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Metabolites, Volume 11, Issue 4 (April 2021) – 64 articles

Cover Story (view full-size image): Streptomyces bacteria produce numerous specialized metabolites with industrial and medicinal applications, and they contain many associated biosynthetic gene clusters (BGCs). However, the products of many such BGCs remain unknown as the associated metabolites are produced at either low levels or not at all under laboratory settings. Therefore, we overexpressed the ribosome-recycling factor, ribosomal protein S12, and three S12 variants in Streptomyces clavuligerus to enhance the production of such metabolites. Untargeted metabolomics, in combination with molecular networking and in silico structure prediction, alluded to 28 previously unreported metabolites from S. clavuligerus along with associated BGCs in some cases. Overall, the described strategy can help in the identification of candidate structures to aid novel natural product discovery endeavors. View this paper
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Review
Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment
Metabolites 2021, 11(4), 255; https://doi.org/10.3390/metabo11040255 - 20 Apr 2021
Cited by 14 | Viewed by 2105
Abstract
Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D’s role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs [...] Read more.
Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D’s role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs and systems in the human body. This growing interest is mostly due to the evidence that modest-to-severe vitamin D deficiency is widely prevalent around the world. There is broad agreement that optimal vitamin D status is necessary for bones, muscles, and one’s general health, as well as for the efficacy of antiresorptive and anabolic bone-forming treatments. Food supplementation with vitamin D, or the use of vitamin D supplements, are current strategies to improve vitamin D levels and treat deficiency. This article reviews consolidated and emerging concepts about vitamin D/hormone D metabolism, food sources, deficiency, as well as the different vitamin D supplements available, and current recommendations on the proper use of these compounds. Full article
(This article belongs to the Special Issue Vitamin D and Bone Metabolism)
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Systematic Review
The Barriers and Facilitators of Different Stakeholders When Deprescribing Benzodiazepine Receptor Agonists in Older Patients—A Systematic Review
Metabolites 2021, 11(4), 254; https://doi.org/10.3390/metabo11040254 - 20 Apr 2021
Cited by 2 | Viewed by 1239
Abstract
Treatment of older patients with benzodiazepines and Z-drugs (BZRA) is associated with an increased risk of side effects. However, this treatment is still used among these patients. Deprescribing can be a tool to reduce inappropriate medication. This review aims to identify and compare [...] Read more.
Treatment of older patients with benzodiazepines and Z-drugs (BZRA) is associated with an increased risk of side effects. However, this treatment is still used among these patients. Deprescribing can be a tool to reduce inappropriate medication. This review aims to identify and compare barriers and facilitators of stakeholders involved in BZRA deprescribing in older patients and uncover potential gaps in the research field. The search was conducted in PubMed, EMBASE, PsycINFO, and Cochrane Library. Ten articles based on qualitative data on BZRA deprescribing in older patients (≥65 years) published between 2005–2020 were included. Six articles referred to patients as stakeholders, two referred to physicians, and one to nurses and caregivers, respectively, indicating a need for more studies in the field. More barriers than facilitators were identified. Important findings were the patient willingness to deprescribe BZRA compared to physicians, who did not mention deprescribing to patients due to barriers such as expected patient resistance. Nurses mentioned barriers like lack of knowledge and the feeling that their options were not valued by physicians; education was found to be a shared deprescribing facilitator among the stakeholders. Being aware of deprescribing barriers and facilitators can be helpful in future successful deprescribing interventions. Full article
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Article
Streamlined Multimodal DESI and MALDI Mass Spectrometry Imaging on a Singular Dual-Source FT-ICR Mass Spectrometer
Metabolites 2021, 11(4), 253; https://doi.org/10.3390/metabo11040253 - 20 Apr 2021
Cited by 5 | Viewed by 1514
Abstract
The study of biological specimens by mass spectrometry imaging (MSI) has had a profound influence in the various forms of spatial-omics over the past two decades including applications for the identification of clinical biomarker analysis; the metabolic fingerprinting of disease states; treatment with [...] Read more.
The study of biological specimens by mass spectrometry imaging (MSI) has had a profound influence in the various forms of spatial-omics over the past two decades including applications for the identification of clinical biomarker analysis; the metabolic fingerprinting of disease states; treatment with therapeutics; and the profiling of lipids, peptides and proteins. No singular approach is able to globally map all biomolecular classes simultaneously. This led to the development of many complementary multimodal imaging approaches to solve analytical problems: fusing multiple ionization techniques, imaging microscopy or spectroscopy, or local extractions into robust multimodal imaging methods. However, each fusion typically requires the melding of analytical information from multiple commercial platforms, and the tandem utilization of multiple commercial or third-party software platforms—even in some cases requiring computer coding. Herein, we report the use of matrix-assisted laser desorption/ionization (MALDI) in tandem with desorption electrospray ionization (DESI) imaging in the positive ion mode on a singular commercial orthogonal dual-source Fourier transform ion cyclotron resonance (FT-ICR) instrument for the complementary detection of multiple analyte classes by MSI from tissue. The DESI source was 3D printed and the commercial Bruker Daltonics software suite was used to generate mass spectrometry images in tandem with the commercial MALDI source. This approach allows for the generation of multiple modes of mass spectrometry images without the need for third-party software and a customizable platform for ambient ionization imaging. Highlighted is the streamlined workflow needed to obtain phospholipid profiles, as well as increased depth of coverage of both annotated phospholipid, cardiolipin, and ganglioside species from rat brain with both high spatial and mass resolution. Full article
(This article belongs to the Special Issue Imaging Mass Spectrometry in Metabolome)
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Article
Association between Urinary Metabolites and the Exposure of Intensive Care Newborns to Plasticizers of Medical Devices Used for Their Care Management
Metabolites 2021, 11(4), 252; https://doi.org/10.3390/metabo11040252 - 19 Apr 2021
Cited by 3 | Viewed by 921
Abstract
Care management of newborns in the neonatal intensive care unit (NICU) requires numerous PVC (PolyVinyl Chloride) medical devices (MD) containing plasticizers that can migrate and contaminate the patient. We measured the magnitude of neonates’ exposure to plasticizers (di-ethylhexylphthalate (DEHP) and alternatives) in relation [...] Read more.
