecules. Uremia alters LCFA metabolism so that the risk of cardiovascular events in chronic kidney disease (CKD) is increased. End-stage renal disease (ESRD) patients undergoing dialysis are [...] Read more.
Long-chain fatty acids (LCFAs) serve as energy sources, components of cell membranes, and precursors for signaling molecules. Uremia alters LCFA metabolism so that the risk of cardiovascular events in chronic kidney disease (CKD) is increased. End-stage renal disease (ESRD) patients undergoing dialysis are particularly affected and their hemodialysis (HD) treatment could influence blood LCFA bioaccumulation and transformation. We investigated blood LCFA in HD patients and studied LCFA profiles in vivo by analyzing arterio–venous (A–V) LFCA differences in upper limbs. We collected arterial and venous blood samples from 12 ESRD patients, before and after HD, and analyzed total LCFA levels in red blood cells (RBCs) and plasma by LC–MS/MS tandem mass spectrometry. We observed that differences in arterial and venous LFCA contents within RBCs (RBC LCFA A–V differences) were affected by HD treatment. Numerous saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) n-6 showed negative A–V differences, accumulated during peripheral tissue perfusion of the upper limbs, in RBCs before HD. HD reduced these differences. The omega-3 quotient in the erythrocyte membranes was not affected by HD in either arterial or venous blood. Our data demonstrate that A–V differences in fatty acids status of LCFA are present and active in mature erythrocytes and their bioaccumulation is sensitive to single HD treatment. Full article
(This article belongs to the Section Lipid Metabolism)
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18 pages, 5147 KiB  
Article
Citric Acid as a Potential Prostate Cancer Biomarker Determined in Various Biological Samples
by Magdalena Buszewska-Forajta, Fernanda Monedeiro, Adrian Gołębiowski, Przemysław Adamczyk and Bogusław Buszewski
Metabolites 2022, 12(3), 268; https://doi.org/10.3390/metabo12030268 - 21 Mar 2022
Cited by 11 | Viewed by 3247
Abstract
Despite numerous studies, the molecular mechanism of prostate cancer development is still unknown. Recent investigations indicated that citric acid and lipids—with a special emphasis on fatty acids, steroids and hormones (ex. prolactin)—play a significant role in prostate cancer development and progression. However, citric [...] Read more.
Despite numerous studies, the molecular mechanism of prostate cancer development is still unknown. Recent investigations indicated that citric acid and lipids—with a special emphasis on fatty acids, steroids and hormones (ex. prolactin)—play a significant role in prostate cancer development and progression. However, citric acid is assumed to be a potential biomarker of prostate cancer, due to which, the diagnosis at an early stage of the disease could be possible. For this reason, the main goal of this study is to determine the citric acid concentration in three different matrices. To the best of our knowledge, this is the first time for citric acid to be determined in three different matrices (tissue, urine and blood). Samples were collected from patients diagnosed with prostate cancer and from a selected control group (individuals with benign prostatic hyperplasia). The analyses were performed using the rapid fluorometric test. The obtained results were correlated with both the histopathological data (the Gleason scale as well as the Classification of Malignant Tumors (pTNM) staging scale) and the biochemical data (the values of the following factors: prostate specific antigen, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, total cholesterol, creatinine and prolactin) using chemometric methods. For tissue samples, the results indicated a decreased level of citric acid in the case of prostate cancer. The analyte average concentrations in serum and urine appeared to be corresponding and superior in the positive cohort. This trend was statistically significant in the case of urinary citric acid. Moreover, a significant negative correlation was demonstrated between the concentration of citric acid and the tumor stage. A negative correlation between the total cholesterol and high-density lipoprotein and prolactin was particularly prominent in cancer cases. Conversely, a negative association between low-density lipoprotein and prolactin levels was observed solely in the control group. On the basis of the results, one may assume the influence of hormones, particularly prolactin, on the development of prostate cancer. The present research allowed us to verify the possibility of using citric acid as a potential biomarker for prostate cancer. Full article
(This article belongs to the Topic Proteomics and Metabolomics in Biomedicine)
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15 pages, 2227 KiB  
Article
Untargeted Metabolomics Showed Accumulation of One-Carbon Metabolites to Facilitate DNA Methylation during Extracellular Matrix Detachment of Cancer Cells
by Suza Mohammad Nur, Mohammed Razeeth Shait Mohammed, Mazin A. Zamzami, Hani Choudhry, Aamir Ahmad, Bushra Ateeq, Irfan A. Rather and Mohammad Imran Khan
Metabolites 2022, 12(3), 267; https://doi.org/10.3390/metabo12030267 - 21 Mar 2022
Cited by 4 | Viewed by 3081
Abstract
Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, [...] Read more.
Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, a global substrate for methylation reactions, especially DNA methylation. DNA methylation-mediated repression of NK cell ligands MICA and MICB during ECM detachment has been overlooked. In the current work, we quantitated the impact of ECM detachment on one-carbon metabolites, expression of 1C regulatory pathway genes, and total methylation levels. Our results showed that ECM detachment promotes the accumulation of one-carbon metabolites and induces regulatory pathway genes and total DNA methylation. Furthermore, we measured the expression of well-known targets of DNA methylation in NK cell ligands in cancer cells, namely, MICA/B, during ECM detachment and observed low expression compared to ECM-attached cancer cells. Finally, we treated the ECM-detached cancer cells with vitamin C (a global methylation inhibitor) and observed a reduction in the promoter methylation of NK cell ligands, resulting in MICA/B re-expression. Treatment with vitamin C was also found to reduce global DNA methylation levels in ECM-detached cancer cells. Full article
(This article belongs to the Section Microbiology and Ecological Metabolomics)
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13 pages, 682 KiB  
Review
Bone Fragility in Chronic Kidney Disease Stage 3 to 5: The Use of Vitamin D Supplementation
by Pablo Antonio Ureña Torres, Jean Claude Souberbielle and Martine Cohen Solal
Metabolites 2022, 12(3), 266; https://doi.org/10.3390/metabo12030266 - 20 Mar 2022
Cited by 6 | Viewed by 4308
Abstract
Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha [...] Read more.
