Next Issue
Volume 11, July
Previous Issue
Volume 11, May

Metabolites, Volume 11, Issue 6 (June 2021) – 77 articles

Cover Story (view full-size image): The General Unified Microbiome Profiling Pipeline (GUMPP) is designed for large-scale (HPC level), streamlined, and reproducible analysis of bacterial 16S rRNA data and prediction of microbial metagenomes, enzymatic reactions, and metabolic pathways from amplicon data. The GUMPP workflow introduces reproducible data analyses at each of the three levels of resolution: genus; operational taxonomic units (OTUs); amplicon sequence variants (ASVs). The resulting datasets can be coupled with biostatistical and mathematical machine learning approaches to play a significant role in extracting truly significant and meaningful information for the development of mechanistic hypotheses that are applicable to the development of novel therapies in personalized medicine. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Order results
Result details
Select all
Export citation of selected articles as:
Review
Therapeutic Potential of Date Palm against Human Infertility: A Review
Metabolites 2021, 11(6), 408; https://doi.org/10.3390/metabo11060408 - 21 Jun 2021
Viewed by 834
Abstract
Male and female infertility is a global major health problem. Approximately 15% of couples of a reproductive age are unable to achieve the desired pregnancy within 12 months, despite daily unprotected sexual intercourse, and about 10% of infertilities have no specific reason worldwide. [...] Read more.
Male and female infertility is a global major health problem. Approximately 15% of couples of a reproductive age are unable to achieve the desired pregnancy within 12 months, despite daily unprotected sexual intercourse, and about 10% of infertilities have no specific reason worldwide. Currently, many researchers are interested to investigate the use of natural remedies for preventive and curative purposes of infertility. This review brings together some of the data on the nutritional characteristics of the date palm and its different parts on fertility outcomes and critically evaluates the past and recent literature relevant to the consumption of date fruit against infertility-related problems. Due to its antioxidant potential, dates are considered a functional treatment for reducing the risks of infertility. In males, the date palm has a potent effect on the reproductive parameters including hormonal levels and seminal vesicle parameters as well as sperm motility, count, and viability; whereas, in females, it shows a convincing effect on reproductive parameters including oogenesis process, strengthening of oocytes, regulation of hormones, strengthening of pregnancy, reduction of the need for labor augmentation, and postpartum hemorrhage prevention. Full article
Show Figures

Figure 1

Article
Statistical Integration of ‘Omics Data Increases Biological Knowledge Extracted from Metabolomics Data: Application to Intestinal Exposure to the Mycotoxin Deoxynivalenol
Metabolites 2021, 11(6), 407; https://doi.org/10.3390/metabo11060407 - 21 Jun 2021
Viewed by 659
Abstract
The effects of low doses of toxicants are often subtle and information extracted from metabolomic data alone may not always be sufficient. As end products of enzymatic reactions, metabolites represent the final phenotypic expression of an organism and can also reflect gene expression [...] Read more.
The effects of low doses of toxicants are often subtle and information extracted from metabolomic data alone may not always be sufficient. As end products of enzymatic reactions, metabolites represent the final phenotypic expression of an organism and can also reflect gene expression changes caused by this exposure. Therefore, the integration of metabolomic and transcriptomic data could improve the extracted biological knowledge on these toxicants induced disruptions. In the present study, we applied statistical integration tools to metabolomic and transcriptomic data obtained from jejunal explants of pigs exposed to the food contaminant, deoxynivalenol (DON). Canonical correlation analysis (CCA) and self-organizing map (SOM) were compared for the identification of correlated transcriptomic and metabolomic features, and O2-PLS was used to model the relationship between exposure and selected features. The integration of both ‘omics data increased the number of discriminant metabolites discovered (39) by about 10 times compared to the analysis of the metabolomic dataset alone (3). Besides the disturbance of energy metabolism previously reported, assessing correlations between both functional levels revealed several other types of damage linked to the intestinal exposure to DON, including the alteration of protein synthesis, oxidative stress, and inflammasome activation. This confirms the added value of integration to enrich the biological knowledge extracted from metabolomics. Full article
(This article belongs to the Section Integrative Metabolomics)
Show Figures

Figure 1

Review
What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk
Metabolites 2021, 11(6), 406; https://doi.org/10.3390/metabo11060406 - 21 Jun 2021
Viewed by 1086
Abstract
Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic [...] Read more.
Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic host-microbiota interactions can have deep consequences for host health. However, the mechanisms by which the immune system regulates the microbiota and by which the microbiota shapes host immunity are still not fully understood. This article discusses the contribution of metabolites in the crosstalk between gut microbiota and immune cells. The identification of key metabolites having a causal effect on immune responses and of the mechanisms involved can contribute to a deeper insight into host-microorganism relationships. This will allow a better understanding of the correlation between dysbiosis, microbial-based dysmetabolism, and pathogenesis, thus creating opportunities to develop microbiota-based therapeutics to improve human health. In particular, we systematically review the role of soluble and membrane-bound microbial metabolites in modulating host immunity in the gut, and of immune cells-derived metabolites affecting the microbiota, while discussing evidence of the bidirectional impact of this crosstalk. Furthermore, we discuss the potential strategies to hear the sound of such metabolite-mediated crosstalk. Full article
(This article belongs to the Special Issue Reviews and Advances in Microbial Metabolomics)
Show Figures

