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Metabolites, Volume 12, Issue 10 (October 2022) – 123 articles

Cover Story (view full-size image): Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects. View this paper
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19 pages, 2293 KiB  
Article
The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome
by Yannick Audet-Delage, Michèle Rouleau, Lyne Villeneuve and Chantal Guillemette
Metabolites 2022, 12(10), 1006; https://doi.org/10.3390/metabo12101006 - 21 Oct 2022
Cited by 2 | Viewed by 1947
Abstract
Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 [...] Read more.
Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 were studied as UGT prototypes along with their alternative (alt.) splicing-derived isoforms displaying structural differences. Nineteen biochemical routes were modified, beyond known UGT substrates. Significant variations in glycolysis and pyrimidine pathways, and precursors of the co-substrate UDP-glucuronic acid were observed. Bioactive lipids such as arachidonic acid and endocannabinoids were highly enriched by up to 13.3-fold (p < 0.01) in cells expressing the canonical enzymes. Alt. UGT2B7 induced drastic and unique metabolic perturbations, including higher glucose (18-fold) levels and tricarboxylic acid cycle (TCA) cycle metabolites and abrogated the effects of the UGT2B7 canonical enzyme when co-expressed. UGT1A1 proteins promoted the accumulation of branched-chain amino acids (BCAA) and TCA metabolites upstream of the mitochondrial oxoglutarate dehydrogenase complex (OGDC). Alt. UGT1A1 exacerbated these changes, likely through its interaction with the OGDC component oxoglutarate dehydrogenase-like (OGDHL). This study expands the breadth of biochemical pathways associated with UGT expression and establishes extensive connectivity between UGT enzymes, alt. proteins and other metabolic processes. Full article
(This article belongs to the Special Issue Cellular Metabolism in the Omics Era)
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17 pages, 2720 KiB  
Article
Combining Feature-Based Molecular Networking and Contextual Mass Spectral Libraries to Decipher Nutrimetabolomics Profiles
by Lapo Renai, Marynka Ulaszewska, Fulvio Mattivi, Riccardo Bartoletti, Massimo Del Bubba and Justin J. J. van der Hooft
Metabolites 2022, 12(10), 1005; https://doi.org/10.3390/metabo12101005 - 21 Oct 2022
Cited by 5 | Viewed by 2421
Abstract
Untargeted metabolomics approaches deal with complex data hindering structural information for the comprehensive analysis of unknown metabolite features. We investigated the metabolite discovery capacity and the possible extension of the annotation coverage of the Feature-Based Molecular Networking (FBMN) approach by adding two novel [...] Read more.
Untargeted metabolomics approaches deal with complex data hindering structural information for the comprehensive analysis of unknown metabolite features. We investigated the metabolite discovery capacity and the possible extension of the annotation coverage of the Feature-Based Molecular Networking (FBMN) approach by adding two novel nutritionally-relevant (contextual) mass spectral libraries to the existing public ones, as compared to widely-used open-source annotation protocols. Two contextual mass spectral libraries in positive and negative ionization mode of ~300 reference molecules relevant for plant-based nutrikinetic studies were created and made publicly available through the GNPS platform. The postprandial urinary metabolome analysis within the intervention of Vaccinium supplements was selected as a case study. Following the FBMN approach in combination with the added contextual mass spectral libraries, 67 berry-related and human endogenous metabolites were annotated, achieving a structural annotation coverage comparable to or higher than existing non-commercial annotation workflows. To further exploit the quantitative data obtained within the FBMN environment, the postprandial behavior of the annotated metabolites was analyzed with Pearson product-moment correlation. This simple chemometric tool linked several molecular families with phase II and phase I metabolism. The proposed approach is a powerful strategy to employ in longitudinal studies since it reduces the unknown chemical space by boosting the annotation power to characterize biochemically relevant metabolites in human biofluids. Full article
(This article belongs to the Special Issue Advances in Metabolic Profiling of Biological Samples)
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14 pages, 2145 KiB  
Article
Identification of Metabolic Signature Associated with Idiopathic Inflammatory Myopathy Reveals Polyamine Pathway Alteration in Muscle Tissue
by Jihyun Kang, Jeong Yeon Kim, Youjin Jung, Seon Uk Kim, Eun Young Lee and Joo-Youn Cho
Metabolites 2022, 12(10), 1004; https://doi.org/10.3390/metabo12101004 - 21 Oct 2022
Cited by 3 | Viewed by 1605
Abstract
Idiopathic inflammatory myopathy (IIM) is hard to diagnose without a muscle biopsy. We aimed to identify a metabolite panel for IIM detection by metabolomics approach in serum samples and to explore the metabolomic signature in tissue samples from a mouse model. We obtained [...] Read more.
Idiopathic inflammatory myopathy (IIM) is hard to diagnose without a muscle biopsy. We aimed to identify a metabolite panel for IIM detection by metabolomics approach in serum samples and to explore the metabolomic signature in tissue samples from a mouse model. We obtained serum samples from IIM patients, ankylosing spondylitis (AS) patients, healthy volunteers and muscle tissue samples from IIM murine model. All samples were subjected to a targeted metabolomic approach with various statistical analyses on serum and tissue samples to identify metabolic alterations. Three machine learning methods, such as logistic regression (LR), support vector machine (SVM), and random forest (RF), were applied to build prediction models. A set of 7 predictive metabolites was calculated using backward stepwise selection, and the model was evaluated within 5-fold cross-validation by using three machine algorithms. The model produced an area under the receiver operating characteristic curve values of 0.955 (LR), 0.908 (RF) and 0.918 (SVM). A total of 68 metabolites were significantly changed in mouse tissue. Notably, the most influential pathways contributing to the inflammation of muscle were the polyamine pathway and the beta-alanine pathway. Our metabolomic approach offers the potential biomarkers of IIM and reveals pathologically relevant metabolic pathways that are associated with IIM. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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20 pages, 3303 KiB  
Article
Different Types of Non-Starch Polysaccharides Alter the Growth, Intestinal Flora and Serum Metabolite Profile of Grass Carp, Ctenopharyngodon idella
by Yu Liu, Xinlangji Fu, Hang Zhou, Jiongting Fan, Huajing Huang, Junming Deng and Beiping Tan
Metabolites 2022, 12(10), 1003; https://doi.org/10.3390/metabo12101003 - 21 Oct 2022
Cited by 3 | Viewed by 1741
Abstract
Dietary non-starch polysaccharides (NSPs) broadly influence fish intestinal flora and physiological metabolism, but limited information is available on grass carp (Ctenopharyngodon idella). This study investigated the effects of different types of NSPs on the growth, nutrient metabolism status, gut microbiota, and [...] Read more.
