Metabolites

24 pages, 3320 KiB

Open AccessArticle

Cluster Thinning and Vineyard Site Modulate the Metabolomic Profile of Ribolla Gialla Base and Sparkling Wines

by Domen Škrab, Paolo Sivilotti, Piergiorgio Comuzzo, Sabrina Voce, Francesco Degano, Silvia Carlin, Panagiotis Arapitsas, Domenico Masuero and Urška Vrhovšek

Metabolites 2021, 11(5), 331; https://doi.org/10.3390/metabo11050331 - 20 May 2021

Cited by 12 | Viewed by 3010

Abstract

Depending on the vineyard location, cluster thinning (CT) may represent an effective tool to obtain the desired grape composition and wine quality. The effect of 20% cluster thinning on Ribolla Gialla (Vitis vinifera L.) sparkling wine aroma, lipid compounds, and aromatic amino [...] Read more.

Depending on the vineyard location, cluster thinning (CT) may represent an effective tool to obtain the desired grape composition and wine quality. The effect of 20% cluster thinning on Ribolla Gialla (Vitis vinifera L.) sparkling wine aroma, lipid compounds, and aromatic amino acid (AAA) metabolites composition was studied for three consecutive seasons in two vineyards located in the Friuli Venezia Giulia region, Italy. In the examined sparkling wines, the vintage meteorological conditions exhibited significant influences on the metabolic profile of the samples. Data were normalized by season, and the impact of the CT treatment was evaluated for each vineyard site separately. Crop removal showed a limited positive impact on aroma compounds in sparkling wines from vineyards located in the valley. Concerning the AAA compounds, their concentration was higher in the vineyard at the foot of the hills. Cluster thinning resulted in a drop in concentration, reducing the risk of atypical aging. Despite minor differences according to targeted metabolome profiling, the sensory analysis confirmed the effects of the CT treatment in the valley floor vineyard. Reducing crop in this site, where the yield was higher, promoted a moderate improvement of Ribolla Gialla sparkling wine. In contrast, for wine produced in the vineyard at the foot of the hills, the sensory analysis indicated a preference for wines from the unthinned control samples. Overall, the study indicates that cluster thinning is a viticultural technique that could potentially improve the quality of Ribolla Gialla sparkling wines, but only in situations of excessive grape production. Full article

(This article belongs to the Special Issue Grape and Wine Metabolome Analysis)

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17 pages, 3324 KiB

Open AccessArticle

Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice

by Brian T. Palmisano, Lin Zhu, Bridget Litts, Andreanna Burman, Sophia Yu, Joshua C. Neuman, Uche Anozie, Thao N. Luu, Emery M. Edington and John M. Stafford

Metabolites 2021, 11(5), 330; https://doi.org/10.3390/metabo11050330 - 20 May 2021

Cited by 5 | Viewed by 2775

Abstract

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. [...] Read more.

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. Here, we test the hypothesis that hepatic SHP mediates sex differences in TG metabolism using hepatocyte-specific SHP knockout mice. Plasma TGs in wild-type males were higher than in wild-type females and hepatic deletion of SHP lowered plasma TGs in males but not in females, suggesting hepatic SHP mediates plasma TG metabolism in a sex-specific manner. Additionally, hepatic deletion of SHP failed to lower plasma TGs in gonadectomized male mice or in males with knockdown of the liver androgen receptor, suggesting hepatic SHP modifies plasma TG via an androgen receptor pathway. Furthermore, the TG lowering effect of hepatic deletion of SHP was caused by increased clearance of postprandial TG and accompanied with decreased plasma levels of ApoC1, an inhibitor of lipoprotein lipase activity. These data support a role for hepatic SHP in mediating sex-specific effects on plasma TG metabolism through androgen receptor signaling. Understanding how hepatic SHP regulates TG clearance may lead to novel approaches to lower plasma TGs and mitigate cardiovascular disease risk. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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21 pages, 6204 KiB

Open AccessEditor’s ChoiceArticle

Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis

by Julia K. Meier, Matthias Schnetz, Susanne Beck, Tobias Schmid, Monica Dominguez, Sanela Kalinovic, Andreas Daiber, Bernhard Brüne and Michaela Jung

Metabolites 2021, 11(5), 329; https://doi.org/10.3390/metabo11050329 - 19 May 2021

Cited by 22 | Viewed by 4322

Abstract

While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. [...] Read more.

While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. Applying RNA sequencing analysis in renal CAKI1 tumor cells to explore highly upregulated molecular signatures in response to hLcn-2, we identified a cluster of genes (SLC7A11, GCLM, GLS), which are implicated in regulating ferroptosis. Indeed, hLcn-2-stimulated cells are protected from erastin-induced ferroptosis. We also noticed a rapid increase in reactive oxygen species (ROS) with subsequent activation of the antioxidant Nrf2 pathway. However, knocking down Nrf2 by siRNA was not sufficient to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. In contrast, preventing oxidative stress through N-acetyl-l-cysteine (NAC) supplementation was still able to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. Besides an oxidative stress response, we noticed activation of the integrated stress response (ISR), shown by enhanced phosphorylation of eIF-2α and induction of ATF4 after hLcn-2 addition. ATF4 knockdown as well as inhibition of the ISR sensitized hLcn-2-treated renal tumor cells to ferroptosis, thus linking the ISR to pro-tumor characteristics of hLcn-2. Our study provides mechanistic details to better understand tumor pro-survival pathways initiated by iron-loaded Lcn-2. Full article

(This article belongs to the Section Cell Metabolism)

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36 pages, 954 KiB

Open AccessReview

Tick-Tock Consider the Clock: The Influence of Circadian and External Cycles on Time of Day Variation in the Human Metabolome—A Review

by Thomas P. M. Hancox, Debra J. Skene, Robert Dallmann and Warwick B. Dunn

Metabolites 2021, 11(5), 328; https://doi.org/10.3390/metabo11050328 - 19 May 2021

Cited by 14 | Viewed by 3490

Abstract

The past decade has seen a large influx of work investigating time of day variation in different human biofluid and tissue metabolomes. The driver of this daily variation can be endogenous circadian rhythms driven by the central and/or peripheral clocks, or exogenous diurnal [...] Read more.