Graphical abstract

Article
Respiratory Parameters for the Classification of Dysfunctional Insulin Secretion by Pancreatic Islets
Metabolites 2021, 11(6), 405; https://doi.org/10.3390/metabo11060405 - 21 Jun 2021
Viewed by 776
Abstract
The development of obesity and type 2 diabetes (T2D) has been associated with impaired mitochondrial function. In pancreatic beta (β) cells, mitochondrial energy metabolism plays a central role in triggering and controlling glucose-stimulated insulin secretion (GSIS). Here, we have explored whether mitochondrial bioenergetic [...] Read more.
The development of obesity and type 2 diabetes (T2D) has been associated with impaired mitochondrial function. In pancreatic beta (β) cells, mitochondrial energy metabolism plays a central role in triggering and controlling glucose-stimulated insulin secretion (GSIS). Here, we have explored whether mitochondrial bioenergetic parameters assessed with Seahorse extracellular flux technology can quantitatively predict insulin secretion. We metabolically stressed male C57BL/6 mice by high-fat feeding (HFD) and measured the glucose sensitivity of islet respiration and insulin secretion. The diet-induced obese (DIO) mice developed hyperinsulinemia, but no pathological secretory differences were apparent between isolated DIO and chow islets. Real-time extracellular flux analysis, however, revealed a lower respiratory sensitivity to glucose in DIO islets. Correlation of insulin secretion with respiratory parameters uncovers compromised insulin secretion in DIO islets by oxidative power. Normalization to increased insulin contents during DIO improves the quantitative relation between GSIS and respiration, allowing to classify dysfunctional properties of pancreatic insulin secretion, and thereby serving as valuable biomarker for pancreatic islet glucose responsiveness and health. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
Show Figures

Figure 1

Article
A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life
Metabolites 2021, 11(6), 404; https://doi.org/10.3390/metabo11060404 - 20 Jun 2021
Viewed by 706
Abstract
Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct [...] Read more.
Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed 1H-NMR metabolomics in the gastrocnemius muscle in weanling and young adult Walker-256 tumour-bearing rats at different stages of tumour evolution (initial, intermediate, and advanced). Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host’s age, highlighting the need to adopting the right animal age when studying cancer cachexia. Full article
(This article belongs to the Special Issue Cancer Metabolomic 2020)
Show Figures

Graphical abstract

Article
A Metabolic Choreography of Maize Plants Treated with a Humic Substance-Based Biostimulant under Normal and Starved Conditions
Metabolites 2021, 11(6), 403; https://doi.org/10.3390/metabo11060403 - 20 Jun 2021
Viewed by 823
Abstract
Humic substance (HS)-based biostimulants show potentials as sustainable strategies for improved crop development and stress resilience. However, cellular and molecular mechanisms governing the agronomically observed effects of HS on plants remain enigmatic. Here, we report a global metabolic reprogramming of maize leaves induced [...] Read more.
Humic substance (HS)-based biostimulants show potentials as sustainable strategies for improved crop development and stress resilience. However, cellular and molecular mechanisms governing the agronomically observed effects of HS on plants remain enigmatic. Here, we report a global metabolic reprogramming of maize leaves induced by a humic biostimulant under normal and nutrient starvation conditions. This reconfiguration of the maize metabolism spanned chemical constellations, as revealed by molecular networking approaches. Plant growth and development under normal conditions were characterized by key differential metabolic changes such as increased levels of amino acids, oxylipins and the tricarboxylic acid (TCA) intermediate, isocitric acid. Furthermore, under starvation, the humic biostimulant significantly impacted pathways that are involved in stress-alleviating mechanisms such as redox homeostasis, strengthening of the plant cell wall, osmoregulation, energy production and membrane remodelling. Thus, this study reveals that the humic biostimulant induces a remodelling of inter-compartmental metabolic networks in maize, subsequently readjusting the plant physiology towards growth promotion and stress alleviation. Such insights contribute to ongoing efforts in elucidating modes of action of biostimulants, generating fundamental scientific knowledge that is necessary for development of the biostimulant industry, for sustainable food security. Full article
Show Figures

Figure 1

Review
Asparagine: A Metabolite to Be Targeted in Cancers
Metabolites 2021, 11(6), 402; https://doi.org/10.3390/metabo11060402 - 19 Jun 2021
Viewed by 1013
Abstract
Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a [...] Read more.
Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization. Full article
(This article belongs to the Special Issue Metabolism and Diseases)
Show Figures

Graphical abstract

Article
The Capacity to Secrete Insulin Is Dose-Dependent to Extremely High Glucose Concentrations: A Key Role for Adenylyl Cyclase
Metabolites 2021, 11(6), 401; https://doi.org/10.3390/metabo11060401 - 19 Jun 2021
Viewed by 672
Abstract
Insulin secretion is widely thought to be maximally stimulated in glucose concentrations of 16.7-to-30 mM (300-to-540 mg/dL). However, insulin secretion is seldom tested in hyperglycemia exceeding these levels despite the Guinness World Record being 147.6 mM (2656 mg/dL). We investigated how islets respond [...] Read more.
Insulin secretion is widely thought to be maximally stimulated in glucose concentrations of 16.7-to-30 mM (300-to-540 mg/dL). However, insulin secretion is seldom tested in hyperglycemia exceeding these levels despite the Guinness World Record being 147.6 mM (2656 mg/dL). We investigated how islets respond to 1-h exposure to glucose approaching this record. Insulin secretion from human islets at 12 mM glucose intervals dose-dependently increased until at least 72 mM glucose. Murine islets in 84 mM glucose secreted nearly double the insulin as in 24 mM (p < 0.001). Intracellular calcium was maximally stimulated in 24 mM glucose despite a further doubling of insulin secretion in higher glucose, implying that insulin secretion above 24 mM occurs through amplifying pathway(s). Increased osmolarity of 425-mOsm had no effect on insulin secretion (1-h exposure) or viability (48-h exposure) in murine islets. Murine islets in 24 mM glucose treated with a glucokinase activator secreted as much insulin as islets in 84 mM glucose, indicating that glycolytic capacity exists above 24 mM. Using an incretin mimetic and an adenylyl cyclase activator in 24 mM glucose enhanced insulin secretion above that observed in 84 mM glucose while adenylyl cyclase inhibitor reduced stimulatory effects. These results highlight the underestimated ability of islets to secrete insulin proportionally to extreme hyperglycemia through adenylyl cyclase activity. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
Show Figures