Frequently silent until advanced stages, bone fragility associated with chronic kidney disease-mineral and bone disease (CKD-MBD) is one of the most devastating complications of CKD. Its pathophysiology includes the reduction of active vitamin D metabolites, phosphate accumulation, decreased intestinal calcium absorption, renal alpha klotho production, and elevated fibroblast growth factor 23 (FGF23) levels. Altogether, these factors contribute firstly to secondary hyperparathyroidism, and ultimately, to micro- and macrostructural bone changes, which lead to low bone mineral density and an increased risk of fracture. A vitamin D deficiency is common in CKD patients, and low circulating 25(OH)D levels are invariably associated with high serum parathyroid hormone (PTH) levels as well as with bone mineralization defects, such as osteomalacia in case of severe forms. It is also associated with a variety of non-skeletal diseases, including cardiovascular disease, diabetes mellitus, multiple sclerosis, cancer, and reduced immunological response. Current international guidelines recommend supplementing CKD patients with nutritional vitamin D as in the general population; however, there is no randomized clinical trial (RCT) evaluating the effect of vitamin D (or vitamin D+calcium) supplementation on the risk of fracture in the setting of CKD. It is also unknown what level of circulating 25(OH)D would be sufficient to prevent bone abnormalities and fractures in these patients. The impact of vitamin D supplementation on other surrogate endpoints, including bone mineral density and bone-related circulating biomarkers (PTH, FGF23, bone-specific alkaline phosphatase, sclerostin) has been evaluated in several RTCs; however, the results were not always translated into an improvement in long-term outcomes, such as reduced fracture risk. This review provides a brief and comprehensive update on CKD-related bone fragility and the use of natural vitamin D supplementation in these patients. Full article
(This article belongs to the Special Issue Frontiers in Bone Metabolism and Disorder in Chronic Kidney Disease)
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17 pages, 1094 KiB  
Article
Metabolomic Profiles in Childhood and Adolescence Are Associated with Fetal Overnutrition
by Ellen C. Francis, Katerina Kechris, Catherine C. Cohen, Gregory Michelotti, Dana Dabelea and Wei Perng
Metabolites 2022, 12(3), 265; https://doi.org/10.3390/metabo12030265 - 19 Mar 2022
Cited by 7 | Viewed by 2692
Abstract
Fetal overnutrition predisposes offspring to increased metabolic risk. The current study used metabolomics to assess sustained differences in serum metabolites across childhood and adolescence among youth exposed to three typologies of fetal overnutrition: maternal obesity only, gestational diabetes mellitus (GDM) only, and obesity [...] Read more.
Fetal overnutrition predisposes offspring to increased metabolic risk. The current study used metabolomics to assess sustained differences in serum metabolites across childhood and adolescence among youth exposed to three typologies of fetal overnutrition: maternal obesity only, gestational diabetes mellitus (GDM) only, and obesity + GDM. We included youth exposed in utero to obesity only (BMI ≥ 30; n = 66), GDM only (n = 56), obesity + GDM (n = 25), or unexposed (n = 297), with untargeted metabolomics measured at ages 10 and 16 years. We used linear mixed models to identify metabolites across both time-points associated with exposure to any overnutrition, using a false-discovery-rate correction (FDR) <0.20. These metabolites were included in a principal component analysis (PCA) to generate profiles and assess metabolite profile differences with respect to overnutrition typology (adjusted for prenatal smoking, offspring age, sex, and race/ethnicity). Fetal overnutrition was associated with 52 metabolites. PCA yielded four factors accounting for 17–27% of the variance, depending on age of measurement. We observed differences in three factor patterns with respect to overnutrition typology: sphingomyelin-mannose (8–13% variance), skeletal muscle metabolism (6–10% variance), and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF; 3–4% variance). The sphingomyelin-mannose factor score was higher among offspring exposed to obesity vs. GDM. Exposure to obesity + GDM (vs. GDM or obesity only) was associated with higher skeletal muscle metabolism and CMPF scores. Fetal overnutrition is associated with metabolic changes in the offspring, but differences between typologies of overnutrition account for a small amount of variation in the metabolome, suggesting there is likely greater pathophysiological overlap than difference. Full article
(This article belongs to the Special Issue Advances in Gestational Diabetes and Metabolomics)
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16 pages, 3021 KiB  
Article
A Preliminary Metabolomic Study of Yorkshire Terrier Enteropathy
by Alexandra I. Galler, Kristaps Klavins and Iwan A. Burgener
Metabolites 2022, 12(3), 264; https://doi.org/10.3390/metabo12030264 - 19 Mar 2022
Cited by 7 | Viewed by 2840
Abstract
Perturbations of metabolite profiles in human and canine enteropathies have been reported before. However, data in dogs are scarce and inconsistent. Currently, the metabolite profile in Yorkshire Terrier enteropathy (YTE) and the impact of treatment is unknown. The objective of this study was [...] Read more.
Perturbations of metabolite profiles in human and canine enteropathies have been reported before. However, data in dogs are scarce and inconsistent. Currently, the metabolite profile in Yorkshire Terrier enteropathy (YTE) and the impact of treatment is unknown. The objective of this study was to investigate the plasma metabolome of 13 Yorkshire Terriers with YTE and compare it to 20 healthy Yorkshire Terriers. Furthermore, we studied the impact of treatment on the metabolome. In this prospective observational study, plasma metabolite profiles were analyzed by flow injection analysis-tandem mass spectrometry (FIA-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a targeted metabolomics kit. Metabolite analysis revealed that YTE is accompanied by changes in lipid and bile acid metabolism. YTE was associated with a significant decrease of long-chain fatty acids (octadecenoic acid, eicosadienoic acid, eicosatrienoic acid) and lower levels of long-chain acylcarnitines (tetradecanoylcarnitine, hexadecanoylcarnitine, hexadecenoylcarnitine, octadecenoylcarnitine) compared with healthy controls. Furthermore, taurodeoxycholic acid, a secondary bile acid, was decreased in plasma from YTE patients. These changes might be breed-specific and might be involved in the pathogenesis of YTE. Interestingly, changes in metabolite levels were not recovered after treatment and differed considerably from healthy controls. Full article
(This article belongs to the Special Issue Metabolomics in the Study of Veterinary Disease)
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24 pages, 2527 KiB  
Article
Monitoring Intracellular Metabolite Dynamics in Saccharomyces cerevisiae during Industrially Relevant Famine Stimuli
by Steven Minden, Maria Aniolek, Christopher Sarkizi Shams Hajian, Attila Teleki, Tobias Zerrer, Frank Delvigne, Walter van Gulik, Amit Deshmukh, Henk Noorman and Ralf Takors
Metabolites 2022, 12(3), 263; https://doi.org/10.3390/metabo12030263 - 18 Mar 2022
Cited by 4 | Viewed by 2931
Abstract
Carbon limitation is a common feeding strategy in bioprocesses to enable an efficient microbiological conversion of a substrate to a product. However, industrial settings inherently promote mixing insufficiencies, creating zones of famine conditions. Cells frequently traveling through such regions repeatedly experience substrate shortages [...] Read more.