The past decade has seen a large influx of work investigating time of day variation in different human biofluid and tissue metabolomes. The driver of this daily variation can be endogenous circadian rhythms driven by the central and/or peripheral clocks, or exogenous diurnal rhythms driven by behavioural and environmental cycles, which manifest as regular 24 h cycles of metabolite concentrations. This review, of all published studies to date, establishes the extent of daily variation with regard to the number and identity of ‘rhythmic’ metabolites observed in blood, saliva, urine, breath, and skeletal muscle. The probable sources driving such variation, in addition to what metabolite classes are most susceptible in adhering to or uncoupling from such cycles is described in addition to a compiled list of common rhythmic metabolites. The reviewed studies show that the metabolome undergoes significant time of day variation, primarily observed for amino acids and multiple lipid classes. Such 24 h rhythms, driven by various factors discussed herein, are an additional source of intra/inter-individual variation and are thus highly pertinent to all studies applying untargeted and targeted metabolomics platforms, particularly for the construction of biomarker panels. The potential implications are discussed alongside proposed minimum reporting criteria suggested to acknowledge time of day variation as a potential influence of results and to facilitate improved reproducibility. Full article

(This article belongs to the Section Integrative Metabolomics)

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23 pages, 4353 KiB

Open AccessArticle

Metabolic Profiling from an Asymptomatic Ferret Model of SARS-CoV-2 Infection

by David J. Beale, Rohan Shah, Avinash V. Karpe, Katie E. Hillyer, Alexander J. McAuley, Gough G. Au, Glenn A. Marsh and Seshadri S. Vasan

Metabolites 2021, 11(5), 327; https://doi.org/10.3390/metabo11050327 - 19 May 2021

Cited by 21 | Viewed by 5143

Abstract

Coronavirus disease (COVID-19) is a contagious respiratory disease that is causing significant global morbidity and mortality. Understanding the impact of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection on the host metabolism is still in its infancy but of great importance. Herein, we [...] Read more.

Coronavirus disease (COVID-19) is a contagious respiratory disease that is causing significant global morbidity and mortality. Understanding the impact of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection on the host metabolism is still in its infancy but of great importance. Herein, we investigated the metabolic response during viral shedding and post-shedding in an asymptomatic SARS-CoV-2 ferret model (n = 6) challenged with two SARS-CoV-2 isolates. Virological and metabolic analyses were performed on (minimally invasive) collected oral swabs, rectal swabs, and nasal washes. Fragments of SARS-CoV-2 RNA were only found in the nasal wash samples in four of the six ferrets, and in the samples collected 3 to 9 days post-infection (referred to as viral shedding). Central carbon metabolism metabolites were analyzed during viral shedding and post-shedding periods using a dynamic Multiple Reaction Monitoring (dMRM) database and method. Subsequent untargeted metabolomics and lipidomics of the same samples were performed using a Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-QToF-MS) methodology, building upon the identified differentiated central carbon metabolism metabolites. Multivariate analysis of the acquired data identified 29 significant metabolites and three lipids that were subjected to pathway enrichment and impact analysis. The presence of viral shedding coincided with the challenge dose administered and significant changes in the citric acid cycle, purine metabolism, and pentose phosphate pathways, amongst others, in the host nasal wash samples. An elevated immune response in the host was also observed between the two isolates studied. These results support other metabolomic-based findings in clinical observational studies and indicate the utility of metabolomics applied to ferrets for further COVID-19 research that advances early diagnosis of asymptomatic and mild clinical COVID-19 infections, in addition to assessing the effectiveness of new or repurposed drug therapies. Full article

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28 pages, 3076 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Exploration of Blood Lipoprotein and Lipid Fraction Profiles in Healthy Subjects through Integrated Univariate, Multivariate, and Network Analysis Reveals Association of Lipase Activity and Cholesterol Esterification with Sex and Age

by Yasmijn Balder, Alessia Vignoli, Leonardo Tenori, Claudio Luchinat and Edoardo Saccenti

Metabolites 2021, 11(5), 326; https://doi.org/10.3390/metabo11050326 - 18 May 2021

Cited by 4 | Viewed by 4142

Abstract

In this study, we investigated blood lipoprotein and lipid fraction profiles, quantified using nuclear magnetic resonance, in a cohort of 844 healthy blood donors, integrating standard univariate and multivariate analysis with predictive modeling and network analysis. We observed a strong association of lipoprotein [...] Read more.

In this study, we investigated blood lipoprotein and lipid fraction profiles, quantified using nuclear magnetic resonance, in a cohort of 844 healthy blood donors, integrating standard univariate and multivariate analysis with predictive modeling and network analysis. We observed a strong association of lipoprotein and lipid main fraction profiles with sex and age. Our results suggest an age-dependent remodulation of lipase lipoprotein activity in men and a change in the mechanisms controlling the ratio between esterified and non-esterified cholesterol in both men and women. Full article

(This article belongs to the Collection Advances in Metabolomics)

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16 pages, 4412 KiB

Open AccessArticle

Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells

by Noriaki Minami, Kazuhiro Tanaka, Takashi Sasayama, Eiji Kohmura, Hideyuki Saya and Oltea Sampetrean

Metabolites 2021, 11(5), 325; https://doi.org/10.3390/metabo11050325 - 18 May 2021

Cited by 12 | Viewed by 3508

Abstract

Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but [...] Read more.

Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation. Full article

(This article belongs to the Special Issue The Emerging Role of Cancer Metabolism in the Development and Progression of Malignancy)

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29 pages, 20685 KiB

Open AccessArticle

Effects of Weight Loss and Moderate-Protein, High-Fiber Diet Consumption on the Fasted Serum Metabolome of Cats

by Marissa R. Pallotto, Patrícia M. Oba, Maria R. C. de Godoy, Kirk L. Pappan, Preston R. Buff and Kelly S. Swanson

Metabolites 2021, 11(5), 324; https://doi.org/10.3390/metabo11050324 - 18 May 2021

Cited by 3 | Viewed by 3390

Abstract

Feline obesity elicits a plethora of metabolic responses leading to comorbidities, with potential reversal during weight loss. The specific metabolic alterations and biomarkers of organ dysfunction are not entirely understood. Untargeted, high-throughput metabolomic technologies may allow the identification of biological components that change [...] Read more.