Care management of newborns in the neonatal intensive care unit (NICU) requires numerous PVC (PolyVinyl Chloride) medical devices (MD) containing plasticizers that can migrate and contaminate the patient. We measured the magnitude of neonates’ exposure to plasticizers (di-ethylhexylphthalate (DEHP) and alternatives) in relation to urinary concentrations of their metabolites. Plasticizers’ exposure was evaluated (1) by calculating the amounts of plasticizers prone to be released from each MD used for care management, and (2) by measuring the patients’ urinary levels of each plasticizers’ metabolites. 104 neonates were enrolled. They were exposed to di-isononylphthalate (DINP), especially via transfusion and infusion MD, and to DEHP via ECMO (Extra Corporeal Membrane Oxygenation) and respiratory assistance MD. Mean exposure doses exceeded the derived no-effect level of DINP and DEHP by a 10-fold and a 1000-fold factor. No PVC MD were plasticized with di-isononylcyclohexane-1,2-dicarboxylate (DINCH). High urinary concentrations of DEHP metabolites were directly correlated with DEHP exposure through ECMO MD. Urinary concentrations of DINP metabolites in transfused patients were also high. DINCH metabolites were found in urine, suggesting another route of exposure. Neonates in NICU are considerably exposed to plasticizers, with magnitudes varying with the type of MD used. The high exposure to DEHP and DINP leads to a risk of their metabolites’ toxicity. Full article
(This article belongs to the Special Issue Pharmaceutical Sciences and Metabolism)
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Review
Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment
Metabolites 2021, 11(4), 251; https://doi.org/10.3390/metabo11040251 - 18 Apr 2021
Cited by 13 | Viewed by 1735
Abstract
Asthma in children remains a significant public health challenge affecting 5–20% of children in Europe and is associated with increased morbidity and societal healthcare costs. The high variation in asthma incidence among countries may be attributed to differences in genetic susceptibility and environmental [...] Read more.
Asthma in children remains a significant public health challenge affecting 5–20% of children in Europe and is associated with increased morbidity and societal healthcare costs. The high variation in asthma incidence among countries may be attributed to differences in genetic susceptibility and environmental factors. This respiratory disorder is described as a heterogeneous syndrome of multiple clinical manifestations (phenotypes) with varying degrees of severity and airway hyper-responsiveness, which is based on patient symptoms, lung function and response to pharmacotherapy. However, an accurate diagnosis is often difficult due to diversities in clinical presentation. Therefore, identifying early diagnostic biomarkers and improving the monitoring of airway dysfunction and inflammatory through non-invasive methods are key goals in successful pediatric asthma management. Given that asthma is caused by the interaction between genes and environmental factors, an emerging approach, metabolomics—the systematic analysis of small molecules—can provide more insight into asthma pathophysiological mechanisms, enable the identification of early biomarkers and targeted personalized therapies, thus reducing disease burden and societal cost. The purpose of this review is to present evidence on the utility of metabolomics in pediatric asthma through the analysis of intermediate metabolites of biochemical pathways that involve carbohydrates, amino acids, lipids, organic acids and nucleotides and discuss their potential application in clinical practice. Also, current challenges on the integration of metabolomics in pediatric asthma management and needed next steps are critically discussed. Full article
(This article belongs to the Special Issue Metabolomics in the Identification of Biomarkers of Asthma)
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Article
Mass Spectrometry Imaging as a Tool to Investigate Region Specific Lipid Alterations in Symptomatic Human Carotid Atherosclerotic Plaques
Metabolites 2021, 11(4), 250; https://doi.org/10.3390/metabo11040250 - 18 Apr 2021
Cited by 2 | Viewed by 1203
Abstract
Atherosclerosis is characterized by fatty plaques in large and medium sized arteries. Their rupture can causes thrombi, occlusions of downstream vessels and adverse clinical events. The investigation of atherosclerotic plaques is made difficult by their highly heterogeneous nature. Here we propose a spatially [...] Read more.
Atherosclerosis is characterized by fatty plaques in large and medium sized arteries. Their rupture can causes thrombi, occlusions of downstream vessels and adverse clinical events. The investigation of atherosclerotic plaques is made difficult by their highly heterogeneous nature. Here we propose a spatially resolved approach based on matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to investigate lipids in specific regions of atherosclerotic plaques. The method was applied to a small dataset including symptomatic and asymptomatic human carotid atherosclerosis plaques. Tissue sections of symptomatic and asymptomatic human carotid atherosclerotic plaques were analyzed by MALDI mass spectrometry imaging (MALDI MSI) of lipids, and adjacent sections analyzed by histology and immunofluorescence. These multimodal datasets were used to compare the lipid profiles of specific histopathological regions within the plaque. The lipid profiles of macrophage-rich regions and intimal vascular smooth muscle cells exhibited the largest changes associated with plaque outcome. Macrophage-rich regions from symptomatic lesions were found to be enriched in sphingomyelins, and intimal vascular smooth muscle cells of symptomatic plaques were enriched in cholesterol and cholesteryl esters. The proposed method enabled the MALDI MSI analysis of specific regions of the atherosclerotic lesion, confirming MALDI MSI as a promising tool for the investigation of histologically heterogeneous atherosclerotic plaques. Full article
(This article belongs to the Special Issue Spatial Metabolomics)
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Article
Changes of Hematological and Hemorheological Parameters in Rabbits with Hypercholesterolemia
Metabolites 2021, 11(4), 249; https://doi.org/10.3390/metabo11040249 - 17 Apr 2021
Cited by 2 | Viewed by 835
Abstract
Hypercholesterolemia plays an important role in the development of atherosclerosis, leading to endothelial dysfunction, ischemic events, and increased mortality. Numerous studies suggest the pivotal role of rheological factors in the pathology of atherosclerosis. To get a more detailed hematological and hemorheological profile in [...] Read more.
