Metabolites

16 pages, 1760 KiB

Open AccessArticle

by Samantha V. Crosby, Izzeldin Y. Ahmed, Laura R. Osborn, Zeyuan Wang, Mary A. Schleiff, William E. Fantegrossi, Swati Nagar, Paul L. Prather, Gunnar Boysen and Grover P. Miller

Metabolites 2022, 12(8), 773; https://doi.org/10.3390/metabo12080773 - 22 Aug 2022

Viewed by 1837

Abstract

In 2019, synthetic cannabinoids accounted for more than one-third of new drugs of abuse worldwide; however, assessment of associated health risks is not ethical for controlled and often illegal substances, making CD-1 mouse exposure studies the gold standard. Interpretation of those findings then [...] Read more.

In 2019, synthetic cannabinoids accounted for more than one-third of new drugs of abuse worldwide; however, assessment of associated health risks is not ethical for controlled and often illegal substances, making CD-1 mouse exposure studies the gold standard. Interpretation of those findings then depends on the similarity of mouse and human metabolic pathways. Herein, we report the first comparative analysis of steady-state metabolism of N-(1-adamantyl)-1-(5-pentyl)-1H-indazole-3-carboxamide (5F-APINACA/5F-AKB48) in CD-1 mice and humans using hepatic microsomes. Regardless of species, 5F-APINACA metabolism involved highly efficient sequential adamantyl hydroxylation and oxidative defluorination pathways that competed equally. Secondary adamantyl hydroxylation was less efficient for mice. At low 5F-APINACA concentrations, initial rates were comparable between pathways, but at higher concentrations, adamantyl hydroxylations became less significant due to substrate inhibition likely involving an effector site. For humans, CYP3A4 dominated both metabolic pathways with minor contributions from CYP2C8, 2C19, and 2D6. For CD-1 mice, Cyp3a11 and Cyp2c37, Cyp2c50, and Cyp2c54 contributed equally to adamantyl hydroxylation, but Cyp3a11 was more efficient at oxidative defluorination than Cyp2c members. Taken together, the results of our in vitro steady-state study indicate a high conservation of 5F-APINACA metabolism between CD-1 mice and humans, but deviations can occur due to differences in P450s responsible for the associated reactions. Full article

(This article belongs to the Special Issue Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed by In Vitro / In Vivo Tools)

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15 pages, 1371 KiB

Open AccessArticle

Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment

by Lakshminarayan R. Ranganath, Anna M. Milan, Andrew T. Hughes, Andrew S. Davison, Milad Khedr, Richard Imrich, Mattias Rudebeck, Birgitta Olsson, Brendan P. Norman, George Bou-Gharios and James A. Gallagher

Metabolites 2022, 12(8), 772; https://doi.org/10.3390/metabo12080772 - 22 Aug 2022

Cited by 2 | Viewed by 1263

Abstract

Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and [...] Read more.

Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and the influence of gender in NIT-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24 h urine collected from patients treated with NIT during a 4-year randomized study in NIT vs. no-treatment controls (SONIA 2; Suitability Of Nitisinone In Alkaptonuria 2; EudraCT no. 2013-001633-41) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), TYR, PHE, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine in the NIT-group. All statistical analyses were post hoc. Keratopathy occurred in 10 out of 69 AKU patients, eight of them male. Thirty-five sampling points (serum and 24 h urine) were analysed in patients experiencing KP and 272 in those with no-KP (NKP) during NIT therapy. The KP group had a lower HPLA/TYR ratio and a higher TYR/PHE ratio compared with the NKP group (p < 0.05 for both). There were 24, 45, 100 and 207 sampling points (serum and 24 h urine) in the NIT group which were pre-NIT female, pre-NIT male, NIT female and NIT male, respectively. The PHE/TYR ratio and the HPLA/TYR ratio were lower in males (p < 0.001 and p < 0.01, respectively). In the KP group and in the male group during NIT therapy, adaptive responses to minimise TYR formation were impaired compared to NKP group and females, respectively. Full article

(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)

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14 pages, 2283 KiB

Open AccessArticle

Metabolomics Profiling of Vitamin D Status in Relation to Dyslipidemia

by Hanaa Mousa, Mohamed A. Elrayess, Ilhame Diboun, Simon K. Jackson and Susu M. Zughaier

Metabolites 2022, 12(8), 771; https://doi.org/10.3390/metabo12080771 - 22 Aug 2022

Cited by 7 | Viewed by 2116

Abstract

Vitamin D deficiency is a global disorder associated with several chronic illnesses including dyslipidemia and metabolic syndrome. The impact of this association with both dyslipidemia and vitamin D deficiency on metabolomics profile is not yet fully understood. This study analyses the metabolomics and [...] Read more.

Vitamin D deficiency is a global disorder associated with several chronic illnesses including dyslipidemia and metabolic syndrome. The impact of this association with both dyslipidemia and vitamin D deficiency on metabolomics profile is not yet fully understood. This study analyses the metabolomics and lipidomic signatures in relation to vitamin D status and dyslipidemia. Metabolomics data were collected from Qatar Biobank database and categorized into four groups based on vitamin D and dyslipidemia status. Metabolomics multivariate analysis was performed using the orthogonal partial least square discriminate analysis (OPLS-DA) whilst linear models were used to assess the per-metabolite association with each of the four dyslipidemia/vitamin D combination groups. Our results indicate a high prevalence of vitamin D deficiency among the younger age group, while dyslipidemia was more prominent in the older group. A significant alteration of metabolomics profile was observed among the dyslipidemic and vitamin D deficient individuals in comparison with control groups. These modifications reflected changes in some key pathways including ceramides, diacylglycerols, hemosylceramides, lysophospholipids, phosphatidylcholines, phosphatidylethanol amines, and sphingomyelins. Vitamin D deficiency and dyslipidemia have a deep impact on sphingomyelins profile. The modifications were noted at the level of ceramides and are likely to propagate through downstream pathways. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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19 pages, 5223 KiB

Open AccessArticle

The PROVIT Study—Effects of Multispecies Probiotic Add-on Treatment on Metabolomics in Major Depressive Disorder—A Randomized, Placebo-Controlled Trial

by Kathrin Kreuzer, Alexandra Reiter, Anna Maria Birkl-Töglhofer, Nina Dalkner, Sabrina Mörkl, Marco Mairinger, Eva Fleischmann, Frederike Fellendorf, Martina Platzer, Melanie Lenger, Tanja Färber, Matthias Seidl, Armin Birner, Robert Queissner, Lilli-Marie Stefanie Mendel, Alexander Maget, Alexandra Kohlhammer-Dohr, Alfred Häussl, Jolana Wagner-Skacel, Helmut Schöggl, Daniela Amberger-Otti, Annamaria Painold, Theresa Lahousen-Luxenberger, Brigitta Leitner-Afschar, Johannes Haybaeck, Hansjörg Habisch, Tobias Madl, Eva Reininghaus and Susanne Bengesser Show full author list Hide full author list

Metabolites 2022, 12(8), 770; https://doi.org/10.3390/metabo12080770 - 21 Aug 2022

Cited by 7 | Viewed by 2674

Abstract

The gut–brain axis plays a role in major depressive disorder (MDD). Gut-bacterial metabolites are suspected to reduce low-grade inflammation and influence brain function. Nevertheless, randomized, placebo-controlled probiotic intervention studies investigating metabolomic changes in patients with MDD are scarce. The PROVIT study (registered at [...] Read more.