Feline obesity elicits a plethora of metabolic responses leading to comorbidities, with potential reversal during weight loss. The specific metabolic alterations and biomarkers of organ dysfunction are not entirely understood. Untargeted, high-throughput metabolomic technologies may allow the identification of biological components that change with weight status in cats, increasing our understanding of feline metabolism. The objective of this study was to utilize untargeted metabolomic techniques to identify biomarkers and gain mechanistic insight into the serum metabolite changes associated with reduced food intake and weight loss in overweight cats. During a four-wk baseline period, cats were fed to maintain body weight. For 18 wk following baseline, cats were fed to lose weight at a rate of ~1.5% body weight/wk. Blood serum metabolites were measured at wk 0, 1, 2, 4, 8, 12, and 16. A total of 535 named metabolites were identified, with up to 269 of them being altered (p- and q-values < 0.05) at any time point. A principal component analysis showed a continual shift in metabolite profile as weight loss progressed, with early changes being distinct from those over the long term. The majority of lipid metabolites decreased with weight loss; however, ketone bodies and small lipid particles increased with weight loss. The majority of carbohydrate metabolites decreased with weight loss. Protein metabolites had a variable result, with some increasing, but others decreasing with weight loss. Metabolic mediators of inflammation, oxidative stress, xenobiotics, and insulin resistance decreased with weight loss. In conclusion, global metabolomics identified biomarkers of reduced food intake and weight loss in cats, including decreased markers of inflammation and/or altered macronutrient metabolism. Full article

(This article belongs to the Section Nutrition and Metabolism)

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16 pages, 2807 KiB

Open AccessEditor’s ChoiceArticle

Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

by Jiling Liang, Hu Zhang, Zhengzhong Zeng, Liangwen Wu, Ying Zhang, Yanju Guo, Jun Lv, Cenyi Wang, Jingjing Fan and Ning Chen

Metabolites 2021, 11(5), 323; https://doi.org/10.3390/metabo11050323 - 18 May 2021

Cited by 34 | Viewed by 5173

Abstract

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular [...] Read more.

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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15 pages, 3514 KiB

Open AccessArticle

Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells

by Jae-Eun Song, Tiago C. Alves, Bernardo Stutz, Matija Šestan-Peša, Nicole Kilian, Sungho Jin, Sabrina Diano, Richard G. Kibbey and Tamas L. Horvath

Metabolites 2021, 11(5), 322; https://doi.org/10.3390/metabo11050322 - 18 May 2021

Cited by 16 | Viewed by 3618

Abstract

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa [...] Read more.

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa cells. We observed the association between mitochondrial morphology and lipid droplet accumulation in response to high exogenous fatty acids. We inhibited mitochondrial fission by silencing dynamin-related protein 1(DRP1) and observed the shift in fatty acid storage-usage balance. Inhibition of mitochondrial fission resulted in an increase in fatty acid content of lipid droplets and a decrease in mitochondrial fatty acid oxidation. Next, we overexpressed carnitine palmitoyltransferase-1 (CPT1), a key mitochondrial protein in fatty acid oxidation, to further examine the relationship between mitochondrial fatty acid usage and mitochondrial morphology. Mitochondrial fission plays a role in distributing exogenous fatty acids. CPT1A controlled the respiratory rate of mitochondrial fatty acid oxidation but did not cause a shift in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)

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17 pages, 1400 KiB

Open AccessReview

An Overview of Metabolic Activity, Beneficial and Pathogenic Aspects of Burkholderia Spp.

by Hazem S. Elshafie and Ippolito Camele

Metabolites 2021, 11(5), 321; https://doi.org/10.3390/metabo11050321 - 17 May 2021

Cited by 33 | Viewed by 4893

Abstract

Burkholderia is an important bacterial species which has different beneficial effects, such as promoting the plant growth, including rhizosphere competence for the secretion of allelochemicals, production of antibiotics, and siderophores. In addition, most of Burkholderia species have demonstrated promising biocontrol action against different [...] Read more.

Burkholderia is an important bacterial species which has different beneficial effects, such as promoting the plant growth, including rhizosphere competence for the secretion of allelochemicals, production of antibiotics, and siderophores. In addition, most of Burkholderia species have demonstrated promising biocontrol action against different phytopathogens for diverse crops. In particular, Burkholderia demonstrates significant biotechnological potential as a source of novel antibiotics and bioactive secondary metabolites. The current review is concerned with Burkholderia spp. covering the following aspects: discovering, classification, distribution, plant growth promoting effect, and antimicrobial activity of different species of Burkholderia, shedding light on the most important secondary metabolites, their pathogenic effects, and biochemical characterization of some important species of Burkholderia, such as B. cepacia, B. andropogonis, B. plantarii, B. rhizoxinica, B. glumae, B. caryophylli and B. gladioli. Full article

(This article belongs to the Special Issue Metabolites from Bacterial Pathogens and Their Role in Disease)

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16 pages, 1602 KiB

Open AccessReview

Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease

by Meng Yang, Feng Ma and Min Guan

Metabolites 2021, 11(5), 320; https://doi.org/10.3390/metabo11050320 - 17 May 2021

Cited by 25 | Viewed by 4532

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and may progress to cirrhosis or even hepatocellular carcinoma. A number of steroid hormones are important regulators of lipid homeostasis through fine tuning the expression of genes related to [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and may progress to cirrhosis or even hepatocellular carcinoma. A number of steroid hormones are important regulators of lipid homeostasis through fine tuning the expression of genes related to lipid synthesis, export, and metabolism. Dysregulation of such pathways has been implicated in the pathogenesis of NAFLD. The aim of this review is to clarify the potential impact of steroid hormones on NAFLD. We also highlight potential interventions through modulating steroid hormone levels or the activities of their cognate receptors as therapeutic strategies for preventing NAFLD. Full article

(This article belongs to the Special Issue Steroids in Non-alcoholic Fatty Liver Disease)

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20 pages, 2398 KiB

Open AccessEditor’s ChoiceReview

Browning of White Adipose Tissue as a Therapeutic Tool in the Fight against Atherosclerosis

by Christel L. Roth, Filippo Molica and Brenda R. Kwak

Metabolites 2021, 11(5), 319; https://doi.org/10.3390/metabo11050319 - 14 May 2021

Cited by 17 | Viewed by 4283

Abstract

Despite continuous medical advances, atherosclerosis remains the prime cause of mortality worldwide. Emerging findings on brown and beige adipocytes highlighted that these fat cells share the specific ability of non-shivering thermogenesis due to the expression of uncoupling protein 1. Brown fat is established [...] Read more.