Hypercholesterolemia plays an important role in the development of atherosclerosis, leading to endothelial dysfunction, ischemic events, and increased mortality. Numerous studies suggest the pivotal role of rheological factors in the pathology of atherosclerosis. To get a more detailed hematological and hemorheological profile in hypercholesterolemia, we carried out an experiment on rabbits. Animals were divided into two groups: the control group (Control) was kept on normal rabbit chow, the high-cholesterol diet group (HC) was fed with special increased cholesterol-containing food. Hematological parameters (Sysmex K-4500 automate), whole blood and plasma viscosity (Hevimet-40 capillary viscometer), red blood cell (RBC) aggregation (Myrenne MA-1 aggregometer), deformability and mechanical stability (LoRRca MaxSis Osmoscan ektacytometer) were tested. The white blood cell and platelet count, mean corpuscular volume, and mean corpuscular hemoglobin were significantly higher in the HC group, while the RBC count, hemoglobin, and hematocrit values were lower than the Control data. Viscosity values corrected to 40% hematocrit were higher in the HC group. The RBC aggregation significantly increased in the HC vs. the Control. The HC group showed significantly worse results both in RBCs’ deformability and membrane stability. In conclusion, the atherogenic diet worsens the hematological and macro- and micro-rheological parameters, affecting blood flow properties and microcirculation. Full article
(This article belongs to the Special Issue Hemorheology and Metabolism)
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Article
Identification and Reproducibility of Urinary Metabolomic Biomarkers of Habitual Food Intake in a Cross-Sectional Analysis of the Cancer Prevention Study-3 Diet Assessment Sub-Study
Metabolites 2021, 11(4), 248; https://doi.org/10.3390/metabo11040248 - 17 Apr 2021
Cited by 1 | Viewed by 872
Abstract
Previous cross-sectional metabolomics studies have identified many potential dietary biomarkers, mostly in blood. Few studies examined urine samples although urine is preferred for dietary biomarker discovery. Furthermore, little is known regarding the reproducibility of urinary metabolomic biomarkers over time. We aimed to identify [...] Read more.
Previous cross-sectional metabolomics studies have identified many potential dietary biomarkers, mostly in blood. Few studies examined urine samples although urine is preferred for dietary biomarker discovery. Furthermore, little is known regarding the reproducibility of urinary metabolomic biomarkers over time. We aimed to identify urinary metabolomic biomarkers of diet and assess their reproducibility over time. We conducted a metabolomics analysis among 648 racially/ethnically diverse men and women in the Diet Assessment Sub-study of the Cancer Prevention Study-3 cohort to examine the correlation between >100 food groups/items [101 by a food frequency questionnaire (FFQ), and 105 by repeated 24 h diet recalls (24HRs)] and 1391 metabolites measured in 24 h urine sample replicates, six months apart. Diet–metabolite associations were examined by Pearson’s partial correlation analysis. Biomarkers were evaluated for prediction accuracy assessed using area under the curve (AUC) calculated from the receiver operating characteristic curve and for reproducibility assessed using intraclass correlation coefficients (ICCs). A total of 1708 diet–metabolite associations were identified after Bonferroni correction for multiple comparisons and restricting correlation coefficients to >0.2 or <−0.2 (1570 associations using the FFQ and 933 using 24HRs), 513 unique metabolites correlated with 79 food groups/items. The median ICCs of the 513 putative biomarkers was 0.53 (interquartile range 0.42–0.62). In this study, with comprehensive dietary data and repeated 24 h urinary metabolic profiles, we identified a large number of diet–metabolite correlations and replicated many found in previous studies. Our findings revealed the promise of urine samples for dietary biomarker discovery in a large cohort study and provide important information on biomarker reproducibility, which could facilitate their utilization in future clinical and epidemiological studies. Full article
(This article belongs to the Special Issue Nutritional Metabolomics)
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Article
Improved Bone Quality and Bone Healing of Dystrophic Mice by Parabiosis
Metabolites 2021, 11(4), 247; https://doi.org/10.3390/metabo11040247 - 16 Apr 2021
Viewed by 1012
Abstract
Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression in the sarcolemma of muscle fibers. DMD patients acquire bone abnormalities including osteopenia, fragility fractures, and scoliosis indicating a deficiency in skeletal homeostasis. The dKO (dystrophin/Utrophin double [...] Read more.
Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression in the sarcolemma of muscle fibers. DMD patients acquire bone abnormalities including osteopenia, fragility fractures, and scoliosis indicating a deficiency in skeletal homeostasis. The dKO (dystrophin/Utrophin double knockout) is a more severe mouse model of DMD than the mdx mouse (dystrophin deficient), and display numerous clinically-relevant manifestations, including a spectrum of degenerative changes outside skeletal muscle including bone, articular cartilage, and intervertebral discs. To examine the influence of systemic factors on the bone abnormalities and healing in DMD, parabiotic pairing between dKO mice and mdx mice was established. Notably, heterochronic parabiosis with young mdx mice significantly increased bone mass and improved bone micro-structure in old dKO-hetero mice, which showed progressive bone deterioration. Furthermore, heterochronic parabiosis with WT C56/10J mice significantly improved tibia bone defect healing in dKO-homo mice. These results suggest that systemic blood-borne factor(s) and/or progenitors from WT and young mdx mice can influence the bone deficiencies in dKO mice. Understanding these circulating factors or progenitor cells that are responsible to alleviate the bone abnormalities in dKO mice after heterochronic parabiosis might be useful for the management of poor bone health in DMD. Full article
(This article belongs to the Special Issue Sports and Health Metabolism)
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Article
Metabolic Mechanism of Plant Defense against Rice Blast Induced by Probenazole
Metabolites 2021, 11(4), 246; https://doi.org/10.3390/metabo11040246 - 16 Apr 2021
Cited by 2 | Viewed by 999
Abstract
The probenazole fungicide is used for controlling rice blast (Magnaporthe grisea) primarily by inducing disease resistance of the plant. To investigate the mechanism of induced plant defense, rice seedlings were treated with probenazole at 15 days post emergence, and non-treated plants [...] Read more.