Graphical abstract

Article
A Compositional Model to Predict the Aggregated Isotope Distribution for Average DNA and RNA Oligonucleotides
Metabolites 2021, 11(6), 400; https://doi.org/10.3390/metabo11060400 - 18 Jun 2021
Viewed by 635
Abstract
Structural modifications of DNA and RNA molecules play a pivotal role in epigenetic and posttranscriptional regulation. To characterise these modifications, more and more MS and MS/MS- based tools for the analysis of nucleic acids are being developed. To identify an oligonucleotide in a [...] Read more.
Structural modifications of DNA and RNA molecules play a pivotal role in epigenetic and posttranscriptional regulation. To characterise these modifications, more and more MS and MS/MS- based tools for the analysis of nucleic acids are being developed. To identify an oligonucleotide in a mass spectrum, it is useful to compare the obtained isotope pattern of the molecule of interest to the one that is theoretically expected based on its elemental composition. However, this is not straightforward when the identity of the molecule under investigation is unknown. Here, we present a modelling approach for the prediction of the aggregated isotope distribution of an average DNA or RNA molecule when a particular (monoisotopic) mass is available. For this purpose, a theoretical database of all possible DNA/RNA oligonucleotides up to a mass of 25 kDa is created, and the aggregated isotope distribution for the entire database of oligonucleotides is generated using the BRAIN algorithm. Since this isotope information is compositional in nature, the modelling method is based on the additive log-ratio analysis of Aitchison. As a result, a univariate weighted polynomial regression model of order 10 is fitted to predict the first 20 isotope peaks for DNA and RNA molecules. The performance of the prediction model is assessed by using a mean squared error approach and a modified Pearson’s χ2 goodness-of-fit measure on experimental data. Our analysis has indicated that the variability in spectral accuracy contributed more to the errors than the approximation of the theoretical isotope distribution by our proposed average DNA/RNA model. The prediction model is implemented as an online tool. An R function can be downloaded to incorporate the method in custom analysis workflows to process mass spectral data. Full article
(This article belongs to the Special Issue Computational Methods for Secondary Metabolite Discovery)
Show Figures

Graphical abstract

Article
Differences in Clinical and Dietary Characteristics, Serum Adipokine Levels, and Metabolomic Profiles between Early- and Late-Onset Gout
Metabolites 2021, 11(6), 399; https://doi.org/10.3390/metabo11060399 - 18 Jun 2021
Viewed by 632
Abstract
This study aimed to identify differences in clinical and dietary characteristics, serum adipokine levels, and metabolomic profiles between early- and late-onset gout. Eighty-three men with gout were divided into an early-onset group (n = 38, aged < 40 years) and a late-onset [...] Read more.
This study aimed to identify differences in clinical and dietary characteristics, serum adipokine levels, and metabolomic profiles between early- and late-onset gout. Eighty-three men with gout were divided into an early-onset group (n = 38, aged < 40 years) and a late-onset group (n = 45, aged ≥ 40 years). Dietary and clinical information was obtained at baseline. Serum adipokines, including adiponectin, resistin, leptin, and plasminogen activator inhibitor-1 (PAI-1), were quantified by a Luminex multiplex immunoassay. Metabolite expression levels in plasma were measured in 22 representative samples using metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Average body mass index, rate of consumption of sugar-sweetened beverages, and serum uric acid levels were significantly higher in the early-onset group (p < 0.05), as was the PAI-I concentration (105.01 ± 42.45 ng/mL vs. 83.76 ± 31.16 ng/mL, p = 0.013). Changes in levels of metabolites mostly involved those related to lipid metabolism. In the early-onset group, acylcarnitine analog and propylparaben levels were downregulated and negatively correlated with the PAI-1 concentration whereas LPC (22:6) and LPC (18:0) levels were upregulated and positively correlated with the PAI-1 concentration. Dietary and clinical features, serum adipokine concentrations, and metabolites differed according to whether the gout is early-onset or late-onset. The mechanisms of gout may differ between these groups and require different treatment approaches. Full article
(This article belongs to the Section Lipid Metabolism)
Show Figures

Graphical abstract

Article
High-Throughput Chlorophyll and Carotenoid Profiling Reveals Positive Associations with Sugar and Apocarotenoid Volatile Content in Fruits of Tomato Varieties in Modern and Wild Accessions
Metabolites 2021, 11(6), 398; https://doi.org/10.3390/metabo11060398 - 18 Jun 2021
Viewed by 1692
Abstract
Flavor and nutritional quality has been negatively impacted during the course of domestication and improvement of the cultivated tomato (Solanum lycopersicum). Recent emphasis on consumers has emphasized breeding strategies that focus on flavor-associated chemicals, including sugars, acids, and aroma compounds. [...] Read more.
Flavor and nutritional quality has been negatively impacted during the course of domestication and improvement of the cultivated tomato (Solanum lycopersicum). Recent emphasis on consumers has emphasized breeding strategies that focus on flavor-associated chemicals, including sugars, acids, and aroma compounds. Carotenoids indirectly affect flavor as precursors of aroma compounds, while chlorophylls contribute to sugar production through photosynthesis. However, the relationships between these pigments and flavor content are still unclear. In this study, we developed a simple and high-throughput method to quantify chlorophylls and carotenoids. This method was applied to over one hundred tomato varieties, including S. lycopersicum and its wild relatives (S. l. var. cerasiforme and S. pimpinellifolium), for quantification of these pigments in fruits. The results obtained by integrating data of the pigments, soluble solids, sugars, and aroma compounds indicate that (i) chlorophyll-abundant varieties have relatively higher sugar accumulations and (ii) prolycopene is associated with an abundance of linear carotenoid-derived aroma compounds in one of the orange-fruited varieties, “Dixie Golden Giant”. Our results suggest the importance of these pigments not only as components of fruit color but also as factors influencing flavor traits, such as sugars and aroma. Full article
(This article belongs to the Section Plant Science)
Show Figures