Despite continuous medical advances, atherosclerosis remains the prime cause of mortality worldwide. Emerging findings on brown and beige adipocytes highlighted that these fat cells share the specific ability of non-shivering thermogenesis due to the expression of uncoupling protein 1. Brown fat is established during embryogenesis, and beige cells emerge from white adipose tissue exposed to specific stimuli like cold exposure into a process called browning. The consecutive energy expenditure of both thermogenic adipose tissues has shown therapeutic potential in metabolic disorders like obesity and diabetes. The latest data suggest promising effects on atherosclerosis development as well. Upon cold exposure, mice and humans have a physiological increase in brown adipose tissue activation and browning of white adipocytes is promoted. The use of drugs like β3-adrenergic agonists in murine models induces similar effects. With respect to atheroprotection, thermogenic adipose tissue activation has beneficial outcomes in mice by decreasing plasma triglycerides, total cholesterol and low-density lipoproteins, by increasing high-density lipoproteins, and by inducing secretion of atheroprotective adipokines. Atheroprotective effects involve an unaffected hepatic clearance. Latest clinical data tend to find thinner atherosclerotic lesions in patients with higher brown adipose tissue activity. Strategies for preserving healthy arteries are a major concern for public health. Full article

(This article belongs to the Special Issue Cardiovascular Risk Biomarkers: Deciphering the Metabolism and Interaction Networks)

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21 pages, 315 KiB

Open AccessReview

Postharvest Water Loss of Wine Grape: When, What and Why

by Chiara Sanmartin, Margherita Modesti, Francesca Venturi, Stefano Brizzolara, Fabio Mencarelli and Andrea Bellincontro

Metabolites 2021, 11(5), 318; https://doi.org/10.3390/metabo11050318 - 14 May 2021

Cited by 18 | Viewed by 2888

Abstract

In postharvest science, water loss is always considered a negative factor threatening fruit and vegetable quality, but in the wine field, this physical process is employed to provide high-quality wine, such as Amarone and Passito wines. The main reason for this is the [...] Read more.

In postharvest science, water loss is always considered a negative factor threatening fruit and vegetable quality, but in the wine field, this physical process is employed to provide high-quality wine, such as Amarone and Passito wines. The main reason for this is the significant metabolic changes occurring during wine grape water loss, changes that are highly dependent on the specific water loss rate and level, as well as the ambient conditions under which grapes are kept to achieve dehydration. In this review, hints on the main techniques used to induce postharvest wine grape water loss and information on the most important metabolic changes occurring in grape berries during water loss are reported. The quality of wines produced from dried/dehydrated/withered grapes is also discussed, together with an update on the application of innovative non-destructive techniques in the wine sector. A wide survey of the scientific papers published all over the world on the topic has been carried out. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Food Science)

11 pages, 4687 KiB

Open AccessArticle

Circulating Metabolites Associated with Body Fat and Lean Mass in Adults with Overweight/Obesity

by Christopher Papandreou, Jesús García-Gavilán, Lucía Camacho-Barcia, Thea T. Hansen, Anders Sjödin, Joanne A. Harrold, Jason C. G. Halford and Mònica Bulló

Metabolites 2021, 11(5), 317; https://doi.org/10.3390/metabo11050317 - 13 May 2021

Cited by 12 | Viewed by 3125

Abstract

The interplay between fat mass and lean mass within human metabolism is not completely understood. We aimed to identify specific circulating metabolomic profiles associated with these body composition compartments. Cross-sectional analyses were conducted over 236 adults with overweight/obesity from the Satiety Innovation (SATIN) [...] Read more.

The interplay between fat mass and lean mass within human metabolism is not completely understood. We aimed to identify specific circulating metabolomic profiles associated with these body composition compartments. Cross-sectional analyses were conducted over 236 adults with overweight/obesity from the Satiety Innovation (SATIN) study. Body composition was assessed by dual-energy X-ray absorptiometry. A targeted multiplatform metabolite profiling approach was applied. Associations between 168 circulating metabolites and the body composition measures were assessed using elastic net regression analyses. The accuracy of the multimetabolite weighted models was evaluated using a 10-fold cross-validation approach and the Pearson’s correlation coefficients between metabolomic profiles and body compartments were estimated. Two different profiles including 86 and 65 metabolites were selected for % body fat and lean mass. These metabolites mainly consisted of lipids (sphingomyelins, phosphatidylcholines, lysophosphatidylcholines), acylcarnitines, and amino acids. Several metabolites overlapped between these body composition measures but none of them towards the same direction. The Pearson correlation coefficients between the metabolomic profiles and % body fat or lean mass were 0.80 and 0.79, respectively. Our findings suggest alterations in lipid metabolism, fatty acid oxidation, and protein degradation with increased adiposity and decreased lean body mass. These findings could help us to better understand the interplay between body composition compartments with human metabolic processes. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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20 pages, 1252 KiB

Open AccessArticle

Identification of Potential Distinguishing Markers for the Use of Cannabis-Based Medicines or Street Cannabis in Serum Samples

by Anne Scheunemann, Katrin Elsner, Tanja Germerott, Sergiu Groppa, Cornelius Hess, Isabelle Miederer, Alicia Poplawski and Jörg Röhrich

Metabolites 2021, 11(5), 316; https://doi.org/10.3390/metabo11050316 - 13 May 2021

Cited by 2 | Viewed by 2786

Abstract

Increasing prescription numbers of cannabis-based medicines raise the question of whether uptake of these medicines can be distinguished from recreational cannabis use. In this pilot study, serum cannabinoid profiles after use of cannabis-based medicines were investigated, in order to identify potential distinguishing markers. [...] Read more.

Increasing prescription numbers of cannabis-based medicines raise the question of whether uptake of these medicines can be distinguished from recreational cannabis use. In this pilot study, serum cannabinoid profiles after use of cannabis-based medicines were investigated, in order to identify potential distinguishing markers. Serum samples after use of Sativex^®, Dronabinol or medical cannabis were collected and analyzed for 18 different cannabinoids, using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Analytes included delta-9-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, tetrahydrocannabivarin, cannabidivarin, tetrahydocannabinolic acid A, cannabidiolic acid, cannabinolic acid, cannabigerolic acid, cannabichromenic acid, cannabicyclolic acid, tetrahydrocannabivarinic acid and cannabidivarinic acid. Cannabinoid profiles of study samples were compared to profiles of street cannabis user samples via principal component analysis and Kruskal–Wallis test. Potential distinguishing markers for Dronabinol and Sativex^® intake were identified, including 11-hydroxy-tetrahydrocannabinol/delta-9-tetrahydrocannabinol ratios ≥1 and increased concentrations of 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol or cannabichromene. Larger quantities of minor cannabinoids suggested use of cannabis. Use of medical and street cannabis could not be distinguished, except for use of a cannabidiol-rich strain with higher cannabidiol/delta-9-tetrahydrocannabinol and cannabichromene/delta-9-tetrahydrocannabinol ratios. Findings of the study were used to classify forensic serum samples with self-reported use of cannabis-based medicines. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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28 pages, 9935 KiB

Open AccessReview

Glioblastoma Metabolomics—In Vitro Studies

by Karol Jaroch, Paulina Modrakowska and Barbara Bojko

Metabolites 2021, 11(5), 315; https://doi.org/10.3390/metabo11050315 - 13 May 2021

Cited by 10 | Viewed by 3603

Abstract

In 2016, the WHO introduced new guidelines for the diagnosis of brain gliomas based on new genomic markers. The addition of these new markers to the pre-existing diagnostic methods provided a new level of precision for the diagnosis of glioma and the prediction [...] Read more.