Carbon limitation is a common feeding strategy in bioprocesses to enable an efficient microbiological conversion of a substrate to a product. However, industrial settings inherently promote mixing insufficiencies, creating zones of famine conditions. Cells frequently traveling through such regions repeatedly experience substrate shortages and respond individually but often with a deteriorated production performance. A priori knowledge of the expected strain performance would enable targeted strain, process, and bioreactor engineering for minimizing performance loss. Today, computational fluid dynamics (CFD) coupled to data-driven kinetic models are a promising route for the in silico investigation of the impact of the dynamic environment in the large-scale bioreactor on microbial performance. However, profound wet-lab datasets are needed to cover relevant perturbations on realistic time scales. As a pioneering study, we quantified intracellular metabolome dynamics of Saccharomyces cerevisiae following an industrially relevant famine perturbation. Stimulus-response experiments were operated as chemostats with an intermittent feed and high-frequency sampling. Our results reveal that even mild glucose gradients in the range of 100 μmol·L−1 impose significant perturbations in adapted and non-adapted yeast cells, altering energy and redox homeostasis. Apparently, yeast sacrifices catabolic reduction charges for the sake of anabolic persistence under acute carbon starvation conditions. After repeated exposure to famine conditions, adapted cells show 2.7% increased maintenance demands. Full article
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25 pages, 2559 KiB  
Article
Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia
by Youmna Ghaleb, Sandy Elbitar, Anne Philippi, Petra El Khoury, Yara Azar, Miangaly Andrianirina, Alexia Loste, Yara Abou-Khalil, Gaël Nicolas, Marie Le Borgne, Philippe Moulin, Mathilde Di-Filippo, Sybil Charrière, Michel Farnier, Cécile Yelnick, Valérie Carreau, Jean Ferrières, Jean-Michel Lecerf, Alexa Derksen, Geneviève Bernard, Marie-Soleil Gauthier, Benoit Coulombe, Dieter Lütjohann, Bertrand Fin, Anne Boland, Robert Olaso, Jean-François Deleuze, Jean-Pierre Rabès, Catherine Boileau, Marianne Abifadel and Mathilde Varretadd Show full author list remove Hide full author list
Metabolites 2022, 12(3), 262; https://doi.org/10.3390/metabo12030262 - 18 Mar 2022
Cited by 2 | Viewed by 3492
Abstract
Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes [...] Read more.
Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype. Full article
(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)
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14 pages, 3683 KiB  
Article
Correlating Mass Spectrometry Imaging and Liquid Chromatography-Tandem Mass Spectrometry for Tissue-Based Pharmacokinetic Studies
by Andreas Dannhorn, Emine Kazanc, Gregory Hamm, John G. Swales, Nicole Strittmatter, Gareth Maglennon, Richard J. A. Goodwin and Zoltan Takats
Metabolites 2022, 12(3), 261; https://doi.org/10.3390/metabo12030261 - 18 Mar 2022
Cited by 8 | Viewed by 3387
Abstract
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a standard tool used for absolute quantification of drugs in pharmacokinetic (PK) studies. However, all spatial information is lost during the extraction and elucidation of a drugs biodistribution within the tissue is impossible. In the study presented [...] Read more.
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a standard tool used for absolute quantification of drugs in pharmacokinetic (PK) studies. However, all spatial information is lost during the extraction and elucidation of a drugs biodistribution within the tissue is impossible. In the study presented here we used a sample embedding protocol optimized for mass spectrometry imaging (MSI) to prepare up to 15 rat intestine specimens at once. Desorption electrospray ionization (DESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) were employed to determine the distributions and relative abundances of four benchmarking compounds in the intestinal segments. High resolution MALDI-MSI experiments performed at 10 µm spatial resolution allowed to determine the drug distribution in the different intestinal histological compartments to determine the absorbed and tissue bound fractions of the drugs. The low tissue bound drug fractions, which were determined to account for 56–66% of the total drug, highlight the importance to understand the spatial distribution of drugs within the histological compartments of a given tissue to rationalize concentration differences found in PK studies. The mean drug abundances of four benchmark compounds determined by MSI were correlated with the absolute drug concentrations. Linear regression resulted in coefficients of determination (R2) ranging from 0.532 to 0.926 for MALDI-MSI and R2 values ranging from 0.585 to 0.945 for DESI-MSI, validating a quantitative relation of the imaging data. The good correlation of the absolute tissue concentrations of the benchmark compounds and the MSI data provides a bases for relative quantification of compounds within and between tissues, without normalization to an isotopically labelled standard, provided that the compared tissues have inherently similar ion suppression effects. Full article
(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry)
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13 pages, 4240 KiB  
Article
Broadband-NIRS System Identifies Epileptic Focus in a Child with Focal Cortical Dysplasia—A Case Study
by Aikaterini Vezyroglou, Peter Hebden, Isabel De Roever, Rachel Thornton, Subhabrata Mitra, Alan Worley, Mariana Alves, Emma Dean, Judith Helen Cross and Ilias Tachtsidis
Metabolites 2022, 12(3), 260; https://doi.org/10.3390/metabo12030260 - 17 Mar 2022
Cited by 8 | Viewed by 2798
Abstract
Epileptic seizures are transiently occurring symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Previous functional near-infrared spectroscopy (fNIRS) studies during seizures have focused in only monitoring the brain oxygenation and haemodynamic changes. However, few tools are available to measure [...] Read more.