Graphical abstract

Article
The Effects of Fasting or Ketogenic Diet on Endurance Exercise Performance and Metabolism in Female Mice
Metabolites 2021, 11(6), 397; https://doi.org/10.3390/metabo11060397 - 18 Jun 2021
Viewed by 966
Abstract
The promotion of ketone body (KB) metabolism via ketosis has been suggested as a strategy to increase exercise performance. However, studies in humans and animals have yielded inconsistent results. The purpose of the current study was to examine the effects of ketosis, achieved [...] Read more.
The promotion of ketone body (KB) metabolism via ketosis has been suggested as a strategy to increase exercise performance. However, studies in humans and animals have yielded inconsistent results. The purpose of the current study was to examine the effects of ketosis, achieved via fasting or a short-term ketogenic diet (KD), on endurance exercise performance in female mice. After 8 h of fasting, serum KB significantly increased and serum glucose significantly decreased in fasted compared to fed mice. When subjected to an endurance exercise capacity (EEC) test on a motorized treadmill, both fed and fasted mice showed similar EEC performance. A 5-week KD (90% calories from fat) significantly increased serum KB but did not increase EEC times compared to chow-fed mice. KD mice gained significantly more weight than chow-fed mice and had greater adipose tissue mass. Biochemical tissue analysis showed that KD led to significant increases in triglyceride content in the heart and liver and significant decreases in glycogen content in the muscle and liver. Furthermore, KD downregulated genes involved in glucose and KB oxidation and upregulated genes involved in lipid metabolism in the heart. These findings suggest that a short-term KD is not an effective strategy to enhance exercise performance and may lead to increased adiposity, abnormal endogenous tissue storage, and cardiometabolic remodeling. Full article
(This article belongs to the Special Issue Effect of Exercise on Energy Metabolism)
Show Figures

Graphical abstract

Article
Characterizing Autophagy in the Cold Ischemic Injury of Small Bowel Grafts: Evidence from Rat Jejunum
Metabolites 2021, 11(6), 396; https://doi.org/10.3390/metabo11060396 - 17 Jun 2021
Viewed by 619
Abstract
Cold ischemic injury to the intestine during preservation remains an unresolved issue in transplantation medicine. Autophagy, a cytoplasmic protein degradation pathway, is essential for metabolic adaptation to starvation, hypoxia, and ischemia. It has been implicated in the cold ischemia (CI) of other transplantable [...] Read more.
Cold ischemic injury to the intestine during preservation remains an unresolved issue in transplantation medicine. Autophagy, a cytoplasmic protein degradation pathway, is essential for metabolic adaptation to starvation, hypoxia, and ischemia. It has been implicated in the cold ischemia (CI) of other transplantable organs. This study determines the changes in intestinal autophagy evoked by cold storage and explores the effects of autophagy on ischemic grafts. Cold preservation was simulated by placing the small intestines of Wistar rats in an IGL-1 (Institute George Lopez) solution at 4 °C for varying periods (3, 6, 9, and 12 h). The extent of graft preservation injury (mucosal and cellular injury) and changes in autophagy were measured after each CI time. Subsequently, we determined the differences in apoptosis and preservation injury after activating autophagy with rapamycin or inhibiting it with 3-methyladenine. The results revealed that ischemic injury and autophagy were induced by cold storage. Autophagy peaked at 3 h and subsequently declined. After 12 h of storage, autophagic expression was reduced significantly. Additionally, enhanced intestinal autophagy by rapamycin was associated with less tissue, cellular, and apoptotic damage during and after the 12-h long preservation. After reperfusion, grafts with enhanced autophagy still presented with less injury. Inhibiting autophagy exhibited the opposite trend. These findings demonstrate intestinal autophagy changes in cold preservation. Furthermore, enhanced autophagy was protective against cold ischemia–reperfusion damage of the small bowels. Full article
(This article belongs to the Special Issue Hemorheology and Metabolism)
Show Figures

Figure 1

Article
Evaluating the Robustness of Biomarkers of Dairy Food Intake in a Free-Living Population Using Single- and Multi-Marker Approaches
Metabolites 2021, 11(6), 395; https://doi.org/10.3390/metabo11060395 - 17 Jun 2021
Viewed by 706
Abstract
Studies examining associations between self-reported dairy intake and health are inconclusive, but biomarkers hold promise for elucidating such relationships by offering objective measures of dietary intake. Previous human intervention studies identified several biomarkers for dairy foods in blood and urine using non-targeted metabolomics. [...] Read more.
Studies examining associations between self-reported dairy intake and health are inconclusive, but biomarkers hold promise for elucidating such relationships by offering objective measures of dietary intake. Previous human intervention studies identified several biomarkers for dairy foods in blood and urine using non-targeted metabolomics. We evaluated the robustness of these biomarkers in a free-living cohort in the Netherlands using both single- and multi-marker approaches. Plasma and urine from 246 participants (54 ± 13 years) who completed a food frequency questionnaire were analyzed using liquid and gas chromatography-mass spectrometry. The targeted metabolite panel included 37 previously-identified candidate biomarkers of milk, cheese, and/or yoghurt consumption. Associations between biomarkers and energy-adjusted dairy food intakes were assessed by a ‘single-marker’ generalized linear model, and stepwise regression was used to select the best ‘multi-marker’ panel. Multi-marker models that also accounted for common covariates better captured the subtle differences for milk (urinary galactose, galactitol; sex, body mass index, age) and cheese (plasma pentadecanoic acid, isoleucine, glutamic acid) over single-marker models. No significant associations were observed for yogurt. Further examination of other facets of validity of these biomarkers may improve estimates of dairy food intake in conjunction with self-reported methods, and help reach a clearer consensus on their health impacts. Full article
Show Figures

Graphical abstract

Article
Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss
Metabolites 2021, 11(6), 394; https://doi.org/10.3390/metabo11060394 - 17 Jun 2021
Viewed by 735
Abstract
Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute [...] Read more.
Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes. Full article
(This article belongs to the Special Issue Metabolites and Signaling Pathways)
Show Figures