Dietary non-starch polysaccharides (NSPs) broadly influence fish intestinal flora and physiological metabolism, but limited information is available on grass carp (Ctenopharyngodon idella). This study investigated the effects of different types of NSPs on the growth, nutrient metabolism status, gut microbiota, and serum metabolome of grass carp. Fish were fed with diets containing 4.4% insoluble NSPs (INSP), 9.24% soluble NSPs (SNSP), 13.64% NSPs (4.4% INSP + 9.24% SNSP, NSP) and non NSPs (FM), respectively, for 9 weeks. Results showed that dietary SNSP decreased protein efficiency ratio and serum protein content, but increased feed coefficient ratio, feed intake, plasma blood urea nitrogen content, and plasma aspartate aminotransferase activity (AST); conversely, dietary INSP decreased plasma AST activity. Dietary INSP and SNSP increased serum free cholesterol content. Dietary NSPs altered the abundance of dominant bacteria and serum metabolite profiles. The differential metabolites between groups were significantly enriched in amino acid synthesis and metabolic pathways. In conclusion, dietary INSP exhibited a growth-promoting effect compared to SNSP. Dietary INSP is beneficial for improving nutrient metabolism and intestinal health. Moreover, dietary NSPs may regulate the physiological metabolism and feeding behavior of grass carp by altering amino acid synthesis and metabolism. Full article
(This article belongs to the Special Issue Nutrient Metabolism and Intestinal Health Studies in Aquatic Animals)
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22 pages, 2970 KiB  
Review
Survey for Computer-Aided Tools and Databases in Metabolomics
by Bayan Hassan Banimfreg, Abdulrahim Shamayleh and Hussam Alshraideh
Metabolites 2022, 12(10), 1002; https://doi.org/10.3390/metabo12101002 - 21 Oct 2022
Cited by 6 | Viewed by 2038
Abstract
Metabolomics has advanced from innovation and functional genomics tools and is currently a basis in the big data-led precision medicine era. Metabolomics is promising in the pharmaceutical field and clinical research. However, due to the complexity and high throughput data generated from such [...] Read more.
Metabolomics has advanced from innovation and functional genomics tools and is currently a basis in the big data-led precision medicine era. Metabolomics is promising in the pharmaceutical field and clinical research. However, due to the complexity and high throughput data generated from such experiments, data mining and analysis are significant challenges for researchers in the field. Therefore, several efforts were made to develop a complete workflow that helps researchers analyze data. This paper introduces a review of the state-of-the-art computer-aided tools and databases in metabolomics established in recent years. The paper provides computational tools and resources based on functionality and accessibility and provides hyperlinks to web pages to download or use. This review aims to present the latest computer-aided tools, databases, and resources to the metabolomics community in one place. Full article
(This article belongs to the Special Issue Cellular Metabolism in the Omics Era)
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21 pages, 1736 KiB  
Article
The Potential Protective Effect and Underlying Mechanisms of Physiological Unconjugated Hyperbilirubinemia Mediated by UGT1A1 Antisense Oligonucleotide Therapy in a Mouse Model of Cyclosporine A-Induced Chronic Kidney Disease
by Basma H. Marghani, Mohamed El-Adl, Ahmed I. Ateya, Basma H. Othman, Heba I. Ghamry, Mustafa Shukry, Mohamed Mohamed Soliman and Mohamed Abdo Rizk
Metabolites 2022, 12(10), 999; https://doi.org/10.3390/metabo12100999 - 20 Oct 2022
Cited by 2 | Viewed by 2198
Abstract
Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective [...] Read more.
Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective effects and underlying mechanisms of physiological unconjugated (UC) hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide in a mouse model of CsA-induced chronic kidney disease, and match these with that of chitosan (CH) as a natural chelator against kidney injury. In the current study, CsA-treated mice were given an intravenous injection of UGT1A1 antisense morpholino oligonucleotide (16 µg/kg) every third day for 14 days. In serum samples, bilirubin, creatinine, and urea were determined. Markers of oxidative stress, antioxidant activities, and mRNA expression of target genes PPAR-α, cFn, eNOS, NF-B, AT1-R, ETA-R, Kim-1, and NGAL were measured in the kidney tissues. Moreover, histopathological examinations were carried out on the kidney tissue. Physiological UC hyperbilirubinemia could be a promising protective strategy against CsA-induced kidney disease in transplant recipients. UGT1A1 antisense oligonucleotide-induced physiological UC hyperbilirubinemia serum significantly protected against CsA-induced kidney dysfunction. UCB acts as a signaling molecule that protects against kidney disease through different mechanisms, including antioxidant, anti-inflammatory, and hormonal action, by activating nuclear hormone receptors (PPAR-α). Moreover, it significantly downregulated mRNA expression of NF-kB, ETA-R, iNOS, AT1-R, cFn, Kim-1, and NGAL in the kidney tissue and alleviated CsA-induced kidney histological changes in CsA-treated mice. Full article
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12 pages, 590 KiB  
Article
Effect of Exercise on the Resting Metabolic Rate and Substrate Utilization in Women with Gestational Diabetes Mellitus: Results of a Pilot Study
by Eleftheria Taousani, Dimitra Savvaki, Efrosini Tsirou, Maria G. Grammatikopoulou, Basil C. Tarlatzis, Dimitrios Vavilis and Dimitrios G. Goulis
Metabolites 2022, 12(10), 998; https://doi.org/10.3390/metabo12100998 - 20 Oct 2022
Cited by 1 | Viewed by 1595
Abstract
Regular physical activity during pregnancy has a positive effect on the mother and fetus. However, there is scarce data regarding the effect of exercise in pregnancies complicated by gestational diabetes mellitus (GDM). The aim of the present parallel, non-randomized, open-label, pilot, clinical study [...] Read more.
Regular physical activity during pregnancy has a positive effect on the mother and fetus. However, there is scarce data regarding the effect of exercise in pregnancies complicated by gestational diabetes mellitus (GDM). The aim of the present parallel, non-randomized, open-label, pilot, clinical study was to examine the effect of two exercise programs on the resting metabolic rate (RMR) and substrate utilization in pregnancies complicated by GDM, compared with usual care (advice for the performance of exercise). Forty-three pregnant women diagnosed with GDM between the 24th and 28th gestational week, volunteered to participate. Three groups were formed: Usual care (n = 17), Walking (n = 14), and Mixed Exercise (n = 12). The Usual care group was given advice on maintaining habitual daily activities without any additional exercise. The Walking group exercised regularly by walking, in addition to the habitual daily activities. Finally, the Mixed Exercise group participated in a program combining aerobics and strength exercises. Training intensity was monitored continuously using lightweight, wearable monitoring devices. The Walking and Mixed Exercise groups participated in the training programs after being diagnosed with GDM and maintained them until the last week of gestation. RMR and substrate utilization were analyzed using indirect calorimetry for all participants twice: between 27th and 28th gestational week and as close as possible before delivery. No differences were observed between groups regarding body composition, age, and medical or obstetrical parameters before or after the exercise programs. RMR was increased after the completion of the exercise interventions in both the Walking (p = 0.001) and the Mixed Exercise arms (p = 0.002). In contrast, substrate utilization remained indifferent. In conclusion, regular exercise of moderate intensity (either walking, or a combination of aerobic and strength training) increases RMR in women with GDM compared to the lack of systematic exercise. However, based on the present, pilot data, these exercise regimes do not appear to alter resting substrate utilization. Full article
(This article belongs to the Special Issue Resting Metabolic Rate of Individuals)
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13 pages, 13943 KiB  
Article
Discovery and Validation of Potential Serum Biomarkers with Pro-Inflammatory and DNA Damage Activities in Ulcerative Colitis: A Comprehensive Untargeted Metabolomic Study
by Mingxiao Li, Rui Zhang, Mingjie Xin, Yi Xu, Shijia Liu, Boyang Yu, Boli Zhang and Jihua Liu
Metabolites 2022, 12(10), 997; https://doi.org/10.3390/metabo12100997 - 20 Oct 2022
Cited by 4 | Viewed by 1947
Abstract
Ulcerative colitis is a type of non-specific inflammatory bowel disease with unclear etiology. It is considered a progressive disease with risks of bowel motility disorders, anorectal dysfunction, and even colorectal cancer. Commonly used diagnostic markers have poor specificity and cannot predict the development [...] Read more.