Epileptic seizures are transiently occurring symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Previous functional near-infrared spectroscopy (fNIRS) studies during seizures have focused in only monitoring the brain oxygenation and haemodynamic changes. However, few tools are available to measure actual cellular metabolism during seizures, especially at the bedside. Here we use an in-house developed multichannel broadband NIRS (or bNIRS) system, that, alongside the changes in oxy-, deoxy- haemoglobin concentration (HbO2, HHb), also quantifies the changes in oxidised cytochrome-c-oxidase Δ(oxCCO), a marker of cellular oxygen metabolism, simultaneously over 16 different brain locations. We used bNIRS to measure metabolic activity alongside brain tissue haemodynamics/oxygenation during 17 epileptic seizures at the bedside of a 3-year-old girl with seizures due to an extensive malformation of cortical development in the left posterior quadrant. Simultaneously Video-EEG data was recorded from 12 channels. Whilst we did observe the expected increase in brain tissue oxygenation (HbD) during seizures, it was almost diminished in the area of the focal cortical dysplasia. Furthermore, in the area of seizure origination (epileptic focus) ΔoxCCO decreased significantly at the time of seizure generalization when compared to the mean change in all other channels. We hypothesize that this indicates an incapacity to sustain and increase brain tissue metabolism during seizures in the region of the epileptic focus. Full article
(This article belongs to the Special Issue Optical Assessment of Metabolism)
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22 pages, 1372 KiB  
Review
Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity
by Lidija Križančić Bombek and Maša Čater
Metabolites 2022, 12(3), 259; https://doi.org/10.3390/metabo12030259 - 17 Mar 2022
Cited by 1 | Viewed by 4708
Abstract
Obesity and accompanying type 2 diabetes are among major and increasing worldwide problems that occur fundamentally due to excessive energy intake during its expenditure. Endotherms continuously consume a certain amount of energy to maintain core body temperature via thermogenic processes, mainly in brown [...] Read more.
Obesity and accompanying type 2 diabetes are among major and increasing worldwide problems that occur fundamentally due to excessive energy intake during its expenditure. Endotherms continuously consume a certain amount of energy to maintain core body temperature via thermogenic processes, mainly in brown adipose tissue and skeletal muscle. Skeletal muscle glucose utilization and heat production are significant and directly linked to body glucose homeostasis at rest, and especially during physical activity. However, this glucose balance is impaired in diabetic and obese states in humans and mice, and manifests as glucose resistance and altered muscle cell metabolism. Uncoupling proteins have a significant role in converting electrochemical energy into thermal energy without ATP generation. Different homologs of uncoupling proteins were identified, and their roles were linked to antioxidative activity and boosting glucose and lipid metabolism. From this perspective, uncoupling proteins were studied in correlation to the pathogenesis of diabetes and obesity and their possible treatments. Mice were extensively used as model organisms to study the physiology and pathophysiology of energy homeostasis. However, we should be aware of interstrain differences in mice models of obesity regarding thermogenesis and insulin resistance in skeletal muscles. Therefore, in this review, we gathered up-to-date knowledge on skeletal muscle uncoupling proteins and their effect on insulin sensitivity in mouse models of obesity and diabetes. Full article
(This article belongs to the Special Issue Skeletal Muscle Thermogenesis and Energy Metabolism)
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13 pages, 2114 KiB  
Article
Association between Visceral Adipose Tissue Metabolism and Alzheimer’s Disease Pathology
by Shin Kim, Hyon-Ah Yi, Kyoung Sook Won, Ji Soo Lee and Hae Won Kim
Metabolites 2022, 12(3), 258; https://doi.org/10.3390/metabo12030258 - 17 Mar 2022
Cited by 15 | Viewed by 2670
Abstract
The visceral adipose tissue (VAT) has been recognized as an endocrine organ, and VAT dysfunction could be a risk factor for Alzheimer’s disease (AD). We aimed to evaluate the association of VAT metabolism with AD pathology. This cross-sectional study included 54 older subjects [...] Read more.
The visceral adipose tissue (VAT) has been recognized as an endocrine organ, and VAT dysfunction could be a risk factor for Alzheimer’s disease (AD). We aimed to evaluate the association of VAT metabolism with AD pathology. This cross-sectional study included 54 older subjects with cognitive impairment who underwent 2-deoxy-2-[fluorine-18]-fluoro-D-glucose (18F-FDG) torso positron emission tomography (PET) and 18F-florbetaben brain PET. 18F-FDG uptake in VAT on 18F-FDG PET images was used as a marker of VAT metabolism, and subjects were classified into high and low VAT metabolism groups. A voxel-based analysis revealed that the high VAT metabolism group exhibited a significantly higher cerebral amyloid-β (Aβ) burden than the low VAT metabolism group. In the volume-of-interest analysis, multiple linear regression analyses with adjustment for age, sex, and white matter hyperintensity volume revealed that 18F-FDG uptake in VAT was significantly associated with the cerebral Aβ burden (β = 0.359, p = 0.007). In conclusion, VAT metabolism was associated with AD pathology in older subjects. Our findings suggest that VAT dysfunction could contribute to AD development. Full article
(This article belongs to the Special Issue Lipid Biomarkers in Alzheimer's Disease)
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23 pages, 4488 KiB  
Article
Metabolic Footprinting of Microbial Systems Based on Comprehensive In Silico Predictions of MS/MS Relevant Data
by Alexander Reiter, Jian Asgari, Wolfgang Wiechert and Marco Oldiges
Metabolites 2022, 12(3), 257; https://doi.org/10.3390/metabo12030257 - 17 Mar 2022
Cited by 3 | Viewed by 2607
Abstract
Metabolic footprinting represents a holistic approach to gathering large-scale metabolomic information of a given biological system and is, therefore, a driving force for systems biology and bioprocess development. The ongoing development of automated cultivation platforms increases the need for a comprehensive and rapid [...] Read more.