The gut–brain axis plays a role in major depressive disorder (MDD). Gut-bacterial metabolites are suspected to reduce low-grade inflammation and influence brain function. Nevertheless, randomized, placebo-controlled probiotic intervention studies investigating metabolomic changes in patients with MDD are scarce. The PROVIT study (registered at clinicaltrials.com NCT03300440) aims to close this scientific gap. PROVIT was conducted as a randomized, single-center, double-blind, placebo-controlled multispecies probiotic intervention study in individuals with MDD (n = 57). In addition to clinical assessments, metabolomics analyses (1H Nuclear Magnetic Resonance Spectroscopy) of stool and serum, and microbiome analyses (16S rRNA sequencing) were performed. After 4 weeks of probiotic add-on therapy, no significant changes in serum samples were observed, whereas the probiotic groups’ (n = 28) stool metabolome shifted towards significantly higher concentrations of butyrate, alanine, valine, isoleucine, sarcosine, methylamine, and lysine. Gallic acid was significantly decreased in the probiotic group. In contrast, and as expected, no significant changes resulted in the stool metabolome of the placebo group. Strong correlations between bacterial species and significantly altered stool metabolites were obtained. In summary, the treatment with multispecies probiotics affects the stool metabolomic profile in patients with MDD, which sets the foundation for further elucidation of the mechanistic impact of probiotics on depression. Full article

(This article belongs to the Special Issue Probiotic Bacteria: Metabolisms and Impact on Human Health)

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17 pages, 24808 KiB

Open AccessArticle

Trans-Species Fecal Transplant Revealed the Role of the Gut Microbiome as a Contributor to Energy Metabolism and Development of Skeletal Muscle

by Liyuan Cai, Min Li, Shuyi Zhou, Xiaoyan Zhu, Xianghua Zhang and Qingbiao Xu

Metabolites 2022, 12(8), 769; https://doi.org/10.3390/metabo12080769 - 21 Aug 2022

Cited by 1 | Viewed by 1460

Abstract

The aim of this study was to investigate the influence of the exogenous gut microbiome at early life stages on the development of mice skeletal muscle in adulthood. First, the characteristics of skeletal muscle and the gut microbiota composition of the gut microbiota [...] Read more.

The aim of this study was to investigate the influence of the exogenous gut microbiome at early life stages on the development of mice skeletal muscle in adulthood. First, the characteristics of skeletal muscle and the gut microbiota composition of the gut microbiota donors—Erhualian (EH) pigs (a native Chinese breed)—were studied. EH pigs had significantly higher fiber densities and thinner fiber diameters than Duroc × Landrace × Yorkshire crossed (DLY) pigs (p < 0.05). The expression levels of genes related to oxidized muscle fibers, mitochondrial function, and glucose metabolism in the skeletal muscle of EH pigs were significantly higher than those in DLY pigs (p < 0.05). Moreover, the abundances of 8 gut microbial phyla and 35 genera correlated with the skeletal muscle fiber diameters and densities exhibited significant differences (p < 0.05) between EH and DLY pigs. Subsequently, newborn mice were treated with saline (CG) and fecal microbiota suspensions collected from EH pigs (AG), respectively, for 15 days, starting from the day of birth. In adulthood (60 days), the relative abundances of Parabacteroides, Sutterella, and Dehalobacterium were significantly higher in the feces of the AG mice than those of the CG mice. The microbes contribute to improved functions related to lipid and carbohydrate metabolism. The weight, density, and gene expression related to the oxidized muscle fibers, mitochondrial function, and glucose metabolism of the AG group were significantly higher than those of the CG group (p < 0.05), whereas the fiber diameters in the skeletal muscle of the AG mice were significantly lower (p < 0.05) than those of the CG mice. These results suggested that intervention with exogenous microbiota at early stages of life can affect the fiber size and energy metabolism of their skeletal muscle. Full article

(This article belongs to the Special Issue Gut Microbiome-Associated Nutrition and Metabolism in Livestock Production)

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13 pages, 2991 KiB

Open AccessArticle

An Open-Source Pipeline for Processing Direct Infusion Mass Spectrometry Data of the Human Plasma Metabolome

by Anna Kozlova, Timur Shkrigunov, Semyon Gusev, Maria Guseva, Elena Ponomarenko and Andrey Lisitsa

Metabolites 2022, 12(8), 768; https://doi.org/10.3390/metabo12080768 - 21 Aug 2022

Cited by 1 | Viewed by 1833

Abstract

Direct infusion mass spectrometry (DIMS) is growing in popularity as an effective method for the screening of biological samples in clinical metabolomics. Being quick to execute, DIMS generally requires special skills when interpreting the results of measurements. By inspecting the similarities between two-dimensional [...] Read more.

Direct infusion mass spectrometry (DIMS) is growing in popularity as an effective method for the screening of biological samples in clinical metabolomics. Being quick to execute, DIMS generally requires special skills when interpreting the results of measurements. By inspecting the similarities between two-dimensional electrospray ionization with quadrupole time-of-flight (ESI-QTOF) and matrix-assisted laser desorption/ionization (MALDI) mass spectra, the pipeline for processing QTOF mass spectra using open-source packages (MALDIquant, MSnbase and MetaboAnalystR) was tested. Previously, all algorithmic workflows have relied on the application of software either provided by a vendor or privately developed by enthusiasts. Here, we computationally examined two ways of interpreting the DIMS results of human blood metabolomic profiling. The studied spectra were acquired using ESI-QTOF maXis Impact II (Bruker Daltonics, Billerica, MA, USA), then pre-processed using COMPASS/DataAnalysis commercial software and mapped onto the metabolites using in-lab-developed MatLab scripts. Alternatively, in this work we used the open-source packages MALDIquant, for spectrum pre-processing, and MetaboAnalystR, for data interpretation, instead of the low-availability commercial and home-made tools. Using a set of 100 plasma samples (20 from volunteers with normal body mass index and 80 from patients at different stages of obesity), we observed a high degree of concordance in annotated metabolic pathways between the proprietary DataAnalysis/MatLab pipeline and our freely available solution. Full article

(This article belongs to the Special Issue Metabolomics in the Age of Cloud Computing, AI and Machine Learning)

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18 pages, 3756 KiB

Open AccessProject Report

Acclimation and Compensating Metabolite Responses to UV-B Radiation in Natural and Transgenic Populus spp. Defective in Lignin Biosynthesis

by Tiffany M. Wong, Joe H. Sullivan and Edward Eisenstein

Metabolites 2022, 12(8), 767; https://doi.org/10.3390/metabo12080767 - 20 Aug 2022

Cited by 4 | Viewed by 1349

Abstract

Plants have evolved to protect leaf mesophyll tissue from damage caused by UV-B radiation by producing an array of UV-absorbing secondary metabolites. Flavonoids (phenolic glycosides) and sinapate esters (hydroxycinnamates) have been implicated as UV-B protective compounds because of the accumulation in the leaf [...] Read more.