Ulcerative colitis is a type of non-specific inflammatory bowel disease with unclear etiology. It is considered a progressive disease with risks of bowel motility disorders, anorectal dysfunction, and even colorectal cancer. Commonly used diagnostic markers have poor specificity and cannot predict the development of ulcerative colitis. In this study, 77 serum samples (31 patients, 46 healthy controls) were analyzed using high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and 31 metabolites with significant level changes were found, revealing the relationship of ulcerative colitis to disturbed glutathione metabolism and caffeine metabolism. In addition, pyroglutamic acid, a biomarker of cervical cancer and gastric cancer, was identified with elevated levels in the serum of ulcerative colitis patients. The role of pyroglutamic acid was further analyzed, and the results indicated its positive correlation with the upregulation of inflammatory factors and increased levels of phosphorylated histone H2AX (γH2AX) in IEC-6 cells, which are related to DNA damage. All these results suggest that pyroglutamic acid is not only a biomarker for distinguishing ulcerative colitis status, but that it is also a potential effective metabolite that promotes the transformation of ulcerative colitis to colorectal cancer. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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25 pages, 2511 KiB  
Article
RNAseq Analysis of Brown Adipose Tissue and Thyroid of Newborn Lambs Subjected to Short-Term Cold Exposure Reveals Signs of Early Whitening of Adipose Tissue
by Andrea Graña-Baumgartner, Venkata S. R. Dukkipati, Paul R. Kenyon, Hugh T. Blair, Nicolás López-Villalobos, Kristene Gedye and Patrick J. Biggs
Metabolites 2022, 12(10), 996; https://doi.org/10.3390/metabo12100996 - 20 Oct 2022
Cited by 2 | Viewed by 1741
Abstract
During the early postnatal period, lambs have the ability to thermoregulate body temperature via non-shivering thermogenesis through brown adipose tissue (BAT), which soon after birth begins to transform into white adipose tissue. An RNA seq approach was used to characterize the transcriptome of [...] Read more.
During the early postnatal period, lambs have the ability to thermoregulate body temperature via non-shivering thermogenesis through brown adipose tissue (BAT), which soon after birth begins to transform into white adipose tissue. An RNA seq approach was used to characterize the transcriptome of BAT and thyroid tissue in newborn lambs exposed to cold conditions. Fifteen newborn Romney lambs were selected and divided into three groups: group 1 (n = 3) was a control, and groups 2 and 3 (n = 6 each) were kept indoors for two days at an ambient temperature (20–22 °C) or at a cold temperature (4 °C), respectively. Sequencing was performed using a paired-end strategy through the BGISEQ-500 platform, followed by the identification of differentially expressed genes using DESeq2 and an enrichment analysis by g:Profiler. This study provides an in-depth expression network of the main characters involved in the thermogenesis and fat-whitening mechanisms that take place in the newborn lamb. Data revealed no significant differential expression of key thermogenic factors such as uncoupling protein 1, suggesting that the heat production peak under cold exposure might occur so rapidly and in such an immediate way that it may seem undetectable in BAT by day three of life. Moreover, these changes in expression might indicate the start of the whitening process of the adipose tissue, concluding the non-shivering thermogenesis period. Full article
(This article belongs to the Special Issue Lipid Metabolism in Ruminants)
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21 pages, 3035 KiB  
Article
Polyphenol-Rich Leaf of Annona squamosa Stimulates Insulin Release from BRIN-BD11 Cells and Isolated Mouse Islets, Reduces (CH2O)n Digestion and Absorption, and Improves Glucose Tolerance and GLP-1 (7-36) Levels in High-Fat-Fed Rats
by Prawej Ansari, J.M.A. Hannan, Veronique Seidel and Yasser H.A. Abdel-Wahab
Metabolites 2022, 12(10), 995; https://doi.org/10.3390/metabo12100995 - 20 Oct 2022
Cited by 3 | Viewed by 1882
Abstract
Annona squamosa, commonly known as custard apple, is traditionally used for the treatment of various diseases including diabetes, cardiovascular disease (CVD), and gastritis. This study was undertaken to investigate the effects of an ethanolic (80% v/v) extract of A. [...] Read more.
Annona squamosa, commonly known as custard apple, is traditionally used for the treatment of various diseases including diabetes, cardiovascular disease (CVD), and gastritis. This study was undertaken to investigate the effects of an ethanolic (80% v/v) extract of A. squamosa (EEAS) leaves in vitro on insulin secretion from clonal pancreatic BRIN BD11 β-cells and mouse islets, including mechanistic studies on the effect of EEAS on membrane potential and intracellular calcium ion concentration. Additional in vitro glucose-lowering actions were assessed. For in vivo studies, high-fat-fed (HFF) obese/normal rats were selected. EEAS increased insulin secretion in vitro in a dose-dependent manner. This effect was linked to β-cell membrane depolarisation and cytoplasmic Ca2+ influx. In the presence of isobutyl methylxanthine (IBMX), tolbutamide, or KCl, the insulin-releasing effect of EEAS was increased, suggesting its effect was also mediated via a KATP-independent pathways. EEAS inhibited insulin glycation, glucose absorption, and DPP-IV enzyme activity in vitro and enhanced glucose uptake and insulin action in 3T3L1 cells. In vivo, gut motility, food intake, glucose tolerance, plasma insulin, and active GLP-1 (7-36) levels were improved, whereas plasma DPP-IV levels were reduced in HFF rats. EEAS attenuated the absorption of sucrose and glucose as well as decreased serum glucose levels after sucrose loading and in situ intestinal perfusion in non-diabetic rats. Rutin, proanthocyanidin, and squafosacin G were putatively identified as the anti-hyperglycaemic phytomolecules in EEAS using HPLC followed by LC-MS analysis. This study illustrates the potential of A. squamosa and its phytoconstituents as a source of potential antidiabetic agents. Full article
(This article belongs to the Special Issue Frontiers of Natural Antidiabetic Drug Discovery)
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23 pages, 1086 KiB  
Review
Oxylipins as Potential Regulators of Inflammatory Conditions of Human Lactation
by Rachel E. Walker
Metabolites 2022, 12(10), 994; https://doi.org/10.3390/metabo12100994 - 20 Oct 2022
Cited by 3 | Viewed by 1602
Abstract
Chronic low-grade inflammation can be associated with obesity or subclinical mastitis (SCM), which is associated with poor infant growth in low- to middle-income country settings. It is unknown what physiological mechanisms are involved in low milk supply, but our research group has shown [...] Read more.
Chronic low-grade inflammation can be associated with obesity or subclinical mastitis (SCM), which is associated with poor infant growth in low- to middle-income country settings. It is unknown what physiological mechanisms are involved in low milk supply, but our research group has shown that mothers with low milk supply have higher inflammatory markers. Studies investigating oxylipin signaling have the potential to help explain mechanisms that mediate the impacts of inflammation on milk production. Animal studies have reported various elevated oxylipins during postpartum inflammation, mastitis, and mammary involution in ruminant models. Several investigations have quantified oxylipins in human milk, but very few studies have reported circulating oxylipin concentrations during lactation. In addition, there are technical considerations that must be addressed when reporting oxylipin concentrations in human milk. First, the majority of milk oxylipins are esterified in the triglyceride pool, which is not routinely measured. Second, total milk fat should be considered as a covariate when using milk oxylipins to predict outcomes. Finally, storage and handling conditions of milk samples must be carefully controlled to ensure accurate milk oxylipin quantitation, which may be affected by highly active lipases in human milk. Full article
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11 pages, 1145 KiB  
Article
Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
by Caroline Sychterz, Iain Gardner, Manting Chiang, Ramakrishna Rachumallu, Sibylle Neuhoff, Vidya Perera, Samira Merali, Brian J. Schmidt and Lu Gaohua
Metabolites 2022, 12(10), 1001; https://doi.org/10.3390/metabo12101001 - 20 Oct 2022
Cited by 3 | Viewed by 2350
Abstract
Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme [...] Read more.
Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme abundance, including addition of intermediate and rapid metabolizer phenotypes and changes to the ultra-rapid metabolizer enzyme abundance, with implications for population clearance and DDI predictions. This work details verification of the updates with sensitive CYP2C19 substrates, omeprazole and lansoprazole, using available clinical data from literature. Multiple assessments were performed, including recovery of areas under the concentration-time curve (AUC) and Cmax from compiled datasets for each drug, recovery of victim DDI ratios with CYP2C19 and/or CYP3A4 inhibition and recovery of relative exposure between phenotypes. Simulated data were within respective acceptance criteria for >80% of omeprazole AUC values, >70% of lansoprazole AUC and Cmax, >60% of AUC and Cmax DDI ratios and >80% of exposure ratios between different phenotypes. Recovery of omeprazole Cmax was lower (>50–70% within 2-fold) and possibly attributed to the variety of formulations used in the clinical dataset. Overall, the results demonstrated that the updated data used to parameterize CYP2C19 phenotypes reasonably described the pharmacokinetics of omeprazole and lansoprazole in genotyped or phenotyped individuals. Full article
(This article belongs to the Special Issue Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics)
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18 pages, 1618 KiB  
Review
Effects of Probiotics and Gut Microbiota on Bone Metabolism in Chickens: A Review
by Pan Chen, Tingting Xu, Chaodong Zhang, Xishuai Tong, Aftab Shaukat, Yanfeng He, Kaili Liu and Shucheng Huang
Metabolites 2022, 12(10), 1000; https://doi.org/10.3390/metabo12101000 - 20 Oct 2022
Cited by 11 | Viewed by 3059
Abstract
Broiler leg diseases are a common abnormal bone metabolism issue that leads to poor leg health in growing poultry. Bone metabolism is a complicated regulatory process controlled by genetic, nutritional, feeding management, environmental, or other influencing factors. The gut microbiota constitutes the largest [...] Read more.
Broiler leg diseases are a common abnormal bone metabolism issue that leads to poor leg health in growing poultry. Bone metabolism is a complicated regulatory process controlled by genetic, nutritional, feeding management, environmental, or other influencing factors. The gut microbiota constitutes the largest micro-ecosystem in animals and is closely related to many metabolic disorders, including bone disease, by affecting the absorption of nutrients and the barrier function of the gastrointestinal tract and regulating the immune system and even the brain–gut–bone axis. Recently, probiotic-based dietary supplementation has emerged as an emerging strategy to improve bone health in chickens by regulating bone metabolism based on the gut–bone axis. This review aims to summarize the regulatory mechanisms of probiotics in the gut microbiota on bone metabolism and to provide new insights for the prevention and treatment of bone diseases in broiler chickens. Full article
(This article belongs to the Special Issue Nutritional Metabolic or Clinical Diseases in Mammals and Poultry)
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16 pages, 20270 KiB  
Article
Analysis of Primary Liquid Chromatography Mass Spectrometry Data by Neural Networks for Plant Samples Classification
by Polina Turova, Andrey Stavrianidi, Viktor Svekolkin, Dmitry Lyskov, Ilya Podolskiy, Igor Rodin, Oleg Shpigun and Aleksey Buryak
Metabolites 2022, 12(10), 993; https://doi.org/10.3390/metabo12100993 - 19 Oct 2022
Viewed by 1488
Abstract
Plant samples are potential sources of physiologically active secondary metabolites and their classification is an extremely important task in traditional medicine and other fields of research. In the production of herbal drugs, different plant parts of the same or related species can serve [...] Read more.
Plant samples are potential sources of physiologically active secondary metabolites and their classification is an extremely important task in traditional medicine and other fields of research. In the production of herbal drugs, different plant parts of the same or related species can serve as adulterants for primary plant material. The use of highly informative and relatively easily accessible tools, such as liquid chromatography and low-resolution mass spectrometry, helps to solve these tasks by means of fingerprint analysis. In this study, to reveal specific plant part features for 20 species from one family (Apiaceae), and to preserve the maximum information content, two approaches are suggested. In both cases, minimal raw data pretreatment, including rescaling of time and m/z axes and cutting off some uninformative regions, was applied. For the support vector machine (SVM) method, tensor unfolding was required, while neural networks (NNs) were able to work directly with squared heatmaps as input data. Moreover, five data augmentation variants are proposed, to overcome the typical problem of a lack of data. As a result, a comparable F1-score close to 0.75 was achieved by SVM and two employed NN architectures. Eight marker compounds belonging to chlorophylls, lipids, and coumarin apio-glucosides were tentatively identified as characteristic of their corresponding sample groups: roots, stems, leaves, and fruits. The proposed approaches are simple, information-saving and can be applied to a broad type of tasks in metabolomics. Full article
(This article belongs to the Special Issue Advances in Metabolic Studies in Plant Extraction)
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11 pages, 9462 KiB  
Article
Cluster Analysis Statistical Spectroscopy for the Identification of Metabolites in 1H NMR Metabolomics
by Silke S. Heinzmann, Melanie Waldenberger, Annette Peters and Philippe Schmitt-Kopplin
Metabolites 2022, 12(10), 992; https://doi.org/10.3390/metabo12100992 - 19 Oct 2022
Cited by 1 | Viewed by 1833
Abstract
Metabolite identification in non-targeted NMR-based metabolomics remains a challenge. While many peaks of frequently occurring metabolites are assigned, there is a high number of unknowns in high-resolution NMR spectra, hampering biological conclusions for biomarker analysis. Here, we use a cluster analysis approach to [...] Read more.
Metabolite identification in non-targeted NMR-based metabolomics remains a challenge. While many peaks of frequently occurring metabolites are assigned, there is a high number of unknowns in high-resolution NMR spectra, hampering biological conclusions for biomarker analysis. Here, we use a cluster analysis approach to guide peak assignment via statistical correlations, which gives important information on possible structural and/or biological correlations from the NMR spectrum. Unknown peaks that cluster in close proximity to known peaks form hypotheses for their metabolite identities, thus, facilitating metabolite annotation. Subsequently, metabolite identification based on a database search, 2D NMR analysis and standard spiking is performed, whereas without a hypothesis, a full structural elucidation approach would be required. The approach allows a higher identification yield in NMR spectra, especially once pathway-related subclusters are identified. Full article
(This article belongs to the Special Issue Diet, Drugs and the Gut Microbiome on the Metabolic Phenotype)
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15 pages, 2743 KiB  
Article
GC-TOF-MS-Based Non-Targeted Metabolomic Analysis of Differential Metabolites in Chinese Ultra-Long-Term Industrially Fermented Kohlrabi and Their Associated Metabolic Pathways
by Xin Nie, Hongfan Chen, Lu Xiang, Yulin Zhang, Dayu Liu and Zhiping Zhao
Metabolites 2022, 12(10), 991; https://doi.org/10.3390/metabo12100991 - 19 Oct 2022
Cited by 10 | Viewed by 2181
Abstract
Fermented kohlrabi is a very popular side dish in China. Chinese kohlrabies industrially fermented for 0 years (0Y), 5 years (5Y), and 10 years (10Y) were employed and analyzed by non-targeted metabolomics based on GC-TOF-MS, and the differential metabolites were screened using multivariate [...] Read more.