In 2016, the WHO introduced new guidelines for the diagnosis of brain gliomas based on new genomic markers. The addition of these new markers to the pre-existing diagnostic methods provided a new level of precision for the diagnosis of glioma and the prediction of treatment effectiveness. Yet, despite this new classification tool, glioblastoma (GBM), a grade IV glioma, continues to have one of the highest mortality rates among central nervous system tumors. Metabolomics is a particularly promising tool for the analysis of GBM tumors and potential methods of treating them, as it is the only “omics” approach that is capable of providing a metabolic signature of a tumor’s phenotype. With careful experimental design, cell cultures can be a useful matrix in GBM metabolomics, as they ensure stable conditions and, under proper conditions, are capable of capturing different tumor phenotypes. This paper reviews in vitro metabolomic profiling studies of high-grade gliomas, with a particular focus on sample-preparation techniques, crucial metabolites identified, cell culture conditions, in vitro-in vivo extrapolation, and pharmacometabolomics. Ultimately, this review aims to elucidate potential future directions for in vitro GBM metabolomics. Full article

(This article belongs to the Special Issue Advances in Cellular Metabolomics)

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13 pages, 3207 KiB

Open AccessArticle

Capillary Electrophoresis Mass Spectrometry-Based Metabolomics of Plasma Samples from Healthy Subjects in a Cross-Sectional Japanese Population Study

by Hiroyuki Yamamoto, Makoto Suzuki, Rira Matsuta, Kazunori Sasaki, Moon-Il Kang, Kenjiro Kami, Yota Tatara, Ken Itoh and Shigeyuki Nakaji

Metabolites 2021, 11(5), 314; https://doi.org/10.3390/metabo11050314 - 13 May 2021

Cited by 3 | Viewed by 3625

Abstract

For large-scale metabolomics, such as in cohort studies, normalization protocols using quality control (QC) samples have been established when using data from gas chromatography and liquid chromatography coupled to mass spectrometry. However, normalization protocols have not been established for capillary electrophoresis–mass spectrometry metabolomics. [...] Read more.

For large-scale metabolomics, such as in cohort studies, normalization protocols using quality control (QC) samples have been established when using data from gas chromatography and liquid chromatography coupled to mass spectrometry. However, normalization protocols have not been established for capillary electrophoresis–mass spectrometry metabolomics. In this study, we performed metabolome analysis of 314 human plasma samples using capillary electrophoresis–mass spectrometry. QC samples were analyzed every 10 samples. The results of principal component analysis for the metabolome data from only the QC samples showed variations caused by capillary replacement in the first principal component score and linear variation with continuous measurement in the second principal component score. Correlation analysis between diagnostic blood tests and plasma metabolites normalized by the QC samples was performed for samples from 188 healthy subjects who participated in a Japanese population study. Five highly correlated pairs were identified, including two previously unidentified pairs in normal healthy subjects of blood urea nitrogen and guanidinosuccinic acid, and gamma-glutamyl transferase and cysteine glutathione disulfide. These results confirmed the validity of normalization protocols in capillary electrophoresis–mass spectrometry using large-scale metabolomics and comprehensive analysis. Full article

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16 pages, 3007 KiB

Open AccessArticle

Redox Metabolism Measurement in Mammalian Cells and Tissues by LC-MS

by Boryana Petrova, Anna Warren, Nuria Yulia Vital, Andrew J. Culhane, Adam G. Maynard, Alan Wong and Naama Kanarek

Metabolites 2021, 11(5), 313; https://doi.org/10.3390/metabo11050313 - 13 May 2021

Cited by 10 | Viewed by 4048

Abstract

Cellular redox state is highly dynamic and delicately balanced between constant production of reactive oxygen species (ROS), and neutralization by endogenous antioxidants, such as glutathione. Physiologic ROS levels can function as signal transduction messengers, while high levels of ROS can react with and [...] Read more.

Cellular redox state is highly dynamic and delicately balanced between constant production of reactive oxygen species (ROS), and neutralization by endogenous antioxidants, such as glutathione. Physiologic ROS levels can function as signal transduction messengers, while high levels of ROS can react with and damage various molecules eliciting cellular toxicity. The redox state is reflective of the cell’s metabolic status and can inform on regulated cell-state transitions or various pathologies including aging and cancer. Therefore, methods that enable reliable, quantitative readout of the cellular redox state are imperative for scientists from multiple fields. Liquid-chromatography mass-spectrometry (LC-MS) based methods to detect small molecules that reflect the redox balance in the cell such as glutathione, NADH, and NADPH, have been developed and applied successfully, but because redox metabolites are very labile, these methods are not easily standardized or consolidated. Here, we report a robust LC-MS method for the simultaneous detection of several redox-reactive metabolites that is compatible with parallel global metabolic profiling in mammalian cells. We performed a comprehensive comparison between three commercial hydrophilic interaction chromatography (HILIC) columns, and we describe the application of our method in mammalian cells and tissues. The presented method is easily applicable and will enable the study of ROS function and oxidative stress in mammalian cells by researchers from various fields. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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17 pages, 1587 KiB

Open AccessArticle

Selection of Potential Yeast Probiotics and a Cell Factory for Xylitol or Acid Production from Honeybee Samples

by Farah Zahoor, Chayaphathra Sooklim, Pattanan Songdech, Orawan Duangpakdee and Nitnipa Soontorngun

Metabolites 2021, 11(5), 312; https://doi.org/10.3390/metabo11050312 - 13 May 2021

Cited by 14 | Viewed by 3232

Abstract

Excessive use of antibiotics has detrimental consequences, including antibiotic resistance and gut microbiome destruction. Probiotic-rich diets help to restore good microbes, keeping the body healthy and preventing the onset of chronic diseases. Honey contains not only prebiotic oligosaccharides but, like yogurt and fermented [...] Read more.