Metabolic footprinting represents a holistic approach to gathering large-scale metabolomic information of a given biological system and is, therefore, a driving force for systems biology and bioprocess development. The ongoing development of automated cultivation platforms increases the need for a comprehensive and rapid profiling tool to cope with the cultivation throughput. In this study, we implemented a workflow to provide and select relevant metabolite information from a genome-scale model to automatically build an organism-specific comprehensive metabolome analysis method. Based on in-house literature and predicted metabolite information, the deduced metabolite set was distributed in stackable methods for a chromatography-free dilute and shoot flow-injection analysis multiple-reaction monitoring profiling approach. The workflow was used to create a method specific for Saccharomyces cerevisiae, covering 252 metabolites with 7 min/sample. The method was validated with a commercially available yeast metabolome standard, identifying up to 74.2% of the listed metabolites. As a first case study, three commercially available yeast extracts were screened with 118 metabolites passing quality control thresholds for statistical analysis, allowing to identify discriminating metabolites. The presented methodology provides metabolite screening in a time-optimised way by scaling analysis time to metabolite coverage and is open to other microbial systems simply starting from genome-scale model information. Full article
(This article belongs to the Special Issue Metabolic Pathway Profiling and Untargeted/Targeted Analysis of Metabolites)
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25 pages, 1480 KiB  
Review
Insight into the Evolving Role of PCSK9
by Mateusz Maligłówka, Michał Kosowski, Marcin Hachuła, Marcin Cyrnek, Łukasz Bułdak, Marcin Basiak, Aleksandra Bołdys, Grzegorz Machnik, Rafał Jakub Bułdak and Bogusław Okopień
Metabolites 2022, 12(3), 256; https://doi.org/10.3390/metabo12030256 - 17 Mar 2022
Cited by 27 | Viewed by 5249
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the [...] Read more.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use. Full article
(This article belongs to the Special Issue The PCSK9 Story: Advances in Cholesterol Metabolism, Cardiovascular Complications and Beyond)
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15 pages, 2430 KiB  
Article
A Longitudinal 1H NMR-Based Metabolic Profile Analysis of Urine from Hospitalized Premature Newborns Receiving Enteral and Parenteral Nutrition
by Nuria Esturau-Escofet, Eduardo Rodríguez de San Miguel, Marcela Vela-Amieva, Martha E. García-Aguilera, Circe C. Hernández-Espino, Luis Macias-Kauffer, Carlos López-Candiani, José J. Naveja and Isabel Ibarra-González
Metabolites 2022, 12(3), 255; https://doi.org/10.3390/metabo12030255 - 17 Mar 2022
Cited by 4 | Viewed by 2583
Abstract
Preterm newborns are extremely vulnerable to morbidities, complications, and death. Preterm birth is a global public health problem due to its socioeconomic burden. Nurturing preterm newborns is a critical medical issue because they have limited nutrient stores and it is difficult to establish [...] Read more.
Preterm newborns are extremely vulnerable to morbidities, complications, and death. Preterm birth is a global public health problem due to its socioeconomic burden. Nurturing preterm newborns is a critical medical issue because they have limited nutrient stores and it is difficult to establish enteral feeding, which leads to inadequate growth frequently associated with poor neurodevelopmental outcomes. Parenteral nutrition (PN) provides nutrients to preterm newborns, but its biochemical effects are not completely known. To study the effect of PN treatment on preterm newborns, an untargeted metabolomic 1H nuclear magnetic resonance (NMR) assay was performed on 107 urine samples from 34 hospitalized patients. Multivariate data (Principal Component Analysis, PCA, Orthogonal partial least squares discriminant analysis OPLS-DA, parallel factor analysis PARAFAC-2) and univariate analyses were used to identify the association of specific spectral data with different nutritional types (NTs) and gestational ages. Our results revealed changes in the metabolic profile related to the NT, with the tricarboxylic acid cycle and galactose metabolic pathways being the most impacted pathways. Low citrate and succinate levels, despite higher glucose relative urinary concentrations, seem to constitute the metabolic profile found in the studied critically ill preterm newborns who received PN, indicating an energetic dysfunction that must be taken into account for better nutritional management. Full article
(This article belongs to the Special Issue NMR-Based Metabolic Profiling with Applications in Disease and Food Control)
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11 pages, 3293 KiB  
Article
Pudding Proteomics: Cyclomaltodextrin Glucanotransferase and Microbial Proteases Can Liquefy Extended Shelf Life Dairy Products
by Kristina J. H. Kleinwort, Maria Weigand, Lydia Hoffmann, Roxane L. Degroote, Richard Dietrich, Erwin Märtlbauer, Stefanie M. Hauck and Cornelia A. Deeg
Metabolites 2022, 12(3), 254; https://doi.org/10.3390/metabo12030254 - 17 Mar 2022
Viewed by 2486
Abstract
In recent years, a lack of stability of dairy products with extended shelf life (e.g., yoghurt products, UHT desserts) has occurred, with the corresponding products liquefying significantly after days or weeks. This project aimed to identify the enzymes responsible for the liquefaction of [...] Read more.
In recent years, a lack of stability of dairy products with extended shelf life (e.g., yoghurt products, UHT desserts) has occurred, with the corresponding products liquefying significantly after days or weeks. This project aimed to identify the enzymes responsible for the liquefaction of the affected products based on differential proteomic analyses. No evidence was found for the presence of starch-degrading bacteria in the affected products. With zymography and proteome analysis, we detected the cause of liquefaction in a pudding by contamination of its aroma component with an engineered amylolytic enzyme, cyclomaltodextrin glucanotransferase (CGTase) from Thermoanaerobacterium thermosulfurigenes. In addition, we detected contamination with Pseudomonas-derived proteolytic ATP-dependent Clp protease in one pudding batch and proteases in technically used amylases, which degraded β-caseins in another batch. Identification of these agents with liquefying properties in dairy products are useful for adjustment of production protocols and/or composition of additives, and thus shelf life extension. Full article
(This article belongs to the Section Food Metabolomics)
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12 pages, 1977 KiB  
Article
High Resolution Magic Angle Spinning Proton NMR Study of Alzheimer’s Disease with Mouse Models
by Mark V. Füzesi, Isabella H. Muti, Yannick Berker, Wei Li, Joseph Sun, Piet Habbel, Johannes Nowak, Zhongcong Xie, Leo L. Cheng and Yiying Zhang
Metabolites 2022, 12(3), 253; https://doi.org/10.3390/metabo12030253 - 17 Mar 2022
Cited by 2 | Viewed by 2928
Abstract
Alzheimer’s disease (AD) is a crippling condition that affects millions of elderly adults each year, yet there remains a serious need for improved methods of diagnosis. Metabolomic analysis has been proposed as a potential methodology to better investigate and understand the progression of [...] Read more.