Plants have evolved to protect leaf mesophyll tissue from damage caused by UV-B radiation by producing an array of UV-absorbing secondary metabolites. Flavonoids (phenolic glycosides) and sinapate esters (hydroxycinnamates) have been implicated as UV-B protective compounds because of the accumulation in the leaf epidermis and the strong absorption in the wavelengths corresponding to UV. Environmental adaptations by plants also generate a suite of responses for protection against damage caused by UV-B radiation, with plants from high elevations or low latitudes generally displaying greater adaptation or tolerance to UV-B radiation. In an effort to explore the relationships between plant lignin levels and composition, the origin of growth elevation, and the hierarchical synthesis of UV-screening compounds, a collection of natural variants as well as transgenic Populus spp. were examined for sensitivity or acclimation to UV-B radiation under greenhouse and laboratory conditions. Noninvasive, ecophysiological measurements using epidermal transmittance and chlorophyll fluorescence as well as metabolite measurements using UPLC-MS generally revealed that the synthesis of anthocyanins, flavonoids, and lignin precursors are increased in Populus upon moderate to high UV-B treatment. However, poplar plants with genetic modifications that affect lignin biosynthesis, or natural variants with altered lignin levels and compositions, displayed complex changes in phenylpropanoid metabolites. A balance between elevated metabolic precursors to protective phenylpropanoids and increased biosynthesis of these anthocyanins, flavonoids, and lignin is proposed to play a role in the acclimation of Populus to UV-B radiation and may provide a useful tool in engineering plants as improved bioenergy feedstocks. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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9 pages, 990 KiB

Open AccessArticle

Saccharomyces cerevisiae and Clostridium butyricum Could Improve B-Vitamin Production in the Rumen and Growth Performance of Heat-Stressed Goats

by Liyuan Cai, Rudy Hartanto, Qingbiao Xu, Ji Zhang and Desheng Qi

Metabolites 2022, 12(8), 766; https://doi.org/10.3390/metabo12080766 - 19 Aug 2022

Cited by 5 | Viewed by 1498

Abstract

Heat stress can adversely affect the rumen environment and the growth performance of goats. The present study aimed to investigate the effects of Saccharomyces cerevisiae (SC), Clostridium butyricum (CB), and their mixture on B-vitamin production in the rumen and the growth performance of [...] Read more.

Heat stress can adversely affect the rumen environment and the growth performance of goats. The present study aimed to investigate the effects of Saccharomyces cerevisiae (SC), Clostridium butyricum (CB), and their mixture on B-vitamin production in the rumen and the growth performance of heat-stressed goats. Firstly, twelve Macheng × Boer crossed goats (24.21 ± 2.05 kg, control) were modeled to become heat-stressed goats (HS1). Then, the B-vitamin concentrations in the rumen and the parameters of growth performance were measured in goats. The results showed that heat stress could cause significantly decreased vitamin B1, B2, B6, B12, and niacin concentrations (p < 0.05). It also could cause a significantly reduced dry matter (DM) intake (DMI) and average daily gain (ADG) (p < 0.05). However, the digestibilities of DM, neutral detergent fiber (NDF), and acid detergent fiber (ADF) were significantly increased (p < 0.05) in HS1 compared to controls. Then, these twelve heat-stressed goats were divided equally into four groups: control group (HS2, no probiotic supplemented), SC group (0.30% SC supplemented to the basal diet), CB group (0.05% CB supplemented to the basal diet), and mix group (0.30% SC and 0.05% CB supplemented to the basal diet). They were used in a 4 × 4 Latin square experimental design. The results showed that the concentrations of vitamins B1, B2, and niacin in the rumen and the DMI, ADG, and the digestibility of DM, NDF, and ADF were significantly increased (p < 0.05) with SC, CB, and their mixture supplementation (p < 0.05). These results suggest that dietary supplementation with SC and CB could improve B-vitamin production in the rumen and the growth performance of heat-stressed goats. Full article

(This article belongs to the Special Issue Gut Microbiome-Associated Nutrition and Metabolism in Livestock Production)

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4 pages, 219 KiB

Open AccessEditorial

Special Issue on “Advances in Cholesterol and Lipid Metabolism”

by Allison B. Reiss and Joshua De Leon

Metabolites 2022, 12(8), 765; https://doi.org/10.3390/metabo12080765 - 19 Aug 2022

Cited by 1 | Viewed by 1505

Abstract

Cholesterol and lipid metabolism is a broad topic that encompasses multiple aspects of cellular function in every organ [...] Full article

(This article belongs to the Special Issue Advances in Cholesterol and Lipid Metabolism)

19 pages, 3256 KiB

Open AccessArticle

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques

by Yu Hasegawa, Zhichao Zhang, Ameer Y. Taha, John P. Capitanio, Melissa D. Bauman, Mari S. Golub, Judy Van de Water, Catherine A. VandeVoort, Cheryl K. Walker and Carolyn M. Slupsky

Metabolites 2022, 12(8), 764; https://doi.org/10.3390/metabo12080764 - 19 Aug 2022

Cited by 4 | Viewed by 1800

Abstract

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of [...] Read more.

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors. Full article

(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)

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13 pages, 2387 KiB

Open AccessArticle

Profiling of Volatile Organic Compounds from Four Plant Growth-Promoting Rhizobacteria by SPME–GC–MS: A Metabolomics Study

by Msizi I. Mhlongo, Lizelle A. Piater and Ian A. Dubery

Metabolites 2022, 12(8), 763; https://doi.org/10.3390/metabo12080763 - 19 Aug 2022

Cited by 14 | Viewed by 3349

Abstract

The rhizosphere microbiome is a major determinant of plant health. Plant-beneficial or plant growth-promoting rhizobacteria (PGPR) influence plant growth, plant development and adaptive responses, such as induced resistance/priming. These new eco-friendly choices have highlighted volatile organic compounds (biogenic VOCs) as a potentially inexpensive, [...] Read more.

The rhizosphere microbiome is a major determinant of plant health. Plant-beneficial or plant growth-promoting rhizobacteria (PGPR) influence plant growth, plant development and adaptive responses, such as induced resistance/priming. These new eco-friendly choices have highlighted volatile organic compounds (biogenic VOCs) as a potentially inexpensive, effective and efficient substitute for the use of agrochemicals. Secreted bacterial VOCs are low molecular weight lipophilic compounds with a low boiling point and high vapor pressures. As such, they can act as short- or long-distance signals in the rhizosphere, affecting competing microorganisms and impacting plant health. In this study, secreted VOCs from four PGPR strains (Pseudomonas koreensis (N19), Ps. fluorescens (N04), Lysinibacillus sphaericus (T19) and Paenibacillus alvei (T22)) were profiled by solid-phase micro-extraction gas chromatography mass spectrometry (SPME–GC–MS) combined with a multivariate data analysis. Metabolomic profiling with chemometric analyses revealed novel data on the composition of the secreted VOC blends of the four PGPR strains. Of the 121 annotated metabolites, most are known as bioactives which are able to affect metabolism in plant hosts. These VOCs belong to the following classes: alcohols, aldehydes, ketones, alkanes, alkenes, acids, amines, salicylic acid derivatives, pyrazines, furans, sulfides and terpenoids. The results further demonstrated the presence of species-specific and strain-specific VOCs, characterized by either the absence or presence of specific VOCs in the different strains. These molecules could be further investigated as biomarkers for the classification of an organism as a PGPR and selection for agricultural use. Full article

(This article belongs to the Section Plant Metabolism)

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13 pages, 815 KiB

Open AccessArticle

Effects of Chronic Bifidobacteria Administration in Adult Male Rats on Plasma Metabolites: A Preliminary Metabolomic Study

by Francesca Biggio, Claudia Fattuoni, Maria Cristina Mostallino and Paolo Follesa

Metabolites 2022, 12(8), 762; https://doi.org/10.3390/metabo12080762 - 18 Aug 2022

Viewed by 1590

Abstract

Probiotics are live microorganisms distributed in the gastrointestinal tract that confer health benefits to the host when administered in adequate amounts. Bifidobacteria have been widely tested as a therapeutic strategy in the prevention and treatment of a broad spectrum of gastrointestinal disorders as [...] Read more.