Figure 1

Article
Identification of Koala (Phascolarctos cinereus) Faecal Cortisol Metabolites Using Liquid Chromatography-Mass Spectrometry and Enzyme Immunoassays
Metabolites 2021, 11(6), 393; https://doi.org/10.3390/metabo11060393 - 16 Jun 2021
Cited by 1 | Viewed by 942
Abstract
The koala (Phascolarctos cinereus) is an arboreal folivorous marsupial endemic to Australia. Anthropogenic activities and climate change are threats to this species’ survival and are potential stressors. A suitable non-invasive method is needed to objectively detect stress in koalas. Under conditions [...] Read more.
The koala (Phascolarctos cinereus) is an arboreal folivorous marsupial endemic to Australia. Anthropogenic activities and climate change are threats to this species’ survival and are potential stressors. A suitable non-invasive method is needed to objectively detect stress in koalas. Under conditions of stress, the concentration of the hormone cortisol in plasma or in saliva is elevated, and this would provide a convenient measure; however, collecting blood or saliva from wild animals is both practically difficult and stressful, and so likely to confound any measurement. In contrast, measurement of cortisol metabolites in faeces provides a practical and non-invasive method to objectively measure stress in koalas. Unfortunately, the identity of the main faecal cortisol metabolites of koalas is unknown. In this study, we have used both untargeted liquid chromatography–mass spectrometry (LC-MS) and enzyme immunoassays (EIAs) to identify several faecal cortisol metabolites in two koalas, one female (18 months old, 4.1 kg) and one male (4 years old, 6.95 kg) upon administration of hydrocortisone (cortisol) sodium succinate. The LC-MS analysis identified tetrahydrocortisol along with several other isomers as cortisol metabolites. After a survey of five enzyme immunoassays, we found that two metabolites, tetrahydrocortisol and 3β-allotetrahydrocortisol, could be detected by EIAs that used antibodies that were raised against their structurally similar corticosterone counterparts, tetrahydrocorticosterone and 3β-allotetrahydrocorticosterone, respectively. While the 3β-allotetrahydrocortisol metabolite was detected in the faeces of only one of the two animals studied, tetrahydrocortisol was detected in both. These results ultimately indicate that tetrahydrocortisol is likely the main faecal cortisol metabolite in koalas, and we demonstrate that it can be measured by an EIA (50c) that was originally developed to measure tetrahydrocorticosterone. Full article
Show Figures

Figure 1

Article
Serum Metabolites Responding in a Dose-Dependent Manner to the Intake of a High-Fat Meal in Normal Weight Healthy Men Are Associated with Obesity
Metabolites 2021, 11(6), 392; https://doi.org/10.3390/metabo11060392 - 16 Jun 2021
Viewed by 832
Abstract
Although the composition of the human blood metabolome is influenced both by the health status of the organism and its dietary behavior, the interaction between these two factors has been poorly characterized. This study makes use of a previously published randomized controlled crossover [...] Read more.
Although the composition of the human blood metabolome is influenced both by the health status of the organism and its dietary behavior, the interaction between these two factors has been poorly characterized. This study makes use of a previously published randomized controlled crossover acute intervention to investigate whether the blood metabolome of 15 healthy normal weight (NW) and 17 obese (OB) men having ingested three doses (500, 1000, 1500 kcal) of a high-fat (HF) meal can be used to identify metabolites differentiating these two groups. Among the 1024 features showing a postprandial response, measured between 0 h and 6 h, in the NW group, 135 were dose-dependent. Among these 135 features, 52 had fasting values that were significantly different between NW and OB men, and, strikingly, they were all significantly higher in OB men. A subset of the 52 features was identified as amino acids (e.g., branched-chain amino acids) and amino acid derivatives. As the fasting concentration of most of these metabolites has already been associated with metabolic dysfunction, we propose that challenging normal weight healthy subjects with increasing caloric doses of test meals might allow for the identification of new fasting markers associated with obesity. Full article
(This article belongs to the Special Issue Metabolic Health and Weight II)
Show Figures

Figure 1

Article
Metabolite Profiling in Arabidopsisthaliana with Moderately Impaired Photorespiration Reveals Novel Metabolic Links and Compensatory Mechanisms of Photorespiration
Metabolites 2021, 11(6), 391; https://doi.org/10.3390/metabo11060391 - 15 Jun 2021
Viewed by 756
Abstract
Photorespiration is an integral component of plant primary metabolism. Accordingly, it has been often observed that impairing the photorespiratory flux negatively impacts other cellular processes. In this study, the metabolic acclimation of the Arabidopsisthaliana wild type was compared with the hydroxypyruvate reductase [...] Read more.
Photorespiration is an integral component of plant primary metabolism. Accordingly, it has been often observed that impairing the photorespiratory flux negatively impacts other cellular processes. In this study, the metabolic acclimation of the Arabidopsisthaliana wild type was compared with the hydroxypyruvate reductase 1 (HPR1; hpr1) mutant, displaying only a moderately reduced photorespiratory flux. Plants were analyzed during development and under varying photoperiods with a combination of non-targeted and targeted metabolome analysis, as well as 13C- and 14C-labeling approaches. The results showed that HPR1 deficiency is more critical for photorespiration during the vegetative compared to the regenerative growth phase. A shorter photoperiod seems to slowdown the photorespiratory metabolite conversion mostly at the glycerate kinase and glycine decarboxylase steps compared to long days. It is demonstrated that even a moderate impairment of photorespiration severely reduces the leaf-carbohydrate status and impacts on sulfur metabolism. Isotope labeling approaches revealed an increased CO2 release from hpr1 leaves, most likely occurring from enhanced non-enzymatic 3-hydroxypyruvate decarboxylation and a higher flux from serine towards ethanolamine through serine decarboxylase. Collectively, the study provides evidence that the moderate hpr1 mutant is an excellent tool to unravel the underlying mechanisms governing the regulation of metabolic linkages of photorespiration with plant primary metabolism. Full article
(This article belongs to the Special Issue Photorespiration on Plant Metabolism)
Show Figures

Figure 1

Article
Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors
Metabolites 2021, 11(6), 390; https://doi.org/10.3390/metabo11060390 - 15 Jun 2021
Viewed by 766
Abstract
The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, [...] Read more.
The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD’s bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads. Full article
(This article belongs to the Special Issue Computational Strategies in Metabolite Research)
Show Figures