Excessive use of antibiotics has detrimental consequences, including antibiotic resistance and gut microbiome destruction. Probiotic-rich diets help to restore good microbes, keeping the body healthy and preventing the onset of chronic diseases. Honey contains not only prebiotic oligosaccharides but, like yogurt and fermented foods, is an innovative natural source for probiotic discovery. Here, a collection of three honeybee samples was screened for yeast strains, aiming to characterize their potential in vitro probiotic properties and the ability to produce valuable metabolites. Ninety-four isolates out of one-hundred and four were able to grow at temperatures of 30 °C and 37 °C, while twelve isolates could grow at 42 °C. Fifty-eight and four isolates displayed the ability to grow under stimulated gastrointestinal condition, at pH 2.0–2.5, 0.3% (w/v) bile salt, and 37 °C. Twenty-four isolates showed high autoaggregation of 80–100% and could utilize various sugars, including galactose and xylose. The cell count of these isolates (7–9 log cfu/mL) was recorded and stable during 6 months of storage. Genomic characterization based on the internal transcribed spacer region (ITS) also identified four isolates of Saccharomyces cerevisiae displayed good ability to produce antimicrobial acids. These results provided the basis for selecting four natural yeast isolates as starter cultures for potential probiotic application in functional foods and animal feed. Additionally, these S. cerevisiae isolates also produced high levels of acids from fermented sugarcane molasses, an abundant agricultural waste product from the sugar industry. Furthermore, one of ten identified isolates of Meyerozyma guilliermondiii displayed an excellent ability to produce a pentose sugar xylitol at a yield of 0.490 g/g of consumed xylose. Potentially, yeast isolates of honeybee samples may offer various biotechnological advantages as probiotics or metabolite producers of multiproduct-based lignocellulosic biorefinery. Full article

(This article belongs to the Special Issue Metabolites Produced by Yeast Cells)

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14 pages, 2151 KiB

Open AccessArticle

High Glucose Shifts the Oxylipin Profiles in the Astrocytes towards Pro-Inflammatory States

by Dmitry V. Chistyakov, Sergei V. Goriainov, Alina A. Astakhova and Marina G. Sergeeva

Metabolites 2021, 11(5), 311; https://doi.org/10.3390/metabo11050311 - 13 May 2021

Cited by 5 | Viewed by 3148

Abstract

Hyperglycemia is associated with several complications in the brain, which are also characterized by inflammatory conditions. Astrocytes are responsible for glucose metabolism in the brain and are also important participants of inflammatory responses. Oxylipins are lipid mediators, derived from the metabolism of polyunsaturated [...] Read more.

Hyperglycemia is associated with several complications in the brain, which are also characterized by inflammatory conditions. Astrocytes are responsible for glucose metabolism in the brain and are also important participants of inflammatory responses. Oxylipins are lipid mediators, derived from the metabolism of polyunsaturated fatty acids (PUFAs) and are generally considered to be a link between metabolic and inflammatory processes. High glucose exposure causes astrocyte dysregulation, but its effects on the metabolism of oxylipins are relatively unknown and therefore, constituted the focus of our work. We used normal glucose (NG, 5.5 mM) vs. high glucose (HG, 25 mM) feeding media in primary rat astrocytes-enriched cultures and measured the extracellular release of oxylipins (UPLC-MS/MS) in response to lipopolysaccharide (LPS). The sensitivity of HG and NG growing astrocytes in oxylipin synthesis for various serum concentrations was also tested. Our data reveal shifts towards pro-inflammatory states in HG non-stimulated cells: an increase in the amounts of free PUFAs, including arachidonic (AA), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, and cyclooxygenase (COX) mediated metabolites. Astrocytes cultivated in HG showed a tolerance to the LPS, and an imbalance between inflammatory cytokine (IL-6) and oxylipins release. These results suggest a regulation of COX-mediated oxylipin synthesis in astrocytes as a potential new target in treating brain impairment associated with hyperglycemia. Full article

(This article belongs to the Section Cell Metabolism)

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10 pages, 1304 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Correcting for Naturally Occurring Mass Isotopologue Abundances in Stable-Isotope Tracing Experiments with PolyMID

by Heesoo Jeong, Yan Yu, Henrik J. Johansson, Frank C. Schroeder, Janne Lehtiö and Nathaniel M. Vacanti

Metabolites 2021, 11(5), 310; https://doi.org/10.3390/metabo11050310 - 12 May 2021

Cited by 4 | Viewed by 3954

Abstract

Stable-isotope tracing is a method to measure intracellular metabolic pathway utilization by feeding a cellular system a stable-isotope-labeled tracer nutrient. The power of the method to resolve differential pathway utilization is derived from the enrichment of metabolites in heavy isotopes that are synthesized [...] Read more.

Stable-isotope tracing is a method to measure intracellular metabolic pathway utilization by feeding a cellular system a stable-isotope-labeled tracer nutrient. The power of the method to resolve differential pathway utilization is derived from the enrichment of metabolites in heavy isotopes that are synthesized from the tracer nutrient. However, the readout is complicated by the presence of naturally occurring heavy isotopes that are not derived from the tracer nutrient. Herein we present an algorithm, and a tool that applies it (PolyMID-Correct, part of the PolyMID software package), to computationally remove the influence of naturally occurring heavy isotopes. The algorithm is applicable to stable-isotope tracing data collected on low- and high- mass resolution mass spectrometers. PolyMID-Correct is open source and available under an MIT license. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)

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13 pages, 3422 KiB

Open AccessArticle

Facilitated Qualitative Determination of Insulin, Its Synthetic Analogs, and C-Peptide in Human Urine by Means of LC–HRMS

by Andreas Thomas, Lukas Benzenberg, Lia Bally and Mario Thevis

Metabolites 2021, 11(5), 309; https://doi.org/10.3390/metabo11050309 - 12 May 2021

Cited by 12 | Viewed by 3336

Abstract

The increasing importance to determine bioactive peptide hormones such as insulin, its synthetic analogs, and C-peptide in urine samples represents an analytical challenge. The physiological concentrations of insulin in urine are commonly found at sub-ng/mL levels and thus represent a complex analytical task. [...] Read more.