Alzheimer’s disease (AD) is a crippling condition that affects millions of elderly adults each year, yet there remains a serious need for improved methods of diagnosis. Metabolomic analysis has been proposed as a potential methodology to better investigate and understand the progression of this disease; however, studies of human brain tissue metabolomics are challenging, due to sample limitations and ethical considerations. Comprehensive comparisons of imaging measurements in animal models to identify similarities and differences between aging- and AD-associated metabolic changes should thus be tested and validated for future human non-invasive studies. In this paper, we present the results of our highresolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) studies of AD and wild-type (WT) mouse models, based on animal age, brain regions, including cortex vs. hippocampus, and disease status. Our findings suggest the ability of HRMAS NMR to differentiate between AD and WT mice using brain metabolomics, which potentially can be implemented in in vivo evaluations. Full article
(This article belongs to the Special Issue Animal and Cellular Models in Metabolomics Research Volume 2)
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14 pages, 3490 KiB  
Review
Mechanism of Soy Isoflavone Daidzein-Induced Female-Specific Anorectic Effect
by Mina Fujitani, Takafumi Mizushige, Sudhashree Adhikari, Keshab Bhattarai and Taro Kishida
Metabolites 2022, 12(3), 252; https://doi.org/10.3390/metabo12030252 - 16 Mar 2022
Cited by 3 | Viewed by 2977
Abstract
Epidemiological studies suggest that regular intake of soy isoflavone exerts a preventive effect on postmenopausal obesity and other forms of dysmetabolism. Estrogens inhibit eating behavior. Soy isoflavones may act as estrogen agonist in estrogen-depleted conditions, whereas they may either act as an estrogen [...] Read more.
Epidemiological studies suggest that regular intake of soy isoflavone exerts a preventive effect on postmenopausal obesity and other forms of dysmetabolism. Estrogens inhibit eating behavior. Soy isoflavones may act as estrogen agonist in estrogen-depleted conditions, whereas they may either act as an estrogen antagonist or be ineffective in estrogen-repleted conditions. We investigated the effects of dietary soy isoflavone on food intake under various estrogen conditions using male, ovariectomized (OVX), and non-OVX female rats, and compared the effects with those of estradiol. We found that soy isoflavones reduced food intake in females specifically, regardless of whether ovariectomy had been performed, whereas subcutaneous implantation of estradiol pellet did not reduce food intake in intact female rats, but did so in OVX female and male rats. Contrary to this hypothesis, the reduction in food intake may not be caused by the estrogenic properties of soy isoflavones. It is of great interest to understand the mechanisms underlying the anorectic effects of soy isoflavones. In this non-systematic review, we summarize our recent studies that have investigated the bioactive substances of anorectic action, pharmacokinetic properties of soy isoflavones, and the modification of central and peripheral signals regulating appetite by soy isoflavones, and selected studies that were identified via database mining. Full article
(This article belongs to the Special Issue Prevention and Alleviation of Metabolic Syndrome with Food Factors)
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13 pages, 1939 KiB  
Article
Biological Activity and NMR-Fingerprinting of Balkan Endemic Species Stachys thracica Davidov
by Desislava I. Mantovska, Miroslava K. Zhiponova, Milen I. Georgiev, Kalina Alipieva, Ivanka Tsacheva, Svetlana Simova and Zhenya P. Yordanova
Metabolites 2022, 12(3), 251; https://doi.org/10.3390/metabo12030251 - 16 Mar 2022
Cited by 7 | Viewed by 2837
Abstract
Stachys thracica Davidov is a Balkan endemic species distributed in Bulgaria, Greece, and Turkey. In Bulgaria, it is classified as “rare” and is under the protection of the Bulgarian biodiversity law. The aim of our study was to develop an efficient protocol for [...] Read more.
Stachys thracica Davidov is a Balkan endemic species distributed in Bulgaria, Greece, and Turkey. In Bulgaria, it is classified as “rare” and is under the protection of the Bulgarian biodiversity law. The aim of our study was to develop an efficient protocol for ex situ conservation of S. thracica and to perform comparative NMR-based metabolite profiling and bioactivity assays of extracts from in situ grown, in vitro cultivated, and ex vitro acclimated plants. Micropropagation of S. thracica was achieved by in vitro cultivation of mono-nodal segments on basal MS medium. Ex vitro adaptation was accomplished in the experimental field with 83% survival while conserved genetic identity between in vitro and ex vitro plants as shown by the overall sequence-related amplified polymorphism marker patterns was established. Verbascoside, chlorogenic acid, and trigonelline appeared the main secondary metabolites in in situ, in vitro cultivated, and ex vitro acclimated S. thracica. High total phenolic and flavonoid content as well as antioxidant and radical scavenging activity were observed in in situ and ex vitro plants. Further, the anti-inflammatory activity of S. thracica was tested by hemolytic assay and a high inhibition of the complement system was observed. Initiated in vitro and ex vitro cultures offer an effective tool for the management and better exploitation of the Stachys secondary metabolism and the selection of lines with high content of bioactive molecules and nutraceuticals. Full article
(This article belongs to the Special Issue Bioactive Metabolites from Natural Sources)
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17 pages, 3245 KiB  
Article
FOXO3 Expression in Macrophages Is Lowered by a High-Fat Diet and Regulates Colonic Inflammation and Tumorigenesis
by Rida Iftikhar, Harrison M. Penrose, Angelle N. King, Yunah Kim, Emmanuelle Ruiz, Emad Kandil, Heather L. Machado and Suzana D. Savkovic
Metabolites 2022, 12(3), 250; https://doi.org/10.3390/metabo12030250 - 16 Mar 2022
Cited by 9 | Viewed by 4053
Abstract
Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissues, including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation [...] Read more.
Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissues, including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation and tumorigenesis. We found that in mouse colon, high-fat-diet-(HFD)-related obesity led to diminished FOXO3 levels and increased macrophages. Transcriptomic analysis of mouse peritoneal FOXO3-deficient macrophages showed significant differentially expressed genes (DEGs; FDR < 0.05) similar to HFD obese colons. These DEG-related pathways, linked to mouse colonic inflammation and tumorigenesis, were similar to those in inflammatory bowel disease (IBD) and human colon cancer. Additionally, we identified a specific transcriptional signature for the macrophage-FOXO3 axis (MAC-FOXO382), which separated the transcriptome of affected tissue from control in both IBD (p = 5.2 × 10−8 and colon cancer (p = 1.9 × 10−11), revealing its significance in human colonic pathobiologies. Further, we identified (heatmap) and validated (qPCR) DEGs specific to FOXO3-deficient macrophages with established roles both in IBD and colon cancer (IL-1B, CXCR2, S100A8, S100A9, and TREM1) and those with unexamined roles in these colonic pathobiologies (STRA6, SERPINH1, LAMB1, NFE2L3, OLR1, DNAJC28 and VSIG10). These findings establish an important understanding of how HFD obesity and related metabolites promote colonic pathobiologies. Full article
(This article belongs to the Special Issue Intestinal Epithelial Metabolism and Metabolites as Gatekeepers for Organismal Health)
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19 pages, 3218 KiB  
Article
Matching Drug Metabolites from Non-Targeted Metabolomics to Self-Reported Medication in the Qatar Biobank Study
by Karsten Suhre, Nisha Stephan, Shaza Zaghlool, Chris R. Triggle, Richard J. Robinson, Anne M. Evans and Anna Halama
Metabolites 2022, 12(3), 249; https://doi.org/10.3390/metabo12030249 - 16 Mar 2022
Cited by 8 | Viewed by 3689
Abstract
Modern metabolomics platforms are able to identify many drug-related metabolites in blood samples. Applied to population-based biobank studies, the detection of drug metabolites can then be used as a proxy for medication use or serve as a validation tool for questionnaire-based health assessments. [...] Read more.
Modern metabolomics platforms are able to identify many drug-related metabolites in blood samples. Applied to population-based biobank studies, the detection of drug metabolites can then be used as a proxy for medication use or serve as a validation tool for questionnaire-based health assessments. However, it is not clear how well detection of drug metabolites in blood samples matches information on self-reported medication provided by study participants. Here, we curate free-text responses to a drug-usage questionnaire from 6000 participants of the Qatar Biobank (QBB) using standardized WHO Anatomical Therapeutic Chemical (ATC) Classification System codes and compare the occurrence of these ATC terms to the detection of drug-related metabolites in matching blood plasma samples from 2807 QBB participants for which we collected non-targeted metabolomics data. We found that the detection of 22 drug-related metabolites significantly associated with the self-reported use of the corresponding medication. Good agreement of self-reported medication with non-targeted metabolomics was observed, with self-reported drugs and their metabolites being detected in a same blood sample in 79.4% of the cases. On the other hand, only 29.5% of detected drug metabolites matched to self-reported medication. Possible explanations for differences include under-reporting of over-the-counter medications from the study participants, such as paracetamol, misannotation of low abundance metabolites, such as metformin, and inability of the current methods to detect them. Taken together, our study provides a broad real-world view of what to expect from large non-targeted metabolomics measurements in population-based biobank studies and indicates areas where further improvements can be made. Full article
(This article belongs to the Special Issue Metabolomics Data Analysis and Quality Assessment)
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26 pages, 4723 KiB  
Article
Metabolomic Characterisation of Discriminatory Metabolites Involved in Halo Blight Disease in Oat Cultivars Caused by Pseudomonas syringae pv. coronafaciens
by Chanel J. Pretorius, Paul A. Steenkamp, Fidele Tugizimana, Lizelle A. Piater and Ian A. Dubery
Metabolites 2022, 12(3), 248; https://doi.org/10.3390/metabo12030248 - 16 Mar 2022
Cited by 10 | Viewed by 3284
Abstract
The metabolome is the underlying biochemical layer of the phenotype and offers a functional readout of the cellular mechanisms involved in a biological system. Since metabolites are considered end-products of regulatory processes at a cellular level, their levels are considered the definitive response [...] Read more.
The metabolome is the underlying biochemical layer of the phenotype and offers a functional readout of the cellular mechanisms involved in a biological system. Since metabolites are considered end-products of regulatory processes at a cellular level, their levels are considered the definitive response of the biological system to genetic or environmental variations. The metabolome thus serves as a metabolic fingerprint of the biochemical events that occur in a biological system under specific conditions. In this study, an untargeted metabolomics approach was applied to elucidate biochemical processes implicated in oat plant responses to Pseudomonas syringae pv. coronafaciens (Ps-c) infection, and to identify signatory markers related to defence responses and disease resistance against halo blight. Metabolic changes in two oat cultivars (“Dunnart” and “SWK001”) responding to Ps-c, were examined at the three-leaf growth stage and metabolome changes monitored over a four-day post-inoculation period. Hydromethanolic extracts were analysed using an ultra-high-performance liquid chromatography (UHPLC) system coupled to a high-definition mass spectrometer (MS) analytical platform. The acquired multi-dimensional data were processed using multivariate statistical analysis and chemometric modelling. The validated chemometric models indicated time- and cultivar-related metabolic changes, defining the host response to the bacterial inoculation. Further multivariate analyses of the data were performed to profile differential signatory markers, putatively associated with the type of launched defence response. These included amino acids, phenolics, phenolic amides, fatty acids, flavonoids, alkaloids, terpenoids, lipids, saponins and plant hormones. Based on the results, metabolic alterations involved in oat defence responses to Ps-c were elucidated and key signatory metabolic markers defining the defence metabolome were identified. The study thus contributes toward a more holistic understanding of the oat metabolism under biotic stress. Full article
(This article belongs to the Special Issue Metabolomics in Agriculture Volume 2)
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13 pages, 1957 KiB  
Article
Metabolites in Cherry Buds to Detect Winter Dormancy
by Frank-M. Chmielewski and Klaus-P. Götz
Metabolites 2022, 12(3), 247; https://doi.org/10.3390/metabo12030247 - 16 Mar 2022
Cited by 11 | Viewed by 2934
Abstract
Winter dormancy is still a “black box” in phenological models, because it evades simple observation. This study presents the first step in the identification of suitable metabolites which could indicate the timing and length of dormancy phases for the sweet cherry cultivar ‘Summit’. [...] Read more.