The probenazole fungicide is used for controlling rice blast (Magnaporthe grisea) primarily by inducing disease resistance of the plant. To investigate the mechanism of induced plant defense, rice seedlings were treated with probenazole at 15 days post emergence, and non-treated plants were used for the control. The plants were infected with M. grisea 5 days after chemical treatment and incubated in a greenhouse. After 7 days, rice seedlings were sampled. The metabolome of rice seedlings was chemically extracted and analyzed using gas chromatography and mass spectrum (GC-MS). The GC-MS data were processed using analysis of variance (ANOVA), principal component analysis (PCA) and metabolic pathway elucidation. Results showed that probenazole application significantly affected the metabolic profile of rice seedlings, and the effect was proportionally leveraged with the increase of probenazole concentration. Probenazole resulted in a change of 54 metabolites. Salicylic acid, γ-aminobutyrate, shikimate and several other primary metabolites related to plant resistance were significantly up-regulated and some metabolites such as phenylalanine, valine and proline were down-regulated in probenazole-treated seedlings. These results revealed a metabolic pathway of rice seedlings induced by probenazole treatment regarding the resistance to M. grisea infection. Full article
(This article belongs to the Special Issue Metabolomics in Plant Defence)
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Article
Urinary Metabolites Enable Differential Diagnosis and Therapeutic Monitoring of Pediatric Inflammatory Bowel Disease
Metabolites 2021, 11(4), 245; https://doi.org/10.3390/metabo11040245 - 15 Apr 2021
Cited by 4 | Viewed by 1512
Abstract
Rates of pediatric Crohn’s disease (CD) and ulcerative colitis (UC) are increasing globally. Differentiation of these inflammatory bowel disease (IBD) subtypes however can be challenging when relying on invasive endoscopic approaches. We sought to identify urinary metabolic signatures of pediatric IBD at diagnosis, [...] Read more.
Rates of pediatric Crohn’s disease (CD) and ulcerative colitis (UC) are increasing globally. Differentiation of these inflammatory bowel disease (IBD) subtypes however can be challenging when relying on invasive endoscopic approaches. We sought to identify urinary metabolic signatures of pediatric IBD at diagnosis, and during induction treatment. Nontargeted metabolite profiling of urine samples from CD (n = 18) and UC (n = 8) in a pediatric retrospective cohort study was performed using multisegment injection-capillary electrophoresis-mass spectrometry. Over 122 urinary metabolites were reliably measured from pediatric IBD patients, and unknown metabolites were identified by tandem mass spectrometry. Dynamic changes in sum-normalized urinary metabolites were also monitored following exclusive enteral nutrition (EEN) or corticosteroid therapy (CS) in repeat urine samples collected over 8 weeks. Higher urinary excretion of indoxyl sulfate, hydroxyindoxyl sulfate, phenylacetylglutamine, and sialic acid were measured in CD as compared to UC patients, but lower threonine, serine, kynurenine, and hypoxanthine (p < 0.05). Excellent discrimination of CD from UC was achieved based on the urinary serine:indoxylsulfate ratio (AUC = 0.972; p = 3.21 × 10−5). Urinary octanoyl glucuronide, pantothenic acid, and pyridoxic acid were also identified as specific dietary biomarkers of EEN in pediatric IBD patients who achieved clinical remission. This work may complement or replace existing strategies in the diagnosis and early management of children with IBD. Full article
(This article belongs to the Section Metabolomic Profiling Technology)
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Article
Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers
Metabolites 2021, 11(4), 244; https://doi.org/10.3390/metabo11040244 - 15 Apr 2021
Cited by 19 | Viewed by 2199
Abstract
The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups [...] Read more.
The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO2, being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Obituary
Obituary for Professor Dr. Jan Evangelista Dyr
Metabolites 2021, 11(4), 243; https://doi.org/10.3390/metabo11040243 - 15 Apr 2021
Viewed by 650
(This article belongs to the Special Issue Thrombosis and Metabolism)
Review
Presence and Implications of Sarcopenia in Non-alcoholic Steatohepatitis
Metabolites 2021, 11(4), 242; https://doi.org/10.3390/metabo11040242 - 15 Apr 2021
Cited by 2 | Viewed by 1081
Abstract
Sarcopenia, defined as the loss of muscle strength, mass, and functionality, confers a poor prognosis in the setting of cirrhosis. Given its clinical significance, a better understanding of the underlying mechanisms leading to cirrhosis, sarcopenia, and their co-occurrence may improve these patients’ outcomes. [...] Read more.
Sarcopenia, defined as the loss of muscle strength, mass, and functionality, confers a poor prognosis in the setting of cirrhosis. Given its clinical significance, a better understanding of the underlying mechanisms leading to cirrhosis, sarcopenia, and their co-occurrence may improve these patients’ outcomes. Non-alcoholic steatohepatitis (NASH) shares many of the same etiologies as sarcopenia, including insulin resistance, chronic inflammation, and ectopic adipocyte deposition, which are hallmarks of metabolic syndrome (MS). NASH thus serves as a prime candidate for further exploration into the underlying pathophysiology and relationship between these three conditions. In this review, we discuss the natural history of NASH and sarcopenia, explore the interplay between these conditions in the scope of MS, and seek to better define how an assessment of muscle mass, strength, and functionality in this population is key to improved diagnosis and management of patients with sarcopenia and NASH. Full article
(This article belongs to the Special Issue Steroids in Non-alcoholic Fatty Liver Disease)
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Article
Lipidomics-Based Comparison of Molecular Compositions of Green, Yellow, and Red Bell Peppers
Metabolites 2021, 11(4), 241; https://doi.org/10.3390/metabo11040241 - 14 Apr 2021
Cited by 5 | Viewed by 1041
Abstract
Identifying and annotating the molecular composition of individual foods will improve scientific understanding of how foods impact human health and how much variation exists in the molecular composition of foods of the same species. The complexity of this task includes distinct varieties and [...] Read more.