Probiotics are live microorganisms distributed in the gastrointestinal tract that confer health benefits to the host when administered in adequate amounts. Bifidobacteria have been widely tested as a therapeutic strategy in the prevention and treatment of a broad spectrum of gastrointestinal disorders as well as in the regulation of the “microbiota-gut-brain axis”. Metabolomic techniques can provide details in the study of molecular metabolic mechanisms involved in Bifidobacteria function through the analysis of metabolites that positively contribute to human health. This study was focused on the effects of the chronic assumption of a mixture of Bifidobacteria in adult male rats using a metabolomic approach. Plasma samples were collected at the end of treatment and analyzed with a gas chromatography-mass spectrometry (GC-MS) platform. Partial least square discriminant analysis (PLS-DA) was performed to compare the metabolic pattern in control and probiotic-treated rats. Our results show, in probiotic-treated animals, an increase in metabolites involved in the energetic cycle, such as glucose, erythrose, creatinine, taurine and glycolic acid, as well as 3-hydroxybutyric acid. This is an important metabolite of short-chain fatty acids (SCFA) with multitasking roles in energy circuit balance, and it has also been proposed to have a key role in the prevention and treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Metabolomic Analysis of Plasma)

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17 pages, 1789 KiB

Open AccessReview

α/β-Hydrolase Domain-Containing 6 (ABHD6)— A Multifunctional Lipid Hydrolase

by Lisa-Maria Pusch, Lina Riegler-Berket, Monika Oberer, Robert Zimmermann and Ulrike Taschler

Metabolites 2022, 12(8), 761; https://doi.org/10.3390/metabo12080761 - 18 Aug 2022

Cited by 4 | Viewed by 2249

Abstract

α/β-hydrolase domain-containing 6 (ABHD6) belongs to the α/β-hydrolase fold superfamily and was originally discovered in a functional proteomic approach designed to discover monoacylglycerol (MAG) hydrolases in the mouse brain degrading the endocannabinoid 2-arachidonoylglycerol. Subsequent studies confirmed that ABHD6 acts as an MAG hydrolase [...] Read more.

α/β-hydrolase domain-containing 6 (ABHD6) belongs to the α/β-hydrolase fold superfamily and was originally discovered in a functional proteomic approach designed to discover monoacylglycerol (MAG) hydrolases in the mouse brain degrading the endocannabinoid 2-arachidonoylglycerol. Subsequent studies confirmed that ABHD6 acts as an MAG hydrolase regulating cannabinoid receptor-dependent and -independent signaling processes. The enzyme was identified as a negative modulator of insulin secretion and regulator of energy metabolism affecting the pathogenesis of obesity and metabolic syndrome. It has been implicated in the metabolism of the lysosomal co-factor bis(monoacylglycerol)phosphate and in the surface delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Finally, ABHD6 was shown to affect cancer cell lipid metabolism and tumor malignancy. Here, we provide new insights into the experimentally derived crystal structure of ABHD6 and its possible orientation in biological membranes, and discuss ABHD6′s functions in health and disease. Full article

(This article belongs to the Special Issue Multipurpose Enzymes in Lipid Metabolism)

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15 pages, 1645 KiB

Open AccessArticle

A Micro-Scale Analytical Method for Determining Glycogen Turnover by NMR and FTMS

by Timothy L. Scott, Juan Zhu, Teresa A. Cassel, Sara Vicente-Muñoz, Penghui Lin, Richard M. Higashi, Andrew N. Lane and Teresa W.-M. Fan

Metabolites 2022, 12(8), 760; https://doi.org/10.3390/metabo12080760 - 18 Aug 2022

Viewed by 1505

Abstract

Glycogen is a readily deployed intracellular energy storage macromolecule composed of branched chains of glucose anchored to the protein glycogenin. Although glycogen primarily occurs in the liver and muscle, it is found in most tissues, and its metabolism has been shown to be [...] Read more.

Glycogen is a readily deployed intracellular energy storage macromolecule composed of branched chains of glucose anchored to the protein glycogenin. Although glycogen primarily occurs in the liver and muscle, it is found in most tissues, and its metabolism has been shown to be important in cancers and immune cells. Robust analysis of glycogen turnover requires stable isotope tracing plus a reliable means of quantifying total and labeled glycogen derived from precursors such as ¹³C₆-glucose. Current methods for analyzing glycogen are time- and sample-consuming, at best semi-quantitative, and unable to measure stable isotope enrichment. Here we describe a microscale method for quantifying both intact and acid-hydrolyzed glycogen by ultra-high-resolution Fourier transform mass spectrometric (UHR-FTMS) and/or NMR analysis in stable isotope resolved metabolomics (SIRM) studies. Polar metabolites, including intact glycogen and their ¹³C positional isotopomer distributions, are first measured in crude biological extracts by high resolution NMR, followed by rapid and efficient acid hydrolysis to glucose under N₂ in a focused beam microwave reactor, with subsequent analysis by UHR-FTMS and/or NMR. We optimized the microwave digestion time, temperature, and oxygen purging in terms of recovery versus degradation and found 10 min at 110–115 °C to give >90% recovery. The method was applied to track the fate of ¹³C₆-glucose in primary human lung BEAS-2B cells, human macrophages, murine liver and patient-derived tumor xenograft (PDTX) in vivo, and the fate of ²H₇-glucose in ex vivo lung organotypic tissue cultures of a lung cancer patient. We measured the incorporation of ¹³C₆-glucose into glycogen and its metabolic intermediates, UDP-Glucose and glucose-1-phosphate, to demonstrate the utility of the method in tracing glycogen turnover in cells and tissues. The method offers a quantitative, sensitive, and convenient means to analyze glycogen turnover in mg amounts of complex biological materials. Full article

(This article belongs to the Section Cell Metabolism)

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21 pages, 3254 KiB

Open AccessArticle

Mechanism Analysis of Metabolic Fatty Liver on Largemouth Bass (Micropterus salmoides) Based on Integrated Lipidomics and Proteomics

by Moyong Xue, Ting Yao, Min Xue, Frédéric Francis, Yuchang Qin, Ming Jia, Junguo Li and Xu Gu

Metabolites 2022, 12(8), 759; https://doi.org/10.3390/metabo12080759 - 17 Aug 2022

Cited by 4 | Viewed by 2259

Abstract

Metabolic fatty liver disease caused by high-starch diet restricted the intensive and sustainable development of carnivorous fish such as largemouth bass. In this study, the combination liver proteomic and lipidomic approach was employed to investigate the key signaling pathways and identify the critical [...] Read more.

Metabolic fatty liver disease caused by high-starch diet restricted the intensive and sustainable development of carnivorous fish such as largemouth bass. In this study, the combination liver proteomic and lipidomic approach was employed to investigate the key signaling pathways and identify the critical biomarkers of fatty liver in largemouth bass. Joint analysis of the correlated differential proteins and lipids revealed nine common metabolic pathways; it was determined that FABP1 were significantly up-regulated in terms of transporting more triglycerides into the liver, while ABCA1 and VDAC1 proteins were significantly down-regulated in terms of preventing the transport of lipids and cholesterol out of the liver, leading to triglyceride accumulation in hepatocyte, eventually resulting in metabolic fatty liver disease. The results indicate that FABP1, ABCA1 and VDAC1 could be potential biomarkers for treating metabolic fatty liver disease of largemouth bass. Full article

(This article belongs to the Special Issue Metabolic Research in Aquatic Animal Nutrition, Physiology and Disease)

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20 pages, 4558 KiB

Open AccessArticle

Effect of Different Climatic Regions and Seasonal Variation on the Antibacterial and Antifungal Activity, and Chemical Profile of Helichrysum aureonitens Sch. Bip

by Wilson Bamise Adeosun, Olusola Bodede and Gerhard Prinsloo

Metabolites 2022, 12(8), 758; https://doi.org/10.3390/metabo12080758 - 17 Aug 2022

Cited by 1 | Viewed by 1219

Abstract

Native South Africans make use of Helichrysum aureonitens Sch. Bip. extracts for the treatment of a variety of infections and they are important in traditional medicinal preparations. This study investigated the effect of seasonal variation and geographical location on the antibacterial and antifungal [...] Read more.