The increasing importance to determine bioactive peptide hormones such as insulin, its synthetic analogs, and C-peptide in urine samples represents an analytical challenge. The physiological concentrations of insulin in urine are commonly found at sub-ng/mL levels and thus represent a complex analytical task. C-peptide concentrations, on the other hand, tend to be in the moderate ng/mL range and are hence much easier to determine. Insulin and C-peptide are important in the diagnostics and management of metabolic disorders such as diabetes mellitus and are also particularly relevant target analytes in professional sports and forensics. All insulins are classified on the World Anti-Doping Agency’s (WADA) list of prohibited substances and methods in sports with a minimum required performance level (MRPL) of 50 pg/mL. Until now, methods combining immunoextraction and subsequent mass spectrometric detection have mostly been used for this purpose. With the method developed here, sample preparation has been simplified considerably and does not require an antibody-based sample purification. This was achieved by a sophisticated mixed-mode solid-phase extraction and subsequent separation with liquid chromatography coupled to high-resolution mass spectrometry. Included target insulins were human, lispro, glulisine, aspart, glargine metabolite, degludec, and additionally, human C-peptide. The method was validated for the synthetic insulin analogs considering WADA requirements including specificity, limit of detection (10–25 pg/mL), limit of identification, recovery (25–100%), robustness, carry over (<2%), and matrix effects. All sample preparation steps were controlled by two stable isotope-labeled internal standards, namely, [[2H10] LeuB6, B11, B15, B17]-insulin and [[13C6] Leu26, 30] C-peptide. Finally, the method was applied to samples from patients with diabetes mellitus treated with synthetic insulins. Full article

(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)

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12 pages, 1037 KiB

Open AccessCommunication

Extracellular Vesicle Analysis by Paper Spray Ionization Mass Spectrometry

by Casey A. Chamberlain, Marguerite Hatch and Timothy J. Garrett

Metabolites 2021, 11(5), 308; https://doi.org/10.3390/metabo11050308 - 11 May 2021

Cited by 9 | Viewed by 3284

Abstract

Paper spray ionization mass spectrometry (PSI-MS) is a direct MS analysis technique with several reported bacterial metabolomics applications. As with most MS-based bacterial studies, all currently reported PSI-MS bacterial analyses have focused on the chemical signatures of the cellular unit. One dimension of [...] Read more.

Paper spray ionization mass spectrometry (PSI-MS) is a direct MS analysis technique with several reported bacterial metabolomics applications. As with most MS-based bacterial studies, all currently reported PSI-MS bacterial analyses have focused on the chemical signatures of the cellular unit. One dimension of the bacterial metabolome that is often lost in such analyses is the exometabolome (extracellular metabolome), including secreted metabolites, lipids, and peptides. A key component of the bacterial exometabolome that is gaining increased attention in the microbiology and biomedical communities is extracellular vesicles (EVs). These excreted structures, produced by cells in all domains of life, contain a variety of biomolecules responsible for a wide array of cellular functions, thus representing a core component of the bacterial secreted metabolome. Although previously examined using other MS approaches, no reports currently exist for a PSI-MS analysis of bacterial EVs, nor EVs from any other organism (exosomes, ectosomes, etc.). PSI-MS holds unique analytical strengths over other commonly used MS platforms and could thus provide an advantageous approach to EV metabolomics. To address this, we report a novel application representing, to our knowledge, the first PSI-MS analysis of EVs from any organism (using the human gut resident Oxalobacter formigenes as the experimental model, a bacterium whose EVs were never previously investigated). In this report, we show how we isolated and purified EVs from bacterial culture supernatant by EV-specific affinity chromatography, confirmed and characterized these vesicles by nanoparticle tracking analysis, analyzed the EV isolate by PSI-MS, and identified a panel of EV-derived metabolites, lipids, and peptides. This work serves as a pioneering study in the field of MS-based EV analysis and provides a new, rapid, sensitive, and economical approach to EV metabolomics. Full article

(This article belongs to the Special Issue Reviews and Advances in Microbial Metabolomics)

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15 pages, 19039 KiB

Open AccessArticle

Molecular Dynamic Simulations Suggest That Metabolite-Induced Post-Translational Modifications Alter the Behavior of the Fibrinogen Coiled-Coil Domain

by Zofie Sovova, Jiri Suttnar and Jan E. Dyr

Metabolites 2021, 11(5), 307; https://doi.org/10.3390/metabo11050307 - 11 May 2021

Cited by 3 | Viewed by 2118

Abstract

Fibrinogen is an abundant blood plasma protein that, inter alia, participates in blood coagulation. It polymerizes to form a fibrin clot that is among the major components of the thrombus. Fibrinogen reactions with various reactive metabolites may induce post-translational modifications (PTMs) into the [...] Read more.

Fibrinogen is an abundant blood plasma protein that, inter alia, participates in blood coagulation. It polymerizes to form a fibrin clot that is among the major components of the thrombus. Fibrinogen reactions with various reactive metabolites may induce post-translational modifications (PTMs) into the protein structure that affect the architecture and properties of fibrin clots. We reviewed the previous literature to find the positions of PTMs of fibrinogen. For 7 out of 307 reported PTMs, we used molecular dynamics simulations to characterize their effect on the behavior of the fibrinogen coiled-coil domain. Interactions of the γ-coil with adjacent chains give rise to π-helices in Aα and Bβ chains of even unmodified fibrinogen. The examined PTMs suppress fluctuations of the γ-coil, which may affect the fibrinolysis and stiffness of the fibrin fibers. Citrullination of AαR104 and oxidations of γP70 and γP76 to glutamic semialdehyde unfold the α-helical structure of Aα and Bβ chains. Oxidation of γM78 to methionine sulfoxide induces the formation of an α-helix in the γ-coil region. Our findings suggest that certain PTMs alter the protein secondary structure. Thus, the altered protein structure may indicate the presence of PTMs in the molecule and consequently of certain metabolites within the system. Full article

(This article belongs to the Special Issue Thrombosis and Metabolism)

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12 pages, 522 KiB

Open AccessBrief Report

Glycolysis Metabolites and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Trial

by Nerea Becerra-Tomás, Miguel Ruiz-Canela, Pablo Hernández-Alonso, Mònica Bulló, Jun Li, Marta Guasch-Ferré, Estefanía Toledo, Clary B. Clish, Ramon Estruch, Emilio Ros, Montserrat Fitó, Chih-Hao Lee, Kerry Pierce, Fernando Arós, Lluís Serra-Majem, Liming Liang, Cristina Razquin, Enrique Gómez-Gracia, Miguel A. Martínez-González, Frank B. Hu, Dolores Corella and Jordi Salas-Salvadó Show full author list Hide full author list

Metabolites 2021, 11(5), 306; https://doi.org/10.3390/metabo11050306 - 11 May 2021

Cited by 4 | Viewed by 3033

Abstract

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and [...] Read more.