Identifying and annotating the molecular composition of individual foods will improve scientific understanding of how foods impact human health and how much variation exists in the molecular composition of foods of the same species. The complexity of this task includes distinct varieties and variations in natural occurring pigments of foods. Lipidomics, a sub-field of metabolomics, has emerged as an effective tool to help decipher the molecular composition of foods. For this proof-of-principle research, we determined the lipidomic profiles of green, yellow and red bell peppers (Capsicum annuum) using liquid chromatography mass spectrometry and a novel tool for automated annotation of compounds following database searches. Among 23 samples analyzed from 6 peppers (2 green, 1 yellow, and 3 red), over 8000 lipid compounds were detected with 315 compounds (106 annotated) found in all three colors. Assessments of relationships between these compounds and pepper color, using linear mixed effects regression and false discovery rate (<0.05) statistical adjustment, revealed 11 compounds differing by color. The compound most strongly associated with color was the carotenoid, β-cryptoxanthin (p-value = 7.4 × 10−5; FDR adjusted p-value = 0.0080). These results support lipidomics as a viable analytical technique to identify molecular compounds that can be used for unique characterization of foods. Full article
(This article belongs to the Special Issue Metabolomic Analysis in Food Science)
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Article
Integrated Metabolomics and Transcriptomics Using an Optimised Dual Extraction Process to Study Human Brain Cancer Cells and Tissues
Metabolites 2021, 11(4), 240; https://doi.org/10.3390/metabo11040240 - 14 Apr 2021
Viewed by 1179
Abstract
The integration of untargeted metabolomics and transcriptomics from the same population of cells or tissue enhances the confidence in the identified metabolic pathways and understanding of the enzyme–metabolite relationship. Here, we optimised a simultaneous extraction method of metabolites/lipids and RNA from ependymoma cells [...] Read more.
The integration of untargeted metabolomics and transcriptomics from the same population of cells or tissue enhances the confidence in the identified metabolic pathways and understanding of the enzyme–metabolite relationship. Here, we optimised a simultaneous extraction method of metabolites/lipids and RNA from ependymoma cells (BXD-1425). Relative to established RNA (mirVana kit) or metabolite (sequential solvent addition and shaking) single extraction methods, four dual-extraction techniques were evaluated and compared (methanol:water:chloroform ratios): cryomill/mirVana (1:1:2); cryomill-wash/Econospin (5:1:2); rotation/phenol-chloroform (9:10:1); Sequential/mirVana (1:1:3). All methods extracted the same metabolites, yet rotation/phenol-chloroform did not extract lipids. Cryomill/mirVana and sequential/mirVana recovered the highest amounts of RNA, at 70 and 68% of that recovered with mirVana kit alone. sequential/mirVana, involving RNA extraction from the interphase of our established sequential solvent addition and shaking metabolomics-lipidomics extraction method, was the most efficient approach overall. Sequential/mirVana was applied to study a) the biological effect caused by acute serum starvation in BXD-1425 cells and b) primary ependymoma tumour tissue. We found (a) 64 differentially abundant metabolites and 28 differentially expressed metabolic genes, discovering four gene-metabolite interactions, and (b) all metabolites and 62% lipids were above the limit of detection, and RNA yield was sufficient for transcriptomics, in just 10 mg of tissue. Full article
(This article belongs to the Special Issue Metabolomics Methodologies and Applications II)
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Article
Specialized Metabolites from Ribosome Engineered Strains of Streptomyces clavuligerus
Metabolites 2021, 11(4), 239; https://doi.org/10.3390/metabo11040239 - 13 Apr 2021
Cited by 2 | Viewed by 1669
Abstract
Bacterial specialized metabolites are of immense importance because of their medicinal, industrial, and agricultural applications. Streptomyces clavuligerus is a known producer of such compounds; however, much of its metabolic potential remains unknown, as many associated biosynthetic gene clusters are silent or expressed at [...] Read more.
Bacterial specialized metabolites are of immense importance because of their medicinal, industrial, and agricultural applications. Streptomyces clavuligerus is a known producer of such compounds; however, much of its metabolic potential remains unknown, as many associated biosynthetic gene clusters are silent or expressed at low levels. The overexpression of ribosome recycling factor (frr) and ribosome engineering (induced rpsL mutations) in other Streptomyces spp. has been reported to increase the production of known specialized metabolites. Therefore, we used an overexpression strategy in combination with untargeted metabolomics, molecular networking, and in silico analysis to annotate 28 metabolites in the current study, which have not been reported previously in S. clavuligerus. Many of the newly described metabolites are commonly found in plants, further alluding to the ability of S. clavuligerus to produce such compounds under specific conditions. In addition, the manipulation of frr and rpsL led to different metabolite production profiles in most cases. Known and putative gene clusters associated with the production of the observed compounds are also discussed. This work suggests that the combination of traditional strain engineering and recently developed metabolomics technologies together can provide rapid and cost-effective strategies to further speed up the discovery of novel natural products. Full article
(This article belongs to the Section Cell Metabolism)
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A Medicago truncatula Metabolite Atlas Enables the Visualization of Differential Accumulation of Metabolites in Root Tissues
Metabolites 2021, 11(4), 238; https://doi.org/10.3390/metabo11040238 - 13 Apr 2021
Viewed by 1175
Abstract
Plant roots are composed of many differentiated tissue types, with each tissue exhibiting differential quantitative and qualitative accumulation of metabolites. The large-scale nontargeted metabolite profiles of these differentiated tissues are complex, which complicates the interpretation and development of hypotheses relative to the biological [...] Read more.
Plant roots are composed of many differentiated tissue types, with each tissue exhibiting differential quantitative and qualitative accumulation of metabolites. The large-scale nontargeted metabolite profiles of these differentiated tissues are complex, which complicates the interpretation and development of hypotheses relative to the biological roles of differentially localized metabolites. Thus, we created a data visualization tool to aid in the visualization and understanding of differential metabolite accumulations in Medicago truncatula roots. This was achieved through the development of the Medicago truncatula Metabolite Atlas based upon an adaptation of the Arabidopsis Electronic Fluorescent Pictograph (eFP) Browser. Medicago truncatula roots were dissected into border cells, root cap, elongation zone, mature root, and root secretions. Each tissue was then analyzed by UHPLC-QTOF-MS and GC-Q-MS. Data were uploaded into a MySQL database and displayed in the Medicago truncatula Metabolite Atlas. The data revealed unique differential spatial localization of many metabolites, some of which are discussed here. Ultimately, the Medicago truncatula Metabolite Atlas compiles metabolite data into a singular, useful, and publicly available web-based tool that enables the visualization and understanding of differential metabolite accumulation and spatial localization. Full article
(This article belongs to the Special Issue Plant Metabolomics II)
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Article
Improved One-Class Modeling of High-Dimensional Metabolomics Data via Eigenvalue-Shrinkage
Metabolites 2021, 11(4), 237; https://doi.org/10.3390/metabo11040237 - 13 Apr 2021
Cited by 1 | Viewed by 1123
Abstract
One-class modelling is a useful approach in metabolomics for the untargeted detection of abnormal metabolite profiles, when information from a set of reference observations is available to model “normal” or baseline metabolite profiles. Such outlying profiles are typically identified by comparing the distance [...] Read more.