Fermented kohlrabi is a very popular side dish in China. Chinese kohlrabies industrially fermented for 0 years (0Y), 5 years (5Y), and 10 years (10Y) were employed and analyzed by non-targeted metabolomics based on GC-TOF-MS, and the differential metabolites were screened using multivariate statistical analysis techniques, including principal component analysis (PCA) and orthogonal partial least squares discrimination analysis (OPLS-DA). The results showed that 47, 38, and 33 differential metabolites were identified in the three treatment groups of 0Y and 5Y (A1), 0Y and 10Y (A2), and 5Y and 10Y (A3), respectively (VIP > 1, p < 0.05). The metabolites were mainly carbohydrates, amino acids, and organic acids. Furthermore, 13 differential metabolites were screened from the three groups, including L-glutamic acid, L-aspartic acid, γ-aminobutyric acid, and other compounds. Four metabolic pathways termed alanine, aspartate, and glutamate metabolism, arginine biosynthesis, arginine and proline metabolism, and glycolysis/gluconeogenesis were the most significant pathways correlated with the differential metabolites, as analyzed according to the Kyoto Encyclopedia of Genes and Genomes (KEGG). The odors for the three ultra-long-term industrially fermented kohlrabies were significantly different, as detected by E-nose. The present work describes the changes in metabolites between different ultra-long-term industrially fermented kohlrabies and the associated metabolic pathways, providing a theoretical basis for the targeted regulation of characteristic metabolite biosynthesis in Chinese fermented kohlrabi. Full article
(This article belongs to the Special Issue Plant Metabolic Genetic Engineering)
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10 pages, 1147 KiB  
Article
Analysis of the Phenotype Differences in Siblings with Alkaptonuria
by Andrea Zatkova, Birgitta Olsson, Lakshminarayan R. Ranganath and Richard Imrich
Metabolites 2022, 12(10), 990; https://doi.org/10.3390/metabo12100990 - 19 Oct 2022
Cited by 4 | Viewed by 1344
Abstract
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), [...] Read more.
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype–phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients. Full article
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12 pages, 285 KiB  
Article
Effects of Protein Source, Whole Wheat and Butyric Acid on Live Performance, Gut Health and Amino Acid Digestibility in Broiler Chickens
by Shafqat N. Qaisrani, Ali I. Hussain, Saima Naveed, Fehmeada Bibi, Chaudhry A. Akram, Talat N. Pasha, Muhammad Asif, Irfan Irshad and Rana M. Bilal
Metabolites 2022, 12(10), 989; https://doi.org/10.3390/metabo12100989 - 19 Oct 2022
Cited by 1 | Viewed by 1465
Abstract
A total of 896 1-day-old straight-run (Ross-308) broilers were used to investigate the interactive effects of protein source (PS), diet structure (DS) and butyric acid (BA) on live performance and carcass characteristics, gut development and its morphology and apparent ileal digestibility (AID) of [...] Read more.
A total of 896 1-day-old straight-run (Ross-308) broilers were used to investigate the interactive effects of protein source (PS), diet structure (DS) and butyric acid (BA) on live performance and carcass characteristics, gut development and its morphology and apparent ileal digestibility (AID) of protein and amino acids (AA). Eight experimental diets comprising 8 replicates with 14 birds each were tested in a 2 × 2 × 2 factorial arrangement with complete randomized design by two levels of BA (0 and 0.1%), two forms of DS (whole vs. ground wheat) and two PS, i.e., soybean meal and canola meal (SBM vs. CM). Throughout the entire experimental period (0 to 35 d), broilers fed SBM-based diets exhibited better (p < 0.05) growth performance (feed intake (FI), body weight gain (BWG) and feed conversion ratio (FCR)), carcass parameters (p < 0.05), gut health (p < 0.05), and nutrient digestibility (p < 0.05) than CM-fed broilers. Dietary whole wheat (WW) positively affected FI (p = 0.001), BWG (p = 0.004) and FCR (p = 0.035) during the overall experimental period. Broilers fed WW had 6, 5, 8, 11 and 10% lower empty relative weights of crop, proventriculus, jejunum, ileum and colon and 25 and 15% heavier gizzard and pancreas, respectively, with longer villus height (p < 0.001), reduced crypt depth (p = 0.031) and longer villus height-to-crypt depth ratio (p < 0.001) than those fed ground-wheat-based diets. Broilers fed WW had greater (p < 0.05) AID of CP and most of the AA. Butyric acid supplementation resulted in improved (p < 0.05) growth performance and digestibility of threonine, valine, leucine, isoleucine, phenylalanine, serine and aspartate. The broilers consuming SBM had 28% lower abdominal fat than those fed CM-based diets. In conclusion, harmful consequences of a less digestible PS can partially be compensated by the inclusion of WW, and supplementation of BA further reduces these detrimental effects. Full article
17 pages, 2165 KiB  
Article
Plasma Metabolomics Reveals β-Glucan Improves Muscle Strength and Exercise Capacity in Athletes
by Ruwen Wang, Xianmin Wu, Kaiqing Lin, Shanshan Guo, Yuning Hou, Renyan Ma, Qirong Wang and Ru Wang
Metabolites 2022, 12(10), 988; https://doi.org/10.3390/metabo12100988 - 18 Oct 2022
Cited by 4 | Viewed by 2251
Abstract
The present study aimed to assess the changes in muscle strength and plasma metabolites in athletes with β-glucan supplementation. A total of 29 athletes who met the inclusion criteria were recruited for this study (ChiCTR2200058091) and were randomly divided into a placebo group [...] Read more.
The present study aimed to assess the changes in muscle strength and plasma metabolites in athletes with β-glucan supplementation. A total of 29 athletes who met the inclusion criteria were recruited for this study (ChiCTR2200058091) and were randomly divided into a placebo group (n = 14) and β-glucan group (n = 15). During the trial, the experimental group received β-glucan supplementation (2 g/d β-glucan) for 4 weeks and the control group received an equal dose of placebo supplementation (0 g/d β-glucan), with both groups maintaining their regular diet and exercise habits during the trial. The athletes’ exercise performance, muscle strength, and plasma metabolome changes were analyzed after 4 weeks of β-glucan supplementation. The results showed a significant increase in mean grip strength (kg), right hand grip strength (kg), left triceps strength (kg), and upper limb muscle mass (kg) in the experimental group after the 4-week intervention compared to the preintervention period (p < 0.05). A comparison of the difference between the two groups after the intervention showed that there were significant differences between the control group and the experimental group in mean grip strength (kg) and right-hand grip strength (kg) (p < 0.05). Athletes in the experimental group showed significant improvements in 1 min double rocking jump (pcs), VO2max (ml/kg-min) (p < 0.05). The β-glucan intake increased the creatine-related pathway metabolites in plasma. Overall, these results suggest that 4 weeks of β-glucan supplementation can improve muscle strength in athletes, with the potential to increase aerobic endurance and enhance immune function, possibly by affecting creatine-related pathways. Full article
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23 pages, 811 KiB  
Article
Effects of a Metabolic Mixture on Gut Inflammation and Permeability in Elderly Patients with Chronic Kidney Disease: A Proof-of-Concept Study
by Roberto Aquilani, Piergiorgio Bolasco, Stefano Murtas, Roberto Maestri, Paolo Iadarola, Cristian Testa, Maria Luisa Deiana, Maria Paola Esposito, Rita Contu, Mariella Cadeddu, Romina Secci and Federica Boschi
Metabolites 2022, 12(10), 987; https://doi.org/10.3390/metabo12100987 - 18 Oct 2022
Cited by 4 | Viewed by 1942
Abstract
Intestinal barrier dysfunction is a risk factor for the progression of Chronic Kidney Disease (CKD). In this proof-of-concept study, we tested the effects of a mixture of Essential Amino Acids (EAAs) and mitochondrial substrates on intestinal inflammation and permeability of CKD patients. Eight [...] Read more.