Native South Africans make use of Helichrysum aureonitens Sch. Bip. extracts for the treatment of a variety of infections and they are important in traditional medicinal preparations. This study investigated the effect of seasonal variation and geographical location on the antibacterial and antifungal activities of H. aureonitens. Material was collected in two different seasons: early spring, with high rainfall and high temperatures (October), and late autumn, with low rainfall and lower temperatures (May). Further analysis was carried out using ¹H-NMR based metabolomics to analyse and compare the chemical profiles of the plants in both seasons and locations. Plant materials were collected from two sites for each season, at Wakefield farm (KwaZulu-Natal), representing a colder, wetter environment, and Telperion (Mpumalanga), representing a drier and warmer environment. Leaves of H. aureonitens were tested against bacteria (Proteus vulgaris (P. vulgaris) and Bacillus subtilis (B. subtilis)) as well as fungi (Aspergillus flavus (A. flavus), Aspergillus nomius (A. nomius), Cladosporium cladosporioides (C. cladosporioides), Fusarium oxysporum (F. oxysporum) and Penicillum halotolerans (P. halotolerans)). Extracts from the October harvest showed significant activities against the Gram-negative bacterium P. vulgaris compared to the May harvest, with an MIC value of 62.5 µg/mL. Similar activity was observed between the extracts from the wet season across the two geographically different locations. There was generally very good antifungal activity observed for all the species, with the exception of A. nomius, which had MIC values ranging from 0.39–1.56 µg/mL. Extracts of plant materials harvested in the wetter region had a significantly higher activity against A. flavus and F. oxysporum in both seasons than those from plants harvested in the drier region. Telperion-harvested plants exhibited better activity against F. oxysporum in the autumn. Hydrogen-1 NMR metabolomic analysis confirmed the significant effects of the seasons and the peculiar climates of different localities on the secondary metabolite profile of H. aureonitens. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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17 pages, 2806 KiB

Open AccessArticle

Insulin Secretory Actions of Ethanol Extract of Eucalyptus citriodora Leaf, including Plasma DPP-IV and GLP-1 Levels in High-Fat-Fed Rats, as Well as Characterization of Biologically Effective Phytoconstituents

by Prawej Ansari, Samara T. Choudhury and Yasser H. A. Abdel-Wahab

Metabolites 2022, 12(8), 757; https://doi.org/10.3390/metabo12080757 - 17 Aug 2022

Cited by 8 | Viewed by 2138

Abstract

Due to the numerous adverse effects of synthetic drugs, researchers are currently studying traditional medicinal plants to find alternatives for diabetes treatment. Eucalyptus citriodora is known to be used as a remedy for various illnesses, including diabetes. This study aimed to explore the [...] Read more.

Due to the numerous adverse effects of synthetic drugs, researchers are currently studying traditional medicinal plants to find alternatives for diabetes treatment. Eucalyptus citriodora is known to be used as a remedy for various illnesses, including diabetes. This study aimed to explore the effects of ethanol extract of Eucalyptus citriodora (EEEC) on in vitro and in vivo systems, including the mechanism/s of action. The methodology used involved the measurement of insulin secretion from clonal pancreatic β-cells, BRIN BD11, and mouse islets. Other in vitro systems further examined EEEC’s glucose-lowering properties. Obese rats fed a high-fat-fed diet (HFF) were selected for in vivo evaluation, and phytoconstituents were detected via RP-HPLC followed by LC-MS. EEEC induced insulin secretion in a concentration-dependent manner with modulatory effects, similar to 1 µM glucagon-like peptide 1 (GLP-1), which were partly declined in the presence of Ca^2+-channel blocker (Verapamil), K_ATP-channel opener (Diazoxide), and Ca²⁺ chelation. The insulin secretory effects of EEEC were augmented by isobutyl methylxanthine (IBMX), which persisted in the context of tolbutamide or a depolarizing concentration of KCl. EEEC enhanced insulin action in 3T3-L1 cells and reduced glucose absorption, and protein glycation in vitro. In HFF rats, it improved glucose tolerance and plasma insulin, attenuated plasma DPP-IV, and induced active GLP-1 (7-36) levels in circulation. Rhodomyrtosone B, Quercetin-3-O-β-D-glucopyranoside, rhodomyrtosone E, and quercitroside were identified as possible phytoconstituents that may be responsible for EEEC effects. Thus, these findings revealed that E. citriodora could be used as an adjunct nutritional supplement to manage type 2 diabetes. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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21 pages, 6799 KiB

Open AccessArticle

Deterioration in the Quality of Recalcitrant Quercus robur Seeds during Six Months of Storage at Subzero Temperatures: Ineffective Activation of Prosurvival Mechanisms and Evidence of Freezing Stress from an Untargeted Metabolomic Study

by Agnieszka Szuba, Ewa Marzena Kalemba, Mikołaj Krzysztof Wawrzyniak, Jan Suszka and Paweł Chmielarz

Metabolites 2022, 12(8), 756; https://doi.org/10.3390/metabo12080756 - 17 Aug 2022

Cited by 5 | Viewed by 1754

Abstract

Pedunculate oak (Quercus robur L.) is an economically important forest-forming species in Poland that produces seeds that are sensitive to desiccation; therefore, short-lived seeds are classified as recalcitrant. Such seeds display active metabolism throughout storage. Acorns stored under controlled conditions (moisture content [...] Read more.

Pedunculate oak (Quercus robur L.) is an economically important forest-forming species in Poland that produces seeds that are sensitive to desiccation; therefore, short-lived seeds are classified as recalcitrant. Such seeds display active metabolism throughout storage. Acorns stored under controlled conditions (moisture content of 40%, temperature −3 °C) maintain viability for up to 1.5–2 years. Meanwhile, oaks only produce large numbers of seeds every few years during so-called mast years. This results in a scarcity of good-quality seeds for continuous nursery production and restoration. The recalcitrant storage behavior and the requirements of foresters make it necessary to develop a new protocol for longer acorn storage at lower temperatures. Two storage temperatures were tested: −3 °C (currently used in forest practice) and −7 °C. Our results showed that acorns stored for six months exhibited deterioration and reduced germination capacity, as well as reduced seedling performance, particularly when acorns were stored at −7 °C. To elucidate the decrease in quality during storage, an untargeted metabolomics study was performed for the first time and supported with the analysis of carbohydrates and percentages of carbon (C) and nitrogen (N). Embryonic axes were characterized by a lower C:N ratio and higher hydration. A total of 1985 metabolites were detected, and 303 were successfully identified and quantified, revealing 44 known metabolites that displayed significantly up- or downregulated abundance. We demonstrated for the first time that the significant deterioration of seed germination potential, particularly in seeds stored at −7 °C, was accompanied by an increased abundance of phenolic compounds and carbohydrates but also amino acids and phosphorylated monosaccharides, particularly in the embryonic axes. The increased abundance of defense-related metabolites (1,2,4-Benzenetriol; BTO), products of ascorbic acid degradation (threonic and isothreonic acid), as well as antifreezing compounds (sugar alcohols, predominantly threitol), was reported in seed stored at −7 °C. We hypothesize that seed deterioration was caused by freezing stress experienced during six months of storage at −7 °C, a decline in antioxidative potential and the unsuccessful rerouting of the energy-production pathways. Additionally, our data are a good example of the application of high-throughput metabolomic tools in forest management. Full article

(This article belongs to the Section Plant Metabolism)

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20 pages, 7278 KiB

Open AccessArticle

Predicting Hypertension Subtypes with Machine Learning Using Targeted Metabolites and Their Ratios

by Smarti Reel, Parminder S. Reel, Zoran Erlic, Laurence Amar, Alessio Pecori, Casper K. Larsen, Martina Tetti, Christina Pamporaki, Cornelia Prehn, Jerzy Adamski, Aleksander Prejbisz, Filippo Ceccato, Carla Scaroni, Matthias Kroiss, Michael C. Dennedy, Jaap Deinum, Graeme Eisenhofer, Katharina Langton, Paolo Mulatero, Martin Reincke, Gian Paolo Rossi, Livia Lenzini, Eleanor Davies, Anne-Paule Gimenez-Roqueplo, Guillaume Assié, Anne Blanchard, Maria-Christina Zennaro, Felix Beuschlein and Emily R. Jefferson Show full author list Hide full author list

Metabolites 2022, 12(8), 755; https://doi.org/10.3390/metabo12080755 - 16 Aug 2022

Cited by 5 | Viewed by 2828

Abstract

Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence [...] Read more.

Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing’s syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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22 pages, 3802 KiB

Open AccessArticle

LDL Promotes Disorders in β-Cell Cholesterol Metabolism, Implications on Insulin Cellular Communication Mediated by EVs

by Lizbeth Guevara-Olaya, Brenda Chimal-Vega, César Yahel Castañeda-Sánchez, Leslie Y. López-Cossio, Angel Pulido-Capiz, Octavio Galindo-Hernández, Raúl Díaz-Molina, Josefina Ruiz Esparza-Cisneros and Victor García-González

Metabolites 2022, 12(8), 754; https://doi.org/10.3390/metabo12080754 - 16 Aug 2022

Cited by 3 | Viewed by 2133

Abstract

Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin–angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein [...] Read more.

Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin–angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein (LDL) hypercholesterolemia could disrupt the tissue communication between Langerhans β-cells and hepatocytes, wherein extracellular vesicles (EVs) are secreted by β-cells, and exposition to LDL can impair these phenomena. β-cells activate compensatory mechanisms to maintain insulin and metabolic homeostasis; therefore, the work aimed to characterize the impact of LDL on β-cell cholesterol metabolism and the implication on insulin secretion, connected with the regulation of cellular communication mediated by EVs on hepatocytes. Our results suggest that β-cells can endocytose LDL, promoting an increase in de novo cholesterol synthesis targets. Notably, LDL treatment increased mRNA levels and insulin secretion; this hyperinsulinism condition was associated with the transcription factor PDX-1. However, a compensatory response that maintains basal levels of intracellular calcium was described, mediated by the overexpression of calcium targets PMCA1/4, SERCA2, and NCX1, together with the upregulation of the unfolded protein response (UPR) through the activation of IRE1 and PERK arms to maintain protein homeostasis. The LDL treatment induced metainflammation by IL-6, NF-κB, and COX-2 overexpression. Furthermore, LDL endocytosis triggered an imbalance of the RAS components. LDL treatment increased the intracellular levels of cholesterol on lipid droplets; the adaptive β-cell response was portrayed by the overexpression of cholesterol transporters ABCA1 and ABCG1. Therefore, lipotoxicity and hyperinsulinism induced by LDL were regulated by the natural compound auraptene, a geranyloxyn coumarin modulator of cholesterol-esterification by ACAT1 enzyme inhibition. EVs isolated from β-cells impaired insulin signaling via mTOR/p70S6Kα in hepatocytes, a phenomenon regulated by auraptene. Our results show that LDL overload plays a novel role in hyperinsulinism, mechanisms associated with a dysregulation of intracellular cholesterol, lipotoxicity, and the adaptive UPR, which may be regulated by coumarin-auraptene; these conditions explain the affectations that occur during the initial stages of insulin resistance. Full article

(This article belongs to the Special Issue The Role of β Cells in Diabetes)

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11 pages, 22861 KiB

Open AccessArticle

Metabolite Signature of Simvastatin Treatment Involves Multiple Metabolic Pathways

by Lilian Fernandes Silva, Rowmika Ravi, Jagadish Vangipurapu and Markku Laakso

Metabolites 2022, 12(8), 753; https://doi.org/10.3390/metabo12080753 - 16 Aug 2022

Cited by 5 | Viewed by 1621

Abstract

Statins inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme and are the most widely used medication for hypercholesterolemia. Previous studies on the metabolite signature of simvastatin treatment have included only a small number of metabolites. We performed a high-throughput liquid chromatography–tandem mass spectroscopy profiling on the [...] Read more.

Statins inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme and are the most widely used medication for hypercholesterolemia. Previous studies on the metabolite signature of simvastatin treatment have included only a small number of metabolites. We performed a high-throughput liquid chromatography–tandem mass spectroscopy profiling on the effects of simvastatin treatment on 1098 metabolite concentrations in the participants of the METSIM (Metabolic Syndrome In Men) study including 1332 participants with simvastatin treatment and 6200 participants without statin treatment. We found that simvastatin exerts profound pleiotropic effects on different metabolite pathways, affecting not only lipids, but also amino acids, peptides, nucleotides, carbohydrates, co-factors, vitamins, and xenobiotics. We identified 321 metabolites significantly associated with simvastatin treatment, and 313 of these metabolites were novel. Our study is the first comprehensive evaluation of the metabolic signature of simvastatin treatment in a large population-based study. Full article

(This article belongs to the Special Issue Metabolomics of Heart Failure and Its Comorbidities)

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19 pages, 3333 KiB

Open AccessFeature PaperArticle

Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes

by Shujing Xu, Lin Sun, Dang Ding, Xujie Zhang, Xinyong Liu and Peng Zhan

Metabolites 2022, 12(8), 752; https://doi.org/10.3390/metabo12080752 - 16 Aug 2022

Cited by 2 | Viewed by 1321

Abstract

PF74 and 11L, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this [...] Read more.

PF74 and 11L, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this study was to clarify the metabolism of PF74 and 11L in HLMs, and provide guidance for future structural optimization. To accomplish this, the phase-I metabolites of PF74 and 11L, resulting from in vitro incubation with HLMs, were investigated via ultra-performance liquid chromatography–ultraviolet–high-resolution mass spectrometry (UPLC–UV–HRMS). The results show that 17 phase-I metabolites were putatively annotated for PF74, whereas 16 phase-I metabolites were found for 11L. The main metabolic pathways of PF74 in HLMs were oxidation and demethylation, and the secondary metabolic pathway was hydrolysis; thus, the di-oxidation and demethylation products (M7, M9, M11, and M14) were found to be major metabolites of PF74 in HLMs. In comparison, the main metabolic pathways of 11L in HLMs were oxidation, demethylation, dehydrogenation, and oxidative deamination, with M6′, M11′, M15′, and M16′ as the main metabolites. We suggest that the indole ring and N-methyl group of PF74, and the aniline group, benzene ring R1′, N-methyl, and methoxy group of 11L, were the main metabolic soft spots. Therefore, our research illuminates structural optimization options in seeking improved HIV-1 CA modulators. Full article

(This article belongs to the Special Issue Drug Discovery Metabolism and Biotransformation)

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18 pages, 771 KiB

Open AccessReview

Analysis of Different Methods of Extracting NSAIDs in Biological Fluid Samples for LC-MS/MS Assays: Scoping Review

by Viviane Silva Siqueira Sandrin, Gabriela Moraes Oliveira, Giovana Maria Weckwerth, Nelson Leonel Del Hierro Polanco, Flávio Augusto Cardoso Faria, Carlos Ferreira Santos and Adriana Maria Calvo

Metabolites 2022, 12(8), 751; https://doi.org/10.3390/metabo12080751 - 16 Aug 2022

Cited by 9 | Viewed by 2133

Abstract

The aim of this study was to carry out a systematic investigation and analysis of different drug extraction methods, specifically non-steroidal anti-inflammatory drugs in biological fluid samples, for Liquid Chromatography in Mass Spectrometry assays (LC-MS/MS). A search was carried out in the main [...] Read more.