One-class modelling is a useful approach in metabolomics for the untargeted detection of abnormal metabolite profiles, when information from a set of reference observations is available to model “normal” or baseline metabolite profiles. Such outlying profiles are typically identified by comparing the distance between an observation and the reference class to a critical limit. Often, multivariate distance measures such as the Mahalanobis distance (MD) or principal component-based measures are used. These approaches, however, are either not applicable to untargeted metabolomics data, or their results are unreliable. In this paper, five distance measures for one-class modeling in untargeted metabolites are proposed. They are based on a combination of the MD and five so-called eigenvalue-shrinkage estimators of the covariance matrix of the reference class. A simple cross-validation procedure is proposed to set the critical limit for outlier detection. Simulation studies are used to identify which distance measure provides the best performance for one-class modeling, in terms of type I error and power to identify abnormal metabolite profiles. Empirical evidence demonstrates that this method has better type I error (false positive rate) and improved outlier detection power than the standard (principal component-based) one-class models. The method is illustrated by its application to liquid chromatography coupled to mass spectrometry (LC-MS) and nuclear magnetic response spectroscopy (NMR) untargeted metabolomics data from two studies on food safety assessment and diagnosis of rare diseases, respectively. Full article
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Article
Metabolite Profile of Treatment-Naive Metabolic Syndrome Subjects in Relation to Cardiovascular Disease Risk
Metabolites 2021, 11(4), 236; https://doi.org/10.3390/metabo11040236 - 13 Apr 2021
Cited by 3 | Viewed by 959
Abstract
Metabolic syndrome (MetSyn) is an important risk factor for type 2 diabetes and cardiovascular diseases (CVD). This study aimed to find distinct plasma metabolite profiles between insulin-resistant and non-insulin resistant subjects with MetSyn and evaluate if MetSyn metabolite profiles are related to CVD [...] Read more.
Metabolic syndrome (MetSyn) is an important risk factor for type 2 diabetes and cardiovascular diseases (CVD). This study aimed to find distinct plasma metabolite profiles between insulin-resistant and non-insulin resistant subjects with MetSyn and evaluate if MetSyn metabolite profiles are related to CVD risk and lipid fluxes. In a cross-sectional study, untargeted metabolomics of treatment-naive males with MetSyn (n = 132) were analyzed together with clinical parameters. In a subset of MetSyn participants, CVD risk was calculated using the Framingham score (n = 111), and lipolysis (n = 39) was measured by a two-step hyperinsulinemic euglycemic clamp using [1,1,2,3,3-2H5] glycerol to calculate lipolysis suppression rates. Peripheral insulin resistance was related to fatty acid metabolism and glycerolphosphorylcholine. Interestingly, although insulin resistance is considered to be a risk factor for CVD, we observed that there was little correspondence between metabolites associated with insulin resistance and metabolites associated with CVD risk. The latter mainly belonged to the androgenic steroid, fatty acid, phosphatidylethanolamine, and phophatidylcholine pathways. These data provide new insights into metabolic changes in mild MetSyn pathophysiology and MetSyn CVD risk related to lipid metabolism. Prospective studies may focus on the pathophysiological role of the here-identified biomarkers. Full article
(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)
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Article
Modeling Between-Subject Variability in Subcutaneous Absorption of a Fast-Acting Insulin Analogue by a Nonlinear Mixed Effects Approach
Metabolites 2021, 11(4), 235; https://doi.org/10.3390/metabo11040235 - 12 Apr 2021
Cited by 4 | Viewed by 989
Abstract
Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective [...] Read more.
Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective dosing and timing of the administration process. In this work, we present a nonlinear mixed effects model describing the between-subject variability observed in the subcutaneous absorption of fast-acting insulin. A set of 14 different models was identified on a large and frequently-sampled database of lispro pharmacokinetic data, collected from 116 subjects with type 1 diabetes. The tested models were compared, and the best one was selected on the basis of the ability to fit the data, the precision of the estimated parameters, and parsimony criteria. The selected model was able to accurately describe the typical trend of plasma insulin kinetics, as well as the between-subject variability present in the absorption process, which was found to be related to the subject’s body mass index. The model provided a deeper understanding of the insulin absorption process and can be incorporated into simulation platforms to test and develop new open- and closed-loop treatment strategies, allowing a step forward toward personalized insulin therapy. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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Article
Targeted Metabolic Profiles of the Leaves and Xylem Sap of Two Sugarcane Genotypes Infected with the Vascular Bacterial Pathogen Leifsonia xyli subsp. xyli
Metabolites 2021, 11(4), 234; https://doi.org/10.3390/metabo11040234 - 12 Apr 2021
Cited by 1 | Viewed by 934
Abstract
Ratoon stunt (RS) is a worldwide disease that reduces biomass up to 80% and is caused by the xylem-dwelling bacterium Leifsonia xyli subsp. xyli. This study identified discriminant metabolites between a resistant (R) and a susceptible (S) sugarcane variety at the early [...] Read more.
Ratoon stunt (RS) is a worldwide disease that reduces biomass up to 80% and is caused by the xylem-dwelling bacterium Leifsonia xyli subsp. xyli. This study identified discriminant metabolites between a resistant (R) and a susceptible (S) sugarcane variety at the early stages of pathogen colonization (30 and 120 days after inoculation—DAI) by untargeted and targeted metabolomics of leaves and xylem sap using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. Bacterial titers were quantified in sugarcane extracts at 180 DAI through real-time polymerase chain reaction. Bacterial titers were at least four times higher on the S variety than in the R one. Global profiling detected 514 features in the leaves and 68 in the sap, while 119 metabolites were quantified in the leaves and 28 in the sap by targeted metabolomics. Comparisons between mock-inoculated treatments indicated a greater abundance of amino acids in the leaves of the S variety and of phenolics, flavonoids, and salicylic acid in the R one. In the xylem sap, fewer differences were detected among phenolics and flavonoids, but also included higher abundances of the signaling molecule sorbitol and glycerol in R. Metabolic changes in the leaves following pathogen inoculation were detected earlier in R than in S and were mostly related to amino acids in R and to phosphorylated compounds in S. Differentially represented metabolites in the xylem sap included abscisic acid. The data represent a valuable resource of potential biomarkers for metabolite-assisted selection of resistant varieties to RS. Full article
(This article belongs to the Special Issue Metabolomics in Plant Defence)
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Review
Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics
Metabolites 2021, 11(4), 233; https://doi.org/10.3390/metabo11040233 - 10 Apr 2021
Cited by 2 | Viewed by 1328
Abstract
Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and [...] Read more.
Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodevelopmental and neurodegenerative disorders resulting in altered neurometabolic coupling. With the advent of mass spectrometry (MS) technology, MS-based metabolomics provides an emerging mechanistic understanding of their global and dynamic metabolic signatures. In this review, we discuss the pathogenetic causes of mitochondrial metabolic disorders and the recent MS-based metabolomic advances on their metabolomic remodeling. We conclude by exploring the MS-based metabolomic functional insights into their biosignatures to improve diagnostic platforms, stratify patients, and design novel targeted therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of Metabolism in Brain Diseases)
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Article
First Genome-Scale Metabolic Model of Dolosigranulum pigrum Confirms Multiple Auxotrophies
Metabolites 2021, 11(4), 232; https://doi.org/10.3390/metabo11040232 - 09 Apr 2021
Cited by 4 | Viewed by 1998
Abstract
Dolosigranulum pigrum is a quite recently discovered Gram-positive coccus. It has gained increasing attention due to its negative correlation with Staphylococcus aureus, which is one of the most successful modern pathogens causing severe infections with tremendous morbidity and mortality due to its [...] Read more.
Dolosigranulum pigrum is a quite recently discovered Gram-positive coccus. It has gained increasing attention due to its negative correlation with Staphylococcus aureus, which is one of the most successful modern pathogens causing severe infections with tremendous morbidity and mortality due to its multiple resistances. As the possible mechanisms behind its inhibition of S. aureus remain unclear, a genome-scale metabolic model (GEM) is of enormous interest and high importance to better study its role in this fight. This article presents the first GEM of D. pigrum, which was curated using automated reconstruction tools and extensive manual curation steps to yield a high-quality GEM. It was evaluated and validated using all currently available experimental data of D. pigrum. With this model, already predicted auxotrophies and biosynthetic pathways could be verified. The model was used to define a minimal medium for further laboratory experiments and to predict various carbon sources’ growth capacities. This model will pave the way to better understand D. pigrum’s role in the fight against S. aureus. Full article
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Article
Profile of Stilbenes and Other Phenolics in Fanagoria White and Red Russian Wines
Metabolites 2021, 11(4), 231; https://doi.org/10.3390/metabo11040231 - 09 Apr 2021
Cited by 4 | Viewed by 809
Abstract
Grapes and wines represent the most important source of edible stilbenes and other phenolic metabolites, which demonstrate a wide range of valuable biological activities. However, there is no information about the profile and content of phenolic compounds in Russian wines. We firstly analyzed [...] Read more.
Grapes and wines represent the most important source of edible stilbenes and other phenolic metabolites, which demonstrate a wide range of valuable biological activities. However, there is no information about the profile and content of phenolic compounds in Russian wines. We firstly analyzed phenolics (stilbenes, phenolic acids, and flavonols) in some representatives of Russian wines, including eleven red and seven white Russian wines from Fanagoria, Krasnodarsky Territory. The Russian red wines contained six stilbenes (trans-resveratrol, cis-resveratrol, trans-, cis-piceid, trans-piceatannol, δ-viniferin), while the white wines contained only five stilbenes (cis-resveratrol, trans-, cis-piceid, trans-piceatannol, trans-resveratrol). More than a half of the total stilbenes in the wines (65% of all stilbenes) were presented by trans-piceid and cis-piceid, while trans-resveratrol reached 16% of all the stilbenes. The red wines also contained six phenolic acids and six flavonols, while the white wines contained six phenolic acids and only three flavonols. Myrecitin-3-O-glucoside, quercetin-3-O-glucoside, and myricetin were the major flavonols in the red wines, while dihydroquercetin-3-O-rhamnoside was the major flavonol in the white wines. The red wines contained markedly higher amounts of stilbenes, phenolic acids, and flavonols than the white wines. Thus, the data showed that young red Russian Fanagoria wines represent a rich source of phenolic compounds. The study also revealed that younger wines were more abundant in phenolics, and wine storage for six months in the dark at +10 °C led to a decrease in the total content of phenolics, primarily monomeric stilbenes and quercetin-3-O-glucoside and quercetin flavonols. Full article
(This article belongs to the Special Issue Grape and Wine Metabolome Analysis)
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Article
Metabolic Profile Discriminates and Predicts Arabidopsis Susceptibility to Virus under Field Conditions
Metabolites 2021, 11(4), 230; https://doi.org/10.3390/metabo11040230 - 09 Apr 2021
Cited by 1 | Viewed by 912
Abstract
As obligatory parasites, plant viruses alter host cellular metabolism. There is a lack of information on the variability of virus-induced metabolic responses among genetically diverse plants in a natural context with daily changing conditions. To decipher the metabolic landscape of plant-virus interactions in [...] Read more.