Graphical abstract

Article
Feature Ranking and Screening for Class-Imbalanced Metabolomics Data Based on Rank Aggregation Coupled with Re-Balance
Metabolites 2021, 11(6), 389; https://doi.org/10.3390/metabo11060389 - 14 Jun 2021
Viewed by 650
Abstract
Feature screening is an important and challenging topic in current class-imbalance learning. Most of the existing feature screening algorithms in class-imbalance learning are based on filtering techniques. However, the variable rankings obtained by various filtering techniques are generally different, and this inconsistency among [...] Read more.
Feature screening is an important and challenging topic in current class-imbalance learning. Most of the existing feature screening algorithms in class-imbalance learning are based on filtering techniques. However, the variable rankings obtained by various filtering techniques are generally different, and this inconsistency among different variable ranking methods is usually ignored in practice. To address this problem, we propose a simple strategy called rank aggregation with re-balance (RAR) for finding key variables from class-imbalanced data. RAR fuses each rank to generate a synthetic rank that takes every ranking into account. The class-imbalanced data are modified via different re-sampling procedures, and RAR is performed in this balanced situation. Five class-imbalanced real datasets and their re-balanced ones are employed to test the RAR’s performance, and RAR is compared with several popular feature screening methods. The result shows that RAR is highly competitive and almost better than single filtering screening in terms of several assessing metrics. Performing re-balanced pretreatment is hugely effective in rank aggregation when the data are class-imbalanced. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
Show Figures

Figure 1

Article
An Improvement of SPME-Based Sampling Technique to Collect Volatile Organic Compounds from Quercus ilex at the Environmental Level
Metabolites 2021, 11(6), 388; https://doi.org/10.3390/metabo11060388 - 14 Jun 2021
Viewed by 792
Abstract
Biogenic Volatile Organic Compounds (BVOCs) include many chemical compounds emitted by plants into the atmosphere. These compounds have a great effect on biosphere–atmosphere interactions and may affect the concentration of atmospheric pollutants, with further consequences on human health and forest ecosystems. Novel methods [...] Read more.
Biogenic Volatile Organic Compounds (BVOCs) include many chemical compounds emitted by plants into the atmosphere. These compounds have a great effect on biosphere–atmosphere interactions and may affect the concentration of atmospheric pollutants, with further consequences on human health and forest ecosystems. Novel methods to measure and determine BVOCs in the atmosphere are of compelling importance considering the ongoing climate changes. In this study, we developed a fast and easy-to-handle analytical methodology to sample these compounds in field experiments using solid-phase microextraction (SPME) fibers at the atmospheric level. An improvement of BVOCs adsorption from SPME fibers was obtained by coupling the fibers with fans to create a dynamic sampling system. This innovative technique was tested sampling Q. ilex BVOCs in field conditions in comparison with the conventional static SPME sampling technique. The results showed a great potential of this dynamic sampling system to collect BVOCs at the atmosphere level, improving the efficiency and sensitivity of SPME fibers. Indeed, our novel device was able to reduce the sampling time, increase the amount of BVOCs collected through the fibers and add information regarding the emissions of these compounds at the environmental level. Full article
(This article belongs to the Special Issue Metabolomics in Plant Environmental Physiology)
Show Figures

Graphical abstract

Article
Ectopic Leptin Production by Intraocular Pancreatic Islet Organoids Ameliorates the Metabolic Phenotype of ob/ob Mice
Metabolites 2021, 11(6), 387; https://doi.org/10.3390/metabo11060387 - 14 Jun 2021
Viewed by 797
Abstract
The pancreatic islets of Langerhans consist of endocrine cells that secrete peptide hormones into the blood circulation in response to metabolic stimuli. When transplanted into the anterior chamber of the eye (ACE), pancreatic islets engraft and maintain morphological features of native islets as [...] Read more.
The pancreatic islets of Langerhans consist of endocrine cells that secrete peptide hormones into the blood circulation in response to metabolic stimuli. When transplanted into the anterior chamber of the eye (ACE), pancreatic islets engraft and maintain morphological features of native islets as well as islet-specific vascularization and innervation patterns. In sufficient amounts, intraocular islets are able to maintain glucose homeostasis in diabetic mice. Islet organoids (pseudo-islets), which are formed by self-reassembly of islet cells following disaggregation and genetic manipulation, behave similarly to native islets. Here, we tested the hypothesis that genetically engineered intraocular islet organoids can serve as production sites for leptin. To test this hypothesis, we chose the leptin-deficient ob/ob mouse as a model system, which becomes severely obese, hyperinsulinemic, hyperglycemic, and insulin resistant. We generated a Tet-OFF-based beta-cell-specific adenoviral expression construct for mouse leptin, which allowed efficient transduction of native beta-cells, optical monitoring of leptin expression by co-expressed fluorescent proteins, and the possibility to switch-off leptin expression by treatment with doxycycline. Intraocular transplantation of islet organoids formed from transduced islet cells, which lack functional leptin receptors, to ob/ob mice allowed optical monitoring of leptin expression and ameliorated their metabolic phenotype by improving bodyweight, glucose tolerance, serum insulin, and C-peptide levels. Full article
(This article belongs to the Special Issue Islet Biology and Metabolism)
Show Figures

Graphical abstract

Review
Hyperpolarized Metabolic MRI—Acquisition, Reconstruction, and Analysis Methods
Metabolites 2021, 11(6), 386; https://doi.org/10.3390/metabo11060386 - 14 Jun 2021
Viewed by 764
Abstract
Hyperpolarized metabolic MRI with 13C-labeled agents has emerged as a powerful technique for in vivo assessments of real-time metabolism that can be used across scales of cells, tissue slices, animal models, and human subjects. Hyperpolarized contrast agents have unique properties compared to conventional MRI scanning and MRI contrast agents that require specialized imaging methods. Hyperpolarized contrast agents have a limited amount of available signal, irreversible decay back to thermal equilibrium, bolus injection and perfusion kinetics, cellular uptake and metabolic conversion kinetics, and frequency shifts between metabolites. This article describes state-of-the-art methods for hyperpolarized metabolic MRI, summarizing data acquisition, reconstruction, and analysis methods in order to guide the design and execution of studies. Full article
Show Figures

Figure 1

Review
Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors
Metabolites 2021, 11(6), 385; https://doi.org/10.3390/metabo11060385 - 14 Jun 2021
Viewed by 807
Abstract
Coenzyme Q (ubiquinone or CoQ) is a conserved polyprenylated lipid essential for mitochondrial respiration. CoQ is composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. A classic pathway leading to CoQ biosynthesis employs 4-hydroxybenzoic acid [...] Read more.
Coenzyme Q (ubiquinone or CoQ) is a conserved polyprenylated lipid essential for mitochondrial respiration. CoQ is composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. A classic pathway leading to CoQ biosynthesis employs 4-hydroxybenzoic acid (4HB). Recent studies with stable isotopes in E. coli, yeast, and plant and animal cells have identified CoQ intermediates and new metabolic pathways that produce 4HB. Stable isotope labeling has identified para-aminobenzoic acid as an alternate ring precursor of yeast CoQ biosynthesis, as well as other natural products, such as kaempferol, that provide ring precursors for CoQ biosynthesis in plants and mammals. In this review, we highlight how stable isotopes can be used to delineate the biosynthetic pathways leading to CoQ. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism and Bioenergetics)
Show Figures