Intestinal barrier dysfunction is a risk factor for the progression of Chronic Kidney Disease (CKD). In this proof-of-concept study, we tested the effects of a mixture of Essential Amino Acids (EAAs) and mitochondrial substrates on intestinal inflammation and permeability of CKD patients. Eight patients with stage 3b-4 CKD and 11 healthy controls after overnight fasting underwent fecal measures of calprotectin and zonulin levels (indicators of gut inflammation and permeability, respectively) and determinations of plasma amino acids. Only CKD patients were supplemented with the mixture (8 g/d diluted in water). Compared to controls, baseline fecal calprotectin, zonulin and plasma levels of some AA in CKD patients were significantly higher (p = 0.005; p = 0.001 and p = 0.02 to 0.003, respectively). After six months of supplementation, CKD baseline fecal levels of calprotectin and zonulin significantly (borderline for zonulin) decreased (p = 0.008 and p = 0.05, respectively). Plasma AA concentrations, including glutamine and alanine, were higher than at the baseline (p: 0.05 to 0.008). The supplementation of this mixture was associated with improved intestinal barrier dysfunction. Increased plasma AA levels might contribute to the improvement of gut barrier dysfunction. Full article
(This article belongs to the Special Issue Drug Permeability and Metabolism in the Gut)
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10 pages, 1086 KiB  
Article
Untargeted Metabolomic Approach to Study the Impact of Aging on Salivary Metabolome in Women
by Pauline Bosman, Valérie Pichon, Ana Carolina Acevedo, Laëtitia Le Pottier, Jacques Olivier Pers, Hélène Chardin and Audrey Combès
Metabolites 2022, 12(10), 986; https://doi.org/10.3390/metabo12100986 - 18 Oct 2022
Cited by 4 | Viewed by 1402
Abstract
Despite the growing interest in salivary metabolomics, few studies have investigated the impact of aging on the salivary metabolome. The alterations in metabolic pathways that occur with aging are likely to be observed in pathologies affecting older people and may interfere with the [...] Read more.
Despite the growing interest in salivary metabolomics, few studies have investigated the impact of aging on the salivary metabolome. The alterations in metabolic pathways that occur with aging are likely to be observed in pathologies affecting older people and may interfere with the search for salivary biomarkers. It is therefore important to investigate the age-related changes occurring in the salivary metabolome. Using reversed phase liquid chromatography and hydrophilic interaction chromatography coupled to mass spectrometry used in positive and negative ionization modes, the salivary metabolic profiles of young (22 to 45 years old) and older people (55 to 92 years old) were obtained. Those profiles were compared with the use of XCMS online to highlight the under or overexpression of some metabolites with aging. A total of 60 metabolites showed differential expression with age. The identification of 26 of them was proposed by the METLIN database and, among them, 17 were validated by standard injections. Aging seemed to affect most of the main metabolic pathways (amino acid metabolism, Krebs cycle, fatty acid synthesis, and nucleic acid synthesis). Moreover, most of the metabolites that were over- or under-expressed with age in this study have already been identified as being potential biomarkers of diseases affecting older people, such as in Alzheimer’s disease. Special attention should be paid in the search for biomarkers of pathologies affecting the elderly to differentiate age-related changes from disease-related changes. Full article
(This article belongs to the Special Issue Salivary Fingerprint in Metabolomics Era: Potential and Challenges)
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13 pages, 1082 KiB  
Communication
LC-HRMS-Based Non-Targeted Metabolomics for the Assessment of Honey Adulteration with Sugar Syrups: A Preliminary Study
by Marianna Martinello, Roberto Stella, Alessandra Baggio, Giancarlo Biancotto and Franco Mutinelli
Metabolites 2022, 12(10), 985; https://doi.org/10.3390/metabo12100985 - 18 Oct 2022
Cited by 5 | Viewed by 2007
Abstract
Honey is a natural product that is in great demand and has a relatively high price, thus making it one of the most common targets of economically motivated adulteration. Its adulteration can be obtained by adding cheaper honey or sugar syrups or by [...] Read more.
Honey is a natural product that is in great demand and has a relatively high price, thus making it one of the most common targets of economically motivated adulteration. Its adulteration can be obtained by adding cheaper honey or sugar syrups or by overfeeding honeybees with sugar syrups. Adulteration techniques are constantly evolving and advanced techniques and instruments are required for its detection. We used non-targeted metabolomics to underscore potential markers of honey adulteration with sugar syrups. The metabolomic profiles of unadulterated honeys and sugar beet, corn and wheat syrups were obtained using hydrophilic interaction liquid chromatography high-resolution mass spectrometry (LC-HRMS). The potential markers have been selected after data processing. Fortified honey (5%, 10% and 20%), honey obtained from overfeeding, and 58 commercial honeys were analyzed. One potential marker appeared with a specific signal for syrups and not for honey. This targeted analysis showed a linear trend in fortified honeys with a calculated limit of quantification around 5% of fortification. Full article
(This article belongs to the Section Food Metabolomics)
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18 pages, 10890 KiB  
Article
Study on the Regulation of Exogenous Hormones on the Absorption of Elements and the Accumulation of Secondary Metabolites in the Medicinal Plant Artemisia argyi Leaves
by Linlin Yang, Yueci Yan, Boyu Zhao, Huaming Xu, Xiuhong Su and Chengming Dong
Metabolites 2022, 12(10), 984; https://doi.org/10.3390/metabo12100984 - 17 Oct 2022
Cited by 7 | Viewed by 1909
Abstract
As an important medicinal plant, we still do not know the effect of exogenous hormones on absorption of elements and accumulation of secondary metabolites in Artemisia argyi leaves. In this work, we analyzed the difference in 21 elements absorbed by A. argyi leaves [...] Read more.
As an important medicinal plant, we still do not know the effect of exogenous hormones on absorption of elements and accumulation of secondary metabolites in Artemisia argyi leaves. In this work, we analyzed the difference in 21 elements absorbed by A. argyi leaves under three exogenous hormone (MeJA, SA and ABA) treatments, and also clarified the correlation between 21 elements and eight bioactive components. Different hormone treatments changed the absorption and enrichment of elements, and the composition also changed significantly. The contents of eight bioactive components changed significantly under different hormone treatments. When A. argyi was stimulated by exogenous hormones, the content of secondary metabolites was adjusted in the leaves through changes in the absorption and enrichment of elements. The widely untargeted metabolomic analysis further confirmed that ABA changes the metabolic direction of secondary metabolites in A. argyi leaves and stimulates the biosynthesis of multiple secondary metabolites including phenylpropanoids, flavonoids, terpenoids, alkaloids and others. These results provide a new perspective for the changes in element absorption and the mechanism of secondary metabolic components in A. argyi leaves under exogenous hormone treatments, and also deepen people’s understanding of the interaction mechanism between medicinal plants and hormones. Full article
(This article belongs to the Special Issue Secondary Metabolites from Plant Sources)
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20 pages, 1294 KiB  
Article
A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study
by Madis Parksepp, Liina Haring, Kalle Kilk, Egon Taalberg, Raul Kangro, Mihkel Zilmer and Eero Vasar
Metabolites 2022, 12(10), 983; https://doi.org/10.3390/metabo12100983 - 17 Oct 2022
Cited by 4 | Viewed by 1740
Abstract
The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the [...] Read more.