As obligatory parasites, plant viruses alter host cellular metabolism. There is a lack of information on the variability of virus-induced metabolic responses among genetically diverse plants in a natural context with daily changing conditions. To decipher the metabolic landscape of plant-virus interactions in a natural setting, twenty-six and ten accessions of Arabidopsis thaliana were inoculated with Turnip mosaic virus (TuMV), in two field experiments over 2 years. The accessions were measured for viral accumulation, above-ground biomass, targeted and untargeted metabolic profiles. The phenotypes of the accessions ranged from susceptibility to resistance. Susceptible and resistant accessions were shown to have different metabolic routes after inoculation. Susceptible genotypes accumulate primary and secondary metabolites upon infection, at the cost of hindered growth. Twenty-one metabolic signatures significantly accumulated in resistant accessions whereas they maintained their growth as mock-inoculated plants without biomass penalty. Metabolic content was demonstrated to discriminate and be highly predictive of the susceptibility of inoculated Arabidopsis. This study is the first to describe the metabolic landscape of plant-virus interactions in a natural setting and its predictive link to susceptibility. It provides new insights on plant-virus interactions. In this undomesticated species and in ecologically realistic conditions, growth and resistance are in a permanent conversation. Full article
(This article belongs to the Special Issue Metabolomics in Plant Defence)
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Erratum
Erratum: Romero-Lopez et al. Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats. Metabolites 2021, 11, 177
Metabolites 2021, 11(4), 229; https://doi.org/10.3390/metabo11040229 - 09 Apr 2021
Viewed by 540
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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Article
Plasma Metabolome and Lipidome Associations with Type 2 Diabetes and Diabetic Nephropathy
Metabolites 2021, 11(4), 228; https://doi.org/10.3390/metabo11040228 - 08 Apr 2021
Cited by 4 | Viewed by 1384
Abstract
We conducted untargeted metabolomics analysis of plasma samples from a cross-sectional case–control study with 30 healthy controls, 30 patients with diabetes mellitus and normal renal function (DM-N), and 30 early diabetic nephropathy (DKD) patients using liquid chromatography-mass spectrometry (LC-MS). We employed two different [...] Read more.
We conducted untargeted metabolomics analysis of plasma samples from a cross-sectional case–control study with 30 healthy controls, 30 patients with diabetes mellitus and normal renal function (DM-N), and 30 early diabetic nephropathy (DKD) patients using liquid chromatography-mass spectrometry (LC-MS). We employed two different modes of MS acquisition on a high-resolution MS instrument for identification and semi-quantification, and analyzed data using an advanced multivariate method for prioritizing differentially abundant metabolites. We obtained semi-quantification data for 1088 unique compounds (~55% lipids), excluding compounds that may be either exogenous compounds or treated as medication. Supervised classification analysis over a confounding-free partial correlation network shows that prostaglandins, phospholipids, nucleotides, sugars, and glycans are elevated in the DM-N and DKD patients, whereas glutamine, phenylacetylglutamine, 3-indoxyl sulfate, acetylphenylalanine, xanthine, dimethyluric acid, and asymmetric dimethylarginine are increased in DKD compared to DM-N. The data recapitulate the well-established plasma metabolome changes associated with DM-N and suggest uremic solutes and oxidative stress markers as the compounds indicating early renal function decline in DM patients. Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Lipidomics)
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Article
Pinus pinaster Early Hormonal Defence Responses to Pinewood Nematode (Bursaphelenchus xylophilus) Infection
Metabolites 2021, 11(4), 227; https://doi.org/10.3390/metabo11040227 - 08 Apr 2021
Cited by 4 | Viewed by 1131
Abstract
The pinewood nematode (PWN) is the causal agent of pine wilt disease, a pathology that affects conifer forests, mainly Pinus spp. PWN infection can induce the expression of phytohormone-related genes; however, changes at the early phytohormone level have not yet been explored. Phytohormones [...] Read more.
The pinewood nematode (PWN) is the causal agent of pine wilt disease, a pathology that affects conifer forests, mainly Pinus spp. PWN infection can induce the expression of phytohormone-related genes; however, changes at the early phytohormone level have not yet been explored. Phytohormones are low-abundance metabolites, and thus, difficult to quantify. Moreover, most methodologies focus mainly on Arabidopsis or crop species. This work aimed to validate a fast (run time 6.6 min) liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS/MS) analytical method to quantify 14 phytohormones in Pinus pinaster stem tissues. This method was further applied to evaluate, for the first time, early phytohormone changes in susceptible and resistant phenotypes of P. pinaster 24, 48 and 72 h after inoculation (HAI) with PWN. A significant increase in salicylic acid (SA, 48 and 72 HAI) and jasmonic acid methyl ester (JA-ME, 72 HAI) was observed in susceptible phenotypes. Results indicate that the higher susceptibility of P. pinaster to PWN infection might result from an inefficient trigger of hypersensitive responses, with the involvement of JA and SA pathways. This work provides an important update in forest research, and adds to the current knowledge of Pinus spp. defence responses to PWN infection. Full article
(This article belongs to the Special Issue Metabolomics in Plant Defence)
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Article
13C Metabolic Flux Analysis Indicates Endothelial Cells Attenuate Metabolic Perturbations by Modulating TCA Activity
Metabolites 2021, 11(4), 226; https://doi.org/10.3390/metabo11040226 - 07 Apr 2021
Cited by 2 | Viewed by 1116
Abstract
Disrupted endothelial metabolism is linked to endothelial dysfunction and cardiovascular disease. Targeted metabolic inhibitors are potential therapeutics; however, their systemic impact on endothelial metabolism remains unknown. In this study, we combined stable isotope labeling with 13C metabolic flux analysis (13C [...] Read more.
Disrupted endothelial metabolism is linked to endothelial dysfunction and cardiovascular disease. Targeted metabolic inhibitors are potential therapeutics; however, their systemic impact on endothelial metabolism remains unknown. In this study, we combined stable isotope labeling with 13C metabolic flux analysis (13C MFA) to determine how targeted inhibition of the polyol (fidarestat), pentose phosphate (DHEA), and hexosamine biosynthetic (azaserine) pathways alters endothelial metabolism. Glucose, glutamine, and a four-carbon input to the malate shuttle were important carbon sources in the baseline human umbilical vein endothelial cell (HUVEC) 13C MFA model. We observed two to three times higher glutamine uptake in fidarestat and azaserine-treated cells. Fidarestat and DHEA-treated HUVEC showed decreased 13C enrichment of glycolytic and TCA metabolites and amino acids. Azaserine-treated HUVEC primarily showed 13C enrichment differences in UDP-GlcNAc. 13C MFA estimated decreased pentose phosphate pathway flux and increased TCA activity with reversed malate shuttle direction in fidarestat and DHEA-treated HUVEC. In contrast, 13C MFA estimated increases in both pentose phosphate pathway and TCA activity in azaserine-treated cells. These data show the potential importance of endothelial malate shuttle activity and suggest that inhibiting glycolytic side branch pathways can change the metabolic network, highlighting the need to study systemic metabolic therapeutic effects. Full article
(This article belongs to the Special Issue Metabolites and Signaling Pathways)
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