The aim of this study was to carry out a systematic investigation and analysis of different drug extraction methods, specifically non-steroidal anti-inflammatory drugs in biological fluid samples, for Liquid Chromatography in Mass Spectrometry assays (LC-MS/MS). A search was carried out in the main databases between 1999 and 2021, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. Data were obtained through PubMed, Lilacs, Embase, Scopus, and Web of Science databases using the Boolean operators AND and OR. Studies were pre-selected by title and abstract by two independent reviewers. The selected texts were read in full, and only those that were complete and compatible with the inclusion and exclusion criteria were eligible for this research. A total of 248 references were obtained in the databases. After removing the duplicates and analyzing the titles and abstracts, 79 references were evaluated and passed to the next phase, which comprised the complete reading of the article. A total of 39 publications were eligible for this study. In 52% of the studies, the authors used the liquid–liquid extraction method (LLE), while in 41%, the solid-phase extraction method (SPE) was used. A total of 5% used microextraction methods and 2% used less-conventional techniques. The literature on the main methods used, the LLE and SPE methods, is extensive and consolidated; however, we found other studies that reported modifications of these traditional techniques, which were equally validated for use in LC-MS/MS. From this review, it is concluded that the diversity of techniques, reliability, and practical information about each analytical method used in this study can be adapted to advances in LC-MS/MS techniques; however, more ecological, economic, and sustainable approaches should be explored in the future. Full article

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15 pages, 1740 KiB

Open AccessArticle

Metabolic Profiling of Heliotropium crispum Aerial Parts Using HPLC and FTIR and In Vivo Evaluation of Its Anti-Ulcer Activity Using an Ethanol Induced Acute Gastric Ulcer Model

by Syeda Farheen Fatima, Saiqa Ishtiaq, Manar O. Lashkar, Fadia S. Youssef, Mohamed L. Ashour and Sameh S. Elhady

Metabolites 2022, 12(8), 750; https://doi.org/10.3390/metabo12080750 - 16 Aug 2022

Cited by 5 | Viewed by 1901

Abstract

This study explored the antiulcer potential of methanol extract and fractions of Heliotropium crispum roots against the ethanol-induced gastric ulcer model in rats. Metabolic profiling of H. crispum aerial parts using Fourier-transform infrared spectroscopy (FTIR) revealed the presence of different metabolites with various [...] Read more.

This study explored the antiulcer potential of methanol extract and fractions of Heliotropium crispum roots against the ethanol-induced gastric ulcer model in rats. Metabolic profiling of H. crispum aerial parts using Fourier-transform infrared spectroscopy (FTIR) revealed the presence of different metabolites with various functional groups. Meanwhile, High Performance Liquid Chromatography (HPLC) revealed the presence of three main peaks assigned to myricetin, quercetin, and kaempferol. In vivo, antiulcer activity results showed that the disease control group displayed five tiny ulcers less than 2 mm in diameter in addition to two hemorrhagic streaks. However, in the standard control group, only one small ulcer was visible for the total methanol extract. Gastric tissues and contents were evaluated to determine many parameters such as ulcer score, ulcer index, percentage inhibition of ulcer, gastric pH, gastric juice volume, and acidity. Results were endorsed by histopathological evaluation; gastric pH and mucus content were significantly increased, but gastric juice volume was significantly decreased. All fractions showed a significant decrease in ulcer index and % inhibition except the n-hexane fraction, whose results were insignificant compared to the disease control group. Thus, it was concluded that H. crispum shows an antiulcer effect by decreasing gastric juice volume and acidity, whereas gastric pH and mucus contents were increased that is attributed to the synergistic action of its detected polyphenolic compounds. Full article

(This article belongs to the Special Issue Metabolomics Analysis of Natural Products Volume II)

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21 pages, 2879 KiB

Open AccessArticle

Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation

by Carlos Guijas, Andrew To, J. Rafael Montenegro-Burke, Xavier Domingo-Almenara, Zaida Alipio-Gloria, Bernard P. Kok, Enrique Saez, Nicole H. Alvarez, Kristen A. Johnson and Gary Siuzdak

Metabolites 2022, 12(8), 749; https://doi.org/10.3390/metabo12080749 - 16 Aug 2022

Cited by 1 | Viewed by 12345

Abstract

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between [...] Read more.

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson–Golabi–Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases. Full article

(This article belongs to the Topic Metabolism and Health)

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14 pages, 1859 KiB

Open AccessArticle

Effect of Expression of Nuclear-Encoded Cytochrome C Oxidase Subunit 4 Isoforms on Metabolic Profiles of Glioma Cells

by Claudia R. Oliva, Md Yousuf Ali, Susanne Flor and Corinne E. Griguer

Metabolites 2022, 12(8), 748; https://doi.org/10.3390/metabo12080748 - 16 Aug 2022

Viewed by 1697

Abstract

Although often effective at treating newly diagnosed glioblastoma (GBM), increasing evidence suggests that chemo- and radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness, as well as treatment resistance. Recent studies have demonstrated that alterations in glioma cell metabolism, induced by a [...] Read more.

Although often effective at treating newly diagnosed glioblastoma (GBM), increasing evidence suggests that chemo- and radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness, as well as treatment resistance. Recent studies have demonstrated that alterations in glioma cell metabolism, induced by a switch in the isoform expression of cytochrome c oxidase subunit 4 (COX4), a key regulatory subunit of mammalian cytochrome c oxidase, could promote these effects. To understand how the two COX4 isoforms (COX4-1 and COX4-2) differentially affect glioma metabolism, glioma samples harvested from COX4-1- or COX4-2-overexpressing U251 cells were profiled using Gas chromatography–mass spectrometry GC-MS and Liquid Chromatography - Tandem Mass Spectrometry LC-MS/MS metabolomics platforms. The concentration of 362 metabolites differed significantly in the two cell types. The two most significantly upregulated pathways associated with COX4-1 overexpression were purine and glutathione metabolism; the two most significantly downregulated metabolic pathways associated with COX4-1 expression were glycolysis and fatty acid metabolism. Our study provides new insights into how Cytochrome c oxidase (CcO) regulatory subunits affect cellular metabolic networks in GBM and identifies potential targets that may be exploited for therapeutic benefit. Full article

(This article belongs to the Topic Cancer Cell Metabolism)

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19 pages, 2083 KiB

Open AccessArticle

Host–Gut Microbiome Metabolic Interactions in PFAS-Impacted Freshwater Turtles (Emydura macquarii macquarii)

by David J. Beale, Thao V. Nguyen, Rohan M. Shah, Andrew Bissett, Akhikun Nahar, Matthew Smith, Viviana Gonzalez-Astudillo, Christoph Braun, Brenda Baddiley and Suzanne Vardy

Metabolites 2022, 12(8), 747; https://doi.org/10.3390/metabo12080747 - 16 Aug 2022

Cited by 6 | Viewed by 3035

Abstract

Per-and polyfluoroalkyl substances (PFAS) are a growing concern for humans, wildlife, and more broadly, ecosystem health. Previously, we characterised the microbial and biochemical impact of elevated PFAS on the gut microbiome of freshwater turtles (Emydura macquarii macquarii) within a contaminated catchment [...] Read more.