The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the early course of the disorder. A total of 112 adults participated in the study (54 patients with first-episode psychosis (FEP) and 58 control subjects). Biomolecule profiles were measured at the onset of first-episode psychosis and 0.6 years and 5.1 years after the initiation of APs. The results of the present study confirmed that specific metabolic–inflammatory imbalance characterizes AP-naïve patients. Short-term (0.6-years) AP treatment has a favourable effect on psychotic symptoms, as well as the recovery of metabolic flexibility and resolution of low-level inflammation. However, 5.1 years of AP treatment resulted in weight gain and increased serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-γ, hexoses, acetylcarnitine, short-chain ACs (C3, C4) and long-chain ACs (C16:2, C18:1, C18:2). In conclusion, despite the improvement in psychotic symptoms, 5.1 years of AP treatment was accompanied by a pronounced metabolic–inflammatory imbalance, which was confirmed by the presence of enhanced pro-inflammatory activity and increased obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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26 pages, 6579 KiB  
Article
Cheminformatics Bioprospection of Broad Spectrum Plant Secondary Metabolites Targeting the Spike Proteins of Omicron Variant and Wild-Type SARS-CoV-2
by Jamiu Olaseni Aribisala, Christiana Eleojo Aruwa, Taofik Olatunde Uthman, Ismaila Olanrewaju Nurain, Kehinde Idowu and Saheed Sabiu
Metabolites 2022, 12(10), 982; https://doi.org/10.3390/metabo12100982 - 17 Oct 2022
Cited by 7 | Viewed by 1941
Abstract
The spike protein (SP) of SARS-CoV-2 (SC-2) is susceptible to high mutation and has contributed to the multiple waves of COVID-19 being experienced. Hence, targeting the SP remains a logical approach in the development of potent therapeutics against SARS-CoV-2. Here, a computational technique [...] Read more.
The spike protein (SP) of SARS-CoV-2 (SC-2) is susceptible to high mutation and has contributed to the multiple waves of COVID-19 being experienced. Hence, targeting the SP remains a logical approach in the development of potent therapeutics against SARS-CoV-2. Here, a computational technique was adopted to identify broad-spectrum plant secondary metabolites with indigenous relevance in the management of respiratory infections against the SPs of the SC-2 wild- type (SC-2WT) and omicron variants. Following 100 ns molecular dynamic (MD) simulation and binding free energy calculation of the top five compounds identified through molecular docking, maysin (SC-2WT (−34.85 kcal/mol), omicron (−38.88 kcal/mol)) and geraniin (SC-2WT (−36.90 kcal/mol) omicron (−31.28 kcal/mol)) had better broad-spectrum activities for the investigated SPs than zafirlukast (SC-2WT (−33.73 kcal/mol) omicron (−22.38 kcal/mol)). Furthermore, 6-hydroxycyanidin-3-rutinoside (−42.97 kcal/mol) and kaempferol-7-glucoside (−37.11 kcal/mol) had the best affinity for the SPs of omicron and SC-2WT, respectively. Interestingly, except for Kaempferol-7-glucoside against omicron SP, all the top-ranked compounds were thermodynamically stable with the SP of both variants, and this observation was linked to the number, nature, and bond length in the resulting complexes in each case. Also, except for geraniin, all the top-ranked compounds had lower toxicity profiles compared to zafirlukast and this could be attributed to their phenolic moieties. Nevertheless, the in vitro and in vivo confirmation of the activities observed in this study is recommended, especially for maysin and geraniin with the best broad-spectrum activity, towards development of COVID-19 drug candidates. Full article
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15 pages, 6390 KiB  
Article
Mechanisms of Ardisia japonica in the Treatment of Hepatic Injury in Rats Based on LC-MS Metabolomics
by Tian Fu, Shuiling Qin, Huajuan He, Kefeng Zhang, Wei Zhang, Xin Tang and Wei Wu
Metabolites 2022, 12(10), 981; https://doi.org/10.3390/metabo12100981 - 17 Oct 2022
Cited by 4 | Viewed by 1999
Abstract
The mechanism of action of Ardisia japonica in the treatment of immune liver injury was systematically analyzed from the perspective of the biological metabolic network by using non-targeted metabolomics combined with biological network analysis tools. A rat model of acute immune hepatic injury [...] Read more.
The mechanism of action of Ardisia japonica in the treatment of immune liver injury was systematically analyzed from the perspective of the biological metabolic network by using non-targeted metabolomics combined with biological network analysis tools. A rat model of acute immune hepatic injury was established by Concanavalin A (Con A) and the efficacy of the treatment of acute immune liver injury was judged by gavage of A. japonica. Liquid chromatography-mass spectrometry (LC-MS)-based plasma metabolomics was used to identify the key metabolites and metabolic pathways for the hepatoprotective effects of A. japonica. The results demonstrated that A. japonica reduced the levels of inflammatory parameters, decreased hepatic malondialdehyde levels, and enhanced hepatic antioxidant enzyme activity in animal experiments. The clustering of metabolomic samples showed significant separation in principal component analysis plots and the three groups in PLS-DA and OPLS-DA models could be clearly distinguished in multivariate statistical analysis. Among the 937 total metabolites, 445 metabolites were significantly different between the control and model groups, while 144 metabolites were identified as metabolites with differences between the model and administration groups, and a total of 39 differential metabolites were identified to affect the metabolic levels of the three groups. The differential metabolites were principally involved in the citric acid cycle, glutathione metabolism, vitamin B6 metabolism, and steroid hormone biosynthesis. This study found that A. japonica can significantly inhibit acute liver injury in rats, and exert a hepatoprotective effect through anti-inflammatory effect, inhibition of lipid peroxidation, improvement of the antioxidant defense system, and regulation of metabolites and related metabolic pathways. This study will provide a theoretical basis for the application of A. japonica in the treatment of the liver injury. Full article
(This article belongs to the Special Issue The Natural Products in the Treatment and Prevention of Diseases)
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16 pages, 1616 KiB  
Article
Identification of Exhaled Metabolites in Children with Cystic Fibrosis
by Ronja Weber, Nathan Perkins, Tobias Bruderer, Srdjan Micic and Alexander Moeller
Metabolites 2022, 12(10), 980; https://doi.org/10.3390/metabo12100980 - 17 Oct 2022
Cited by 5 | Viewed by 1752
Abstract
The early detection of inflammation and infection is important to prevent irreversible lung damage in cystic fibrosis. Novel and non-invasive monitoring tools would be of high benefit for the quality of life of patients. Our group previously detected over 100 exhaled mass-to-charge ( [...] Read more.