Graphical abstract

Article
Agronomic and Metabolomic Side-Effects of a Divergent Selection for Indol-3-Ylmethylglucosinolate Content in Kale (Brassica oleracea var. acephala)
Metabolites 2021, 11(6), 384; https://doi.org/10.3390/metabo11060384 - 14 Jun 2021
Viewed by 864
Abstract
Brassica oleracea var. acephala (kale) is a cruciferous vegetable widely cultivated for its leaves and flower buds in Europe and a food of global interest as a “superfood”. Brassica crops accumulate phytochemicals called glucosinolates (GSLs) which play an important role in plant defense [...] Read more.
Brassica oleracea var. acephala (kale) is a cruciferous vegetable widely cultivated for its leaves and flower buds in Europe and a food of global interest as a “superfood”. Brassica crops accumulate phytochemicals called glucosinolates (GSLs) which play an important role in plant defense against biotic stresses. Studies carried out to date suggest that GSLs may have a role in the adaptation of plants to different environments, but direct evidence is lacking. We grew two kale populations divergently selected for high and low indol-3-ylmethylGSL (IM) content (H-IM and L-IM, respectively) in different environments and analyzed agronomic parameters, GSL profiles and metabolomic profile. We found a significant increase in fresh and dry foliar weight in H-IM kale populations compared to L-IM in addition to a greater accumulation of total GSLs, indole GSLs and, specifically, IM and 1-methoxyindol-3-ylmethylGSL (1MeOIM). Metabolomic analysis revealed a significant different concentration of 44 metabolites in H-IM kale populations compared to L-IM. According to tentative peak identification from MS interpretation, 80% were phenolics, including flavonoids (kaempferol, quercetin and anthocyanin derivates, including acyl flavonoids), chlorogenic acids (esters of hydroxycinnamic acids and quinic acid), hydroxycinnamic acids (ferulic acid and p-coumaric acid) and coumarins. H-IM kale populations could be more tolerant to diverse environmental conditions, possibly due to GSLs and the associated metabolites with predicted antioxidant potential. Full article
(This article belongs to the Special Issue Metabolomics in Agriculture Volume 2)
Show Figures

Figure 1

Article
Metabolic Profiles of Brassica juncea Roots in Response to Cadmium Stress
Metabolites 2021, 11(6), 383; https://doi.org/10.3390/metabo11060383 - 13 Jun 2021
Viewed by 857
Abstract
Brassica juncea has great application potential in phytoremediation of cadmium (Cd)-contaminated soil because of its excellent Cd accumulating and high biomass. In this study, we compared the effects of Cd under 48 h and 7 d stress in roots of Brassica juncea using [...] Read more.
Brassica juncea has great application potential in phytoremediation of cadmium (Cd)-contaminated soil because of its excellent Cd accumulating and high biomass. In this study, we compared the effects of Cd under 48 h and 7 d stress in roots of Brassica juncea using metabolite profiling. The results showed that many metabolic pathways and metabolites in Brassica juncea roots were altered significantly in response to Cd stress. We found that significant differences in levels of amino acids, organic acids, carbohydrates, lipids, flavonoids, alkaloids, and indoles were induced by Cd stress at different times, which played a pivotal role in the adaptation of Brassica juncea roots to Cd stress. Meanwhile, Brassica juncea roots could resist 48 h Cd stress by regulating the biosynthesis of amino acids, linoleic acid metabolism, aminoacyl-tRNA biosynthesis, glycerophospholipid metabolism, ABC transporters, arginine biosynthesis, valine, leucine and isoleucine biosynthesis, and alpha-linolenic acid metabolism; however, they regulated alpha-linolenic acid metabolism, glycerophospholipid metabolism, ABC transporters, and linoleic acid metabolism to resist 7 d Cd stress. A metabolomic expedition to the response of Brassica juncea to Cd stress will help to comprehend its tolerance and accumulation mechanisms of Cd. Full article
(This article belongs to the Special Issue Metabolomics in Plant Environmental Physiology)
Show Figures

Graphical abstract

Article
Dried Blood Spot (DBS) Methodology Study for Biomarker Discovery in Lysosomal Storage Disease (LSD)
Metabolites 2021, 11(6), 382; https://doi.org/10.3390/metabo11060382 - 13 Jun 2021
Viewed by 820
Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited metabolic diseases caused by mutations in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur in approximately 1 in 5000 live births and pose a lifelong risk. Therefore, to [...] Read more.
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited metabolic diseases caused by mutations in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur in approximately 1 in 5000 live births and pose a lifelong risk. Therefore, to achieve the maximum benefit from LSDs therapies, a fast and early diagnosis of the disease is required. In this framework, biomarker discovery is a significant factor in disease diagnosis and in predicting its outcomes. On the other hand, the dried blood spot (DBS) based metabolomics platform can open up new pathways for studying non-directional hypothesis approaches to biomarker discovery. This study aims to increase the efficiency of the developed methods for biomarker development in the context of rare diseases, with an improved impact on the reliability of the detected compounds. Thereby, we conducted two independent experiments and integrated them into the screening of the human blood metabolome: (1) comparison of EDTA blood and filter cards in terms of their suitability for metabolomics studies; (2) optimization of the extraction method: a side-by-side comparison of a series of buffers to the best utility to the disease of interest. The findings were compared to previous studies across parameters such as metabolite coverage, sample type suitability, and stability. The results indicate that measurements of metabolites are susceptible to differences in pre-analytical conditions and extraction solvents. This proposed approach can increase the positive rate of the future development of biomarkers. Altogether, the procedure can be easily adapted and applied to other studies, where the limited number of samples is a common barrier. Full article
Show Figures