Winter dormancy is still a “black box” in phenological models, because it evades simple observation. This study presents the first step in the identification of suitable metabolites which could indicate the timing and length of dormancy phases for the sweet cherry cultivar ‘Summit’. Global metabolite profiling detected 445 named metabolites in flower buds, which can be assigned to different substance groups such as amino acids, carbohydrates, phytohormones, lipids, nucleotides, peptides and some secondary metabolites. During the phases of endo- and ecodormancy, the energy metabolism in the form of glycolysis and the tricarboxylic acid (TCA) cycle was shut down to a minimum. However, the beginning of ontogenetic development was closely related to the up-regulation of the carbohydrate metabolism and thus to the generation of energy for the growth and development of the sweet cherry buds. From the 445 metabolites found in cherry buds, seven were selected which could be suitable markers for the ecodormancy phase, whose duration is limited by the date of endodormancy release (t1) and the beginning of ontogenetic development (t1*). With the exception of abscisic acid (ABA), which has been proven to control bud dormancy, all of these metabolites show nearly constant intensity during this phase. Full article
(This article belongs to the Section Plant Metabolism)
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19 pages, 4381 KiB  
Article
Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study
by Said E. Desouky, Mohammed Abu-Elghait, Eman A. Fayed, Samy Selim, Basit Yousuf, Yasuhiro Igarashi, Basel A. Abdel-Wahab, Amnah Mohammed Alsuhaibani, Kenji Sonomoto and Jiro Nakayama
Metabolites 2022, 12(3), 246; https://doi.org/10.3390/metabo12030246 - 15 Mar 2022
Cited by 15 | Viewed by 3535
Abstract
Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes’ expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and [...] Read more.
Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes’ expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A–D, BU–4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors. Full article
(This article belongs to the Special Issue Bacterial Secondary Metabolite Biosynthesis and Application for Biopharmaceutical and Bioengineering)
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17 pages, 23210 KiB  
Article
Optimization of LC-MS2 Data Acquisition Parameters for Molecular Networking Applied to Marine Natural Products
by Sam Afoullouss, Agata Balsam, A. Louise Allcock and Olivier P. Thomas
Metabolites 2022, 12(3), 245; https://doi.org/10.3390/metabo12030245 - 14 Mar 2022
Cited by 15 | Viewed by 5651
Abstract
Since the introduction of the online open-source GNPS, molecular networking has quickly become a widely applied tool in the field of natural products chemistry, with applications from dereplication, genome mining, metabolomics, and visualization of chemical space. Studies have shown that data dependent acquisition [...] Read more.
Since the introduction of the online open-source GNPS, molecular networking has quickly become a widely applied tool in the field of natural products chemistry, with applications from dereplication, genome mining, metabolomics, and visualization of chemical space. Studies have shown that data dependent acquisition (DDA) parameters affect molecular network topology but are limited in the number of parameters studied. With an aim to optimize LC-MS2 parameters for integrating GNPS-based molecular networking into our marine natural products workflow, a design of experiment (DOE) was used to screen the significance of the effect that eleven parameters have on both Classical Molecular Networking workflow (CLMN) and the new Feature-Based Molecular Networking workflow (FBMN). Our results indicate that four parameters (concentration, run duration, collision energy and number of precursors per cycle) are the most significant data acquisition parameters affecting the network topology. While concentration and the LC duration were found to be the two most important factors to optimize for CLMN, the number of precursors per cycle and collision energy were also very important factors to optimize for FBMN. Full article
(This article belongs to the Section Advances in Metabolomics)
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10 pages, 800 KiB  
Review
INDY as a Therapeutic Target for Cardio-Metabolic Disease
by Dominik Pesta and Jens Jordan
Metabolites 2022, 12(3), 244; https://doi.org/10.3390/metabo12030244 - 14 Mar 2022
Cited by 1 | Viewed by 2738
Abstract
Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, [...] Read more.
Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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23 pages, 1837 KiB  
Hypothesis
Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives
by Ana Paula Candiota and Carles Arús
Metabolites 2022, 12(3), 243; https://doi.org/10.3390/metabo12030243 - 14 Mar 2022
Cited by 2 | Viewed by 3195
Abstract
This hypothesis proposal addresses three major questions: (1) Why do we need imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response? (2) Why are they not available yet? and (3) How can we produce them? We summarize the [...] Read more.
This hypothesis proposal addresses three major questions: (1) Why do we need imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response? (2) Why are they not available yet? and (3) How can we produce them? We summarize the literature data supporting the claim that the immune system is behind the efficacy of most successful glioblastoma therapies but, unfortunately, there are no current short-term imaging biomarkers of its activity. We also discuss how using an immunocompetent murine model of glioblastoma, allowing the cure of mice and the generation of immune memory, provides a suitable framework for glioblastoma therapy response biomarker studies. Both magnetic resonance imaging and magnetic resonance-based metabolomic data (i.e., magnetic resonance spectroscopic imaging) can provide non-invasive assessments of such a system. A predictor based in nosological images, generated from magnetic resonance spectroscopic imaging analyses and their oscillatory patterns, should be translational to clinics. We also review hurdles that may explain why such an oscillatory biomarker was not reported in previous imaging glioblastoma work. Single shot explorations that neglect short-term oscillatory behavior derived from immune system attack on tumors may mislead actual response extent detection. Finally, we consider improvements required to properly predict immune system-mediated early response (1–2 weeks) to therapy. The sensible use of improved biomarkers may enable translatable evidence-based therapeutic protocols, with the possibility of extending preclinical results to human patients. Full article
(This article belongs to the Special Issue Imaging and Spectroscopic Based Methods to Understand Cancer Metabolism and Biology)
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