The early detection of inflammation and infection is important to prevent irreversible lung damage in cystic fibrosis. Novel and non-invasive monitoring tools would be of high benefit for the quality of life of patients. Our group previously detected over 100 exhaled mass-to-charge (m/z) features, using on-line secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS), which distinguish children with cystic fibrosis from healthy controls. The aim of this study was to annotate as many m/z features as possible with putative chemical structures. Compound identification was performed by applying a rigorous workflow, which included the analysis of on-line MS2 spectra and a literature comparison. A total of 49 discriminatory exhaled compounds were putatively identified. A group of compounds including glycolic acid, glyceric acid and xanthine were elevated in the cystic fibrosis group. A large group of acylcarnitines and aldehydes were found to be decreased in cystic fibrosis. The proposed compound identification workflow was used to identify signatures of volatile organic compounds that discriminate children with cystic fibrosis from healthy controls, which is the first step for future non-invasive and personalized applications. Full article
(This article belongs to the Special Issue Personalized Metabolomics)
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28 pages, 10922 KiB  
Systematic Review
The Cardiovascular Benefits and Infections Risk of SGLT2i versus Metformin in Type 2 Diabetes: A Systemic Review and Meta-Analysis
by Chunmei Xu, Liping He, Jing Zhang, Lusi Xu, Jianjun Dong and Lin Liao
Metabolites 2022, 12(10), 979; https://doi.org/10.3390/metabo12100979 - 17 Oct 2022
Cited by 3 | Viewed by 1801
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and metformin are both widely accepted anti-hyperglycemic agents. However, there is still no systematic review evaluating the cardiovascular benefits and risk of infections of SGLT2i versus metformin. To make that clear, we designed this study. Public databases, including [...] Read more.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and metformin are both widely accepted anti-hyperglycemic agents. However, there is still no systematic review evaluating the cardiovascular benefits and risk of infections of SGLT2i versus metformin. To make that clear, we designed this study. Public databases, including the Cochrane library database, PubMed, and Embase were searched for randomized clinical trials (RCTs) fitting the inclusion criteria. Two reviewers extracted the data and appraised the study quality independently. Thirteen RCTs enrolling 4189 patients were eligible for this analysis. Our results showed that compared with metformin, SGLT2i increased the risk of genitourinary tract infections (p < 0.00001). Further subgroup analysis suggested that the occurrence of urinary tract infections (UTI) was not statistically significant (p = 0.18), but the incidence of reproductive tract infections (RTI) was significantly increased in patients in the SGLT2i group compared with that in the metformin group (p < 0.00001). In addition, SGLT2i markedly decreased the levels of cardiovascular risk factor, including body weight, blood pressure, and triglyceride level, and significantly increased the HDL-cholesterol level (p < 0.00001) in patients versus that of metformin. For type 2 diabetes patients with obesity, SGLT2i was associated with more significant reductions in weight and blood pressure compared to metformin without an increased risk of genitourinary infections, and the reduction in fasting plasma glucose was superior in the SGLT2i group; the decrease in HbA1c was similar in both groups. Additionally, no significant publication bias was seen. Based on these findings, SGLT2i provided the similar antihyperglycemic effects, additional cardiovascular benefits, and a potential RTI risk compared with that of metformin. Our results indicate that SGLT2i is a good choice for those patients with metformin intolerance or resistance. Full article
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29 pages, 11282 KiB  
Article
Metabolomic Study of Urine from Workers Exposed to Low Concentrations of Benzene by UHPLC-ESI-QToF-MS Reveals Potential Biomarkers Associated with Oxidative Stress and Genotoxicity
by Michele P. R. Mendes, Maria José N. Paiva, Isabele C. Costa-Amaral, Leandro V. B. Carvalho, Victor O. Figueiredo, Eline S. Gonçalves, Ariane L. Larentis and Leiliane C. André
Metabolites 2022, 12(10), 978; https://doi.org/10.3390/metabo12100978 - 16 Oct 2022
Cited by 4 | Viewed by 1939
Abstract
Benzene is a human carcinogen whose exposure to concentrations below 1 ppm (3.19 mg·m−3) is associated with myelotoxic effects. The determination of biomarkers such as trans-trans muconic acid (AttM) and S-phenylmercapturic acid (SPMA) show exposure without reflecting the toxic effects [...] Read more.
Benzene is a human carcinogen whose exposure to concentrations below 1 ppm (3.19 mg·m−3) is associated with myelotoxic effects. The determination of biomarkers such as trans-trans muconic acid (AttM) and S-phenylmercapturic acid (SPMA) show exposure without reflecting the toxic effects of benzene. For this reason, in this study, the urinary metabolome of individuals exposed to low concentrations of benzene was investigated, with the aim of understanding the biological response to exposure to this xenobiotic and identifying metabolites correlated with the toxic effects induced by it. Ultra-efficient liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer (UHPLC-ESI-Q-ToF-MS) was used to identify metabolites in the urine of environmentally (n = 28) and occupationally exposed (n = 32) to benzene (mean of 22.1 μg·m−3 and 31.8 μg·m−3, respectively). Non-targeted metabolomics analysis by PLS-DA revealed nine urinary metabolites discriminating between groups and statistically correlated with oxidative damage (MDA, thiol) and genetic material (chromosomal aberrations) induced by the hydrocarbon. The analysis of metabolic pathways revealed important alterations in lipid metabolism. These results point to the involvement of alterations in lipid metabolism in the mechanisms of cytotoxic and genotoxic action of benzene. Furthermore, this study proves the potential of metabolomics to provide relevant information to understand the biological response to exposure to xenobiotics and identify early effect biomarkers. Full article
(This article belongs to the Section Environmental Metabolomics)
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18 pages, 3717 KiB  
Article
Integrated Lipidomic and Metabolomics Analysis Revealing the Effects of Frozen Storage Duration on Pork Lipids
by Xiaohui Feng, Jing Li, Longchao Zhang, Zhenghua Rao, Shengnan Feng, Yujiao Wang, Hai Liu and Qingshi Meng
Metabolites 2022, 12(10), 977; https://doi.org/10.3390/metabo12100977 - 16 Oct 2022
Cited by 4 | Viewed by 1952
Abstract
Frozen storage is an important strategy to maintain meat quality for long-term storage and transportation. Lipid oxidation is one of the predominant causes of the deterioration of meat quality during frozen storage. Untargeted lipidomic and targeted metabolomics were employed to comprehensively evaluate the [...] Read more.
Frozen storage is an important strategy to maintain meat quality for long-term storage and transportation. Lipid oxidation is one of the predominant causes of the deterioration of meat quality during frozen storage. Untargeted lipidomic and targeted metabolomics were employed to comprehensively evaluate the effect of frozen duration on pork lipid profiles and lipid oxidative products including free fatty acids and fatty aldehydes. A total of 688 lipids, 40 fatty acids and 14 aldehydes were successfully screened in a pork sample. We found that ether-linked glycerophospholipids, the predominant type of lipids, gradually decreased during frozen storage. Of these ether-linked glycerophospholipids, ether-linked phosphatidylethanolamine and phosphatidylcholine containing more than one unsaturated bond were greatly influenced by frozen storage, resulting in an increase in free polyunsaturated fatty acids and fatty aldehydes. Among these lipid oxidative products, decanal, cis-11,14-eicosenoic acid and cis-5,8,11,14,17-dicosapentaenoic acid can be considered as potential indicators to calculate the freezing time of unknown frozen pork samples. Moreover, over the three-month frozen storage, the first month was a rapid oxidation stage while the other two months were a slow oxidation stage. Full article
(This article belongs to the Section Nutrition and Metabolism)
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