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case–control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR _{for 1 SD increase}: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies. Full article

(This article belongs to the Special Issue Cardiovascular Risk Biomarkers: Deciphering the Metabolism and Interaction Networks)

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16 pages, 1754 KiB

Open AccessEditor’s ChoiceArticle

Untargeted Lipidomic Profiling of Dry Blood Spots Using SFC-HRMS

by Pauline Le Faouder, Julia Soullier, Marie Tremblay-Franco, Anthony Tournadre, Jean-François Martin, Yann Guitton, Caroline Carlé, Sylvie Caspar-Bauguil, Pierre-Damien Denechaud and Justine Bertrand-Michel

Metabolites 2021, 11(5), 305; https://doi.org/10.3390/metabo11050305 - 11 May 2021

Cited by 8 | Viewed by 3263

Abstract

Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated [...] Read more.

Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated in a large number of heterogeneous diseases, such as cancer, diabetes, neurological disorders, and inherited metabolic diseases. Due to the high structural diversity and complexity of lipid species, the presence of isomeric and isobaric lipid species, and their occurrence at a large concentration scale, a complete lipidomic profiling of biological matrices remains challenging, especially in clinical contexts. Using supercritical fluid chromatography coupled with high-resolution mass spectrometry, we have developed and validated an untargeted lipidomic approach to the profiling of plasma and blood. Moreover, we have tested the technique using the Dry Blood Spot (DBS) method and found that it allows for the easy collection of blood for analysis. To develop the method, we performed the optimization of the separation and detection of lipid species on pure standards, reference human plasma (SRM1950), whole blood, and DBS. These analyses allowed an in-house lipid data bank to be built. Using the MS-Dial software, we developed an automatic process for the relative quantification of around 500 lipids species belonging to the 6 main classes of lipids (including phospholipids, sphingolipids, free fatty acids, sterols, and fatty acyl-carnitines). Then, we compared the method using the published data for SRM 1950 and a mouse blood sample, along with another sample of the same blood collected using the DBS method. In this study, we provided a method for blood lipidomic profiling that can be used for the easy sampling of dry blood spots. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Lipidomics)

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13 pages, 1531 KiB

Open AccessFeature PaperArticle

Reconstruction of a Genome-Scale Metabolic Model of Streptomyces albus J1074: Improved Engineering Strategies in Natural Product Synthesis

by Cheewin Kittikunapong, Suhui Ye, Patricia Magadán-Corpas, Álvaro Pérez-Valero, Claudio J. Villar, Felipe Lombó and Eduard J. Kerkhoven

Metabolites 2021, 11(5), 304; https://doi.org/10.3390/metabo11050304 - 11 May 2021

Cited by 12 | Viewed by 3468

Abstract

Streptomyces albus J1074 is recognized as an effective host for heterologous production of natural products. Its fast growth and efficient genetic toolbox due to a naturally minimized genome have contributed towards its advantage in expressing biosynthetic pathways for a diverse repertoire of products [...] Read more.

Streptomyces albus J1074 is recognized as an effective host for heterologous production of natural products. Its fast growth and efficient genetic toolbox due to a naturally minimized genome have contributed towards its advantage in expressing biosynthetic pathways for a diverse repertoire of products such as antibiotics and flavonoids. In order to develop precise model-driven engineering strategies for de novo production of natural products, a genome-scale metabolic model (GEM) was reconstructed for the microorganism based on protein homology to model species Streptomyces coelicolor while drawing annotated data from databases and literature for further curation. To demonstrate its capabilities, the Salb-GEM was used to predict overexpression targets for desirable compounds using flux scanning with enforced objective function (FSEOF). Salb-GEM was also utilized to investigate the effect of a minimized genome on metabolic gene essentialities in comparison to another Streptomyces species, S. coelicolor. Full article

(This article belongs to the Special Issue Computational Biology for Metabolic Modelling)

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15 pages, 1264 KiB

Open AccessArticle

A Comprehensive Targeted Metabolomics Assay for Crop Plant Sample Analysis

by Jiamin Zheng, Mathew Johnson, Rupasri Mandal and David S. Wishart

Metabolites 2021, 11(5), 303; https://doi.org/10.3390/metabo11050303 - 11 May 2021

Cited by 15 | Viewed by 3845

Abstract

Metabolomics plays an important role in various fields from health to agriculture. However, the comprehensive quantitative metabolomic analysis of plants and plant metabolites has not been widely performed. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based plant metabolomics offers the sensitivity and breadth [...] Read more.

Metabolomics plays an important role in various fields from health to agriculture. However, the comprehensive quantitative metabolomic analysis of plants and plant metabolites has not been widely performed. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based plant metabolomics offers the sensitivity and breadth of coverage for both phenotyping and disease diagnosis of plants. Here, we report a high-coverage and quantitative MS-based assay for plant metabolite analysis. The assay detects and quantifies 206 primary and secondary plant metabolites, including many key plant hormones. In total, it measures 28 amino acids and derivatives, 27 organic acids, 20 biogenic amines and derivatives, 40 acylcarnitines, 90 phospholipids and C-6 sugars. All the analysis methods in this assay are based on LC-MS/MS techniques using both positive and negative-mode multiple reaction monitoring (MRM). The recovery rates of spiked plant samples at three different concentration levels (low, medium and high) ranged from 80% to 120%, with satisfactory precision values of less than 20%. This targeted plant metabolomic assay has been successfully applied to the analysis of large numbers of pine and spruce needle samples, canola root samples, as well as cannabis samples. Moreover, the assay was specifically developed in a 96-well plate format, which enables automated, high-throughput sample analysis. This assay has already been used to analyze over 1500 crop plant samples in less than two months. Full article

(This article belongs to the Special Issue Metabolomics in Agriculture Volume 2)

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15 pages, 671 KiB

Open AccessEditor’s ChoiceReview

FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology

by Medha Priyadarshini, Kristen Lednovich, Kai Xu, Sophie Gough, Barton Wicksteed and Brian T. Layden

Metabolites 2021, 11(5), 302; https://doi.org/10.3390/metabo11050302 - 11 May 2021

Cited by 11 | Viewed by 3818

Abstract

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut [...] Read more.

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders. Full article

(This article belongs to the Special Issue Islet Biology and Metabolism)

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