Figure 1

Article
Effects of Dufulin on Oxidative Stress and Metabolomic Profile of Tubifex
Metabolites 2021, 11(6), 381; https://doi.org/10.3390/metabo11060381 - 11 Jun 2021
Viewed by 1102
Abstract
Dufulin is a highly effective antiviral pesticide used in plants. In this study, a seven-day experiment was conducted to evaluate the effects of Dufulin at five different concentrations (1 × 10−4, 1 × 10−3, 1 × 10−2, [...] Read more.
Dufulin is a highly effective antiviral pesticide used in plants. In this study, a seven-day experiment was conducted to evaluate the effects of Dufulin at five different concentrations (1 × 10−4, 1 × 10−3, 1 × 10−2, 0.1, and 1 mg/L) on Tubifex. LC-MS-based metabolome analysis detected a total of 5356 features in positive and 9110 features in negative, of which 41 showed significant changes and were identified as differential metabolites. Four metabolic pathways were selected for further study. Detailed analysis revealed that Dufulin exposure affected the urea cycle of Tubifex, probably via argininosuccinate lyase (ASL) inhibition. It also affected the fatty acid metabolism, leading to changes in the concentration of free fatty acids in Tubifex. Furthermore, the changes in metabolites after exposure to Dufulin at 1 × 10−2 mg/L were different from those at the other concentrations. Full article
(This article belongs to the Special Issue Application of Metabolomic in Ecotoxicology)
Show Figures

Figure 1

Article
Cryptosporidiosis Modulates the Gut Microbiome and Metabolism in a Murine Infection Model
Metabolites 2021, 11(6), 380; https://doi.org/10.3390/metabo11060380 - 11 Jun 2021
Viewed by 988
Abstract
Cryptosporidiosis is a major human health concern globally. Despite well-established methods, misdiagnosis remains common. Our understanding of the cryptosporidiosis biochemical mechanism remains limited, compounding the difficulty of clinical diagnosis. Here, we used a systems biology approach to investigate the underlying biochemical interactions in [...] Read more.
Cryptosporidiosis is a major human health concern globally. Despite well-established methods, misdiagnosis remains common. Our understanding of the cryptosporidiosis biochemical mechanism remains limited, compounding the difficulty of clinical diagnosis. Here, we used a systems biology approach to investigate the underlying biochemical interactions in C57BL/6J mice infected with Cryptosporidium parvum. Faecal samples were collected daily following infection. Blood, liver tissues and luminal contents were collected 10 days post infection. High-resolution liquid chromatography and low-resolution gas chromatography coupled with mass spectrometry were used to analyse the proteomes and metabolomes of these samples. Faeces and luminal contents were additionally subjected to 16S rRNA gene sequencing. Univariate and multivariate statistical analysis of the acquired data illustrated altered host and microbial energy pathways during infection. Glycolysis/citrate cycle metabolites were depleted, while short-chain fatty acids and D-amino acids accumulated. An increased abundance of bacteria associated with a stressed gut environment was seen. Host proteins involved in energy pathways and Lactobacillus glyceraldehyde-3-phosphate dehydrogenase were upregulated during cryptosporidiosis. Liver oxalate also increased during infection. Microbiome–parasite relationships were observed to be more influential than the host–parasite association in mediating major biochemical changes in the mouse gut during cryptosporidiosis. Defining this parasite–microbiome interaction is the first step towards building a comprehensive cryptosporidiosis model towards biomarker discovery, and rapid and accurate diagnostics. Full article
(This article belongs to the Section Environmental Science)
Show Figures

Figure 1

Article
The Pharmacometabodynamics of Gefitinib after Intravenous Administration to Mice: A Preliminary UPLC–IM–MS Study
Metabolites 2021, 11(6), 379; https://doi.org/10.3390/metabo11060379 - 11 Jun 2021
Viewed by 893
Abstract
The effects of intravenous gefitinib (10 mg/kg), an anilinoquinazoline thymidylate kinase inhibitor (TKI), selective for the epidermal growth factor receptor (EGFR), on the urinary metabotypes of mice were studied. We hypothesized that, in response to the administration of gefitinib, there might be significant [...] Read more.
The effects of intravenous gefitinib (10 mg/kg), an anilinoquinazoline thymidylate kinase inhibitor (TKI), selective for the epidermal growth factor receptor (EGFR), on the urinary metabotypes of mice were studied. We hypothesized that, in response to the administration of gefitinib, there might be significant changes in the excretion of many endogenous metabolites in the urine, which could be correlated with the plasma pharmacokinetics (PK) of the drug. In order to investigate this conjecture, urine from male C57 BL6 mice was collected before IV dosing (10 mg/kg) and at 0–3, 3–8, and 8–24 h post-dose. The samples were profiled by UPLC/IM/MS and compared with the profiles obtained from undosed control mice with the data analyzed using multivariate statistical analysis (MVA). This process identified changes in endogenous metabolites over time and these were compared with drug and drug metabolite PK and excretion. While the MVA of these UPLC/IM/MS data did indeed reveal time-related changes for endogenous metabolites that appeared to be linked to drug administration, this analysis did not highlight the presence of either the drug or its metabolites in urine. Endogenous metabolites affected by gefitinib administration were identified by comparison of mass spectral, retention time and ion mobility-derived collision cross section data (compared to authentic standards wherever possible). The changes in endogenous metabolites resulting from gefitinib administration showed both increases (e.g., tryptophan, taurocholic acid, and the dipeptide lysyl-arginine) and decreases (e.g., deoxyguanosine, 8-hydroxydeoxyguanosine, and asparaginyl-histidine) relative to the control animals. By 8–24 h, the post-dose concentrations of most metabolites had returned to near control values. From these studies, we conclude that changes in the amounts of endogenous metabolites excreted in the urine mirrored, to some extent, the plasma pharmacokinetics of the drug. This phenomenon is similar to pharmacodynamics, where the pharmacological effects are related to the drug concentrations, and by analogy, we have termed this effect “pharmacometabodynamics”. Full article
(This article belongs to the Special Issue Metabolomics in Drug Discovery and Development)
Show Figures

Figure 1

Previous Issue
Next Issue
Back to TopTop