Per-and polyfluoroalkyl substances (PFAS) are a growing concern for humans, wildlife, and more broadly, ecosystem health. Previously, we characterised the microbial and biochemical impact of elevated PFAS on the gut microbiome of freshwater turtles (Emydura macquarii macquarii) within a contaminated catchment in Queensland, Australia. However, the understanding of PFAS impacts on this species and other aquatic organisms is still very limited, especially at the host–gut microbiome molecular interaction level. To this end, the present study aimed to apply these leading-edge omics technologies within an integrated framework that provides biological insight into the host turtle–turtle gut microbiome interactions of PFAS-impacted wild-caught freshwater turtles. For this purpose, faecal samples from PFAS-impacted turtles (n = 5) and suitable PFAS-free reference turtles (n = 5) were collected and analysed. Data from 16S rRNA gene amplicon sequencing and metabolomic profiling of the turtle faeces were integrated using MetOrigin to assign host, microbiome, and co-metabolism activities. Significant variation in microbial composition was observed between the two turtle groups. The PFAS-impacted turtles showed a higher relative abundance of Firmicutes and a lower relative abundance of Bacteroidota than the reference turtles. The faecal metabolome showed several metabolites and pathways significantly affected by PFAS exposure. Turtles exposed to PFAS displayed altered amino acid and butanoate metabolisms, as well as altered purine and pyrimidine metabolism. It is predicted from this study that PFAS-impacted both the metabolism of the host turtle and its gut microbiota which in turn has the potential to influence the host’s physiology and health. Full article

(This article belongs to the Special Issue Application of Metabolomic in Ecotoxicology)

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14 pages, 2577 KiB

Open AccessArticle

Relationship between Body Composition and Biochemical Parameters with Antioxidant Status in a Healthy Cohort of Postmenopausal Women

by Héctor Vázquez-Lorente, Lourdes Herrera-Quintana, Jorge Molina-López, Yenifer Gamarra-Morales, Beatriz López-González and Elena Planells

Metabolites 2022, 12(8), 746; https://doi.org/10.3390/metabo12080746 - 14 Aug 2022

Cited by 1 | Viewed by 1267

Abstract

An adequate prooxidant–antioxidant balance—which may be influenced by body composition and biochemical status—is essential to maintain human health, especially in circumstances under which the antioxidant defense decreases, such as menopause. The present study aimed to examine the relationship between body composition and biochemical [...] Read more.

An adequate prooxidant–antioxidant balance—which may be influenced by body composition and biochemical status—is essential to maintain human health, especially in circumstances under which the antioxidant defense decreases, such as menopause. The present study aimed to examine the relationship between body composition and biochemical parameters with antioxidant status in a healthy cohort of postmenopausal women. This cross-sectional study was carried out in a cohort of 78 postmenopausal women aged 44–76 years. The body composition profile was assessed through bioelectrical impedance. The determination of the total antioxidant capacity and superoxide dismutase activity was conducted by the colorimetric method, and glutathione peroxidase activity was determined by the enzymatic immunological method. The vitamin D levels were measured by ultra-performance liquid chromatography–tandem mass spectrometry. The mineral status was assessed through flame atomic absorption spectrophotometry. The rest of the biochemical parameters were assessed through an immunoassay. The total antioxidant capacity and antioxidant gap were negatively influenced by body composition (all p ≤ 0.049) and positively related to protein metabolism parameters (all p ≤ 0.048), whereas circulating levels of different micronutrients (all p ≤ 0.048) and enzymes (all p ≤ 0.047) appeared to play an important role in the glutathione peroxidase and superoxide dismutase activities. In conclusion, the menopause-related antioxidant status changes may be influenced by key body composition and biochemical profiles. To confirm this statement, further trials aiming to evaluate the body composition and biochemical intervention-induced changes upon antioxidant defense are needed. Full article

(This article belongs to the Special Issue Dietary Antioxidants and Metabolic Diseases)

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13 pages, 4345 KiB

Open AccessReview

Targeting Ferroptosis in Colorectal Cancer

by Xiaojie Liang, Zhihuan You, Xinhao Chen and Jun Li

Metabolites 2022, 12(8), 745; https://doi.org/10.3390/metabo12080745 - 12 Aug 2022

Cited by 6 | Viewed by 3082

Abstract

Ferroptosis is a unique way of regulating cell death (RCD), which is quite different from other programmed cell deaths such as autophagy. It presents iron overload, accumulation of reactive oxygen species (ROS), and lipid peroxidation. A ferroptotic cell usually has an intact cell [...] Read more.

Ferroptosis is a unique way of regulating cell death (RCD), which is quite different from other programmed cell deaths such as autophagy. It presents iron overload, accumulation of reactive oxygen species (ROS), and lipid peroxidation. A ferroptotic cell usually has an intact cell structure as well as shrinking mitochondria with decreased or vanishing cristae, concentrated membrane density, and ruptured outer membrane. Recently, increasing investigations have discovered that tumor cells have a much greater iron demand than the normal ones, making them more sensitive to ferroptosis. In other words, ferroptosis may inhibit the progress of the tumor, which can be used in the therapy of tumor patients, especially for those with chemotherapy resistance. Therefore, ferroptosis has become one hot spot in the field of tumor research in recent years. Colorectal cancer (CRC) is one common type of gastrointestinal malignancy. The incidence of CRC appears to have an upward trend year by year since the enhancement of living standards. Although surgery and chemoradiotherapy have largely improved the prognosis of patients with CRC, some patients still appear to have severe adverse reactions and drug resistance. Moreover, much research has verified that ferroptosis has a necessary association with the occurrence and progression of gastrointestinal tumors. In this review, we provide a comprehensive evaluation of the main mechanisms of iron metabolism, lipid metabolism, and amino acid metabolism involved in the occurrence of ferroptosis, as well as the research progress of ferroptosis in CRC. Full article

(This article belongs to the Special Issue Metabolites and Cancer Signaling)

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Open AccessArticle

¹H NMR Urinary Metabolomic Analysis in Older Adults after Hip Fracture Surgery May Provide Valuable Information for Patient Profiling—A Preliminary Investigation

by Wafa Douzi, Delphine Bon, Sara Suikkanen, Paula Soukkio, Nadège Boildieu, Arja Nenonen, Markku Hupli, Katriina Kukkonen-Harjula and Benoit Dugué

Metabolites 2022, 12(8), 744; https://doi.org/10.3390/metabo12080744 - 12 Aug 2022

Cited by 1 | Viewed by 2456

Abstract

In these times of precision and personalized medicine, profiling patients to identify their needs is crucial to providing the best and most cost-effective treatment. In this study, we used urine metabolomics to explore the characterization of older adults with hip fractures and to [...] Read more.

In these times of precision and personalized medicine, profiling patients to identify their needs is crucial to providing the best and most cost-effective treatment. In this study, we used urine metabolomics to explore the characterization of older adults with hip fractures and to explore the forecasting of patient outcomes. Overnight urine specimens were collected from 33 patients (mean age 80 ± 8 years) after hip fracture surgery during their stay at a rehabilitation hospital. The specimens were analyzed with ¹H NMR spectroscopy. We performed a metabolomics study regarding assessments of frailty status, Functional Independence Measure (FIM), and Short Physical Performance Battery (SPPB). The main metabolic variations concerned 10 identified metabolites: paracetamol derivatives (4 peaks: 2.15 ppm; 2.16 ppm; 7.13 ppm and 7.15 ppm); hippuric acid; acetate; acetone; dimethylamine; glycine; alanine; lactate; valine; TMAO. At baseline, the urinary levels of these metabolites were significantly higher (i) in frail compared with non-frail patients, (ii) in persons with poorer FIM scores, and (iii) in persons with poorer compared SPPB scores. Our findings suggested that patients with increased levels of urine metabolites associated with metabolic, inflammatory, and renal disorders presented clear signs of frailty, impaired functional independence, and poor physical performance. Metabolomics could be a valuable tool to further characterize older adults, especially after major medical events. Full article

(This article belongs to the Special Issue The Metabolic Adaptations in Non-pharmacological Interventions)

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Metabolites, Volume 12, Issue 8 (August 2022) – 101 articles

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