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Metabolites, Volume 13, Issue 5 (May 2023) – 96 articles

Cover Story (view full-size image): Bipolar disorder (BD) causes changes in a person's mood, energy, and ability to function, with a prevalence of 60 million people worldwide. Significant deficiency to understand and diagnose BD is based on the complexity of this disease, including diverse genetic, environmental, and biochemical factors, and establishing a diagnosis based on subjective recognition of symptoms without any clinical test of biomarker identification. An 1H-NMR-based metabolomic study applying chemometrics of serum samples of Serbian patients with BD was conducted, providing the identification of 22 metabolites for this disease. The same established nine metabolites in three different ethnic and geographic origins (Serbia, Brazil, and China) might have a crucial role in the realization of a universal set of NMR biomarkers for BD. View this paper
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24 pages, 3358 KiB  
Article
Exploring the Biologically Active Metabolites Produced by Bacillus cereus for Plant Growth Promotion, Heat Stress Tolerance, and Resistance to Bacterial Soft Rot in Arabidopsis
by Sih-Huei Tsai, Yi-Chun Hsiao, Peter E. Chang, Chen-En Kuo, Mei-Chun Lai and Huey-wen Chuang
Metabolites 2023, 13(5), 676; https://doi.org/10.3390/metabo13050676 - 22 May 2023
Cited by 4 | Viewed by 1551
Abstract
Eight gene clusters responsible for synthesizing bioactive metabolites associated with plant growth promotion were identified in the Bacillus cereus strain D1 (BcD1) genome using the de novo whole-genome assembly method. The two largest gene clusters were responsible for synthesizing volatile organic compounds (VOCs) [...] Read more.
Eight gene clusters responsible for synthesizing bioactive metabolites associated with plant growth promotion were identified in the Bacillus cereus strain D1 (BcD1) genome using the de novo whole-genome assembly method. The two largest gene clusters were responsible for synthesizing volatile organic compounds (VOCs) and encoding extracellular serine proteases. The treatment with BcD1 resulted in an increase in leaf chlorophyll content, plant size, and fresh weight in Arabidopsis seedlings. The BcD1-treated seedlings also accumulated higher levels of lignin and secondary metabolites including glucosinolates, triterpenoids, flavonoids, and phenolic compounds. Antioxidant enzyme activity and DPPH radical scavenging activity were also found to be higher in the treated seedlings as compared with the control. Seedlings pretreated with BcD1 exhibited increased tolerance to heat stress and reduced disease incidence of bacterial soft rot. RNA-seq analysis showed that BcD1 treatment activated Arabidopsis genes for diverse metabolite synthesis, including lignin and glucosinolates, and pathogenesis-related proteins such as serine protease inhibitors and defensin/PDF family proteins. The genes responsible for synthesizing indole acetic acid (IAA), abscisic acid (ABA), and jasmonic acid (JA) were expressed at higher levels, along with WRKY transcription factors involved in stress regulation and MYB54 for secondary cell wall synthesis. This study found that BcD1, a rhizobacterium producing VOCs and serine proteases, is capable of triggering the synthesis of diverse secondary metabolites and antioxidant enzymes in plants as a defense strategy against heat stress and pathogen attack. Full article
(This article belongs to the Special Issue Metabolic Alterations and Gene Regulation in Plants under Stress)
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46 pages, 8438 KiB  
Review
Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis—A Narrative Review
by Dhruvi Lathigara, Devesh Kaushal and Robert Beaumont Wilson
Metabolites 2023, 13(5), 675; https://doi.org/10.3390/metabo13050675 - 21 May 2023
Cited by 9 | Viewed by 4829
Abstract
The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular [...] Read more.
The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular mechanisms that induce obesity are also involved in the twelve Hallmarks of Cancer, with the fundamental process being the consumption of a highly processed, energy-dense diet and the deposition of fat in white adipose tissue and the liver. The generation of crown-like structures, with macrophages surrounding senescent or necrotic adipocytes or hepatocytes, leads to a perpetual state of chronic inflammation, oxidative stress, hyperinsulinaemia, aromatase activity, activation of oncogenic pathways and loss of normal homeostasis. Metabolic reprogramming, epithelial mesenchymal transition, HIF-1α signalling, angiogenesis and loss of normal host immune-surveillance are particularly important. Obesity-associated carcinogenesis is closely related to metabolic syndrome, hypoxia, visceral adipose tissue dysfunction, oestrogen synthesis and detrimental cytokine, adipokine and exosomal miRNA release. This is particularly important in the pathogenesis of oestrogen-sensitive cancers, including breast, endometrial, ovarian and thyroid cancer, but also ‘non-hormonal’ obesity-associated cancers such as cardio-oesophageal, colorectal, renal, pancreatic, gallbladder and hepatocellular adenocarcinoma. Effective weight loss interventions may improve the future incidence of overall and obesity-associated cancer. Full article
(This article belongs to the Section Nutrition and Metabolism)
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22 pages, 4434 KiB  
Review
The Interplay between Gut Microbiota and Oral Medications and Its Impact on Advancing Precision Medicine
by Sara Mousa, Muhammad Sarfraz and Walaa K. Mousa
Metabolites 2023, 13(5), 674; https://doi.org/10.3390/metabo13050674 - 21 May 2023
Cited by 4 | Viewed by 2247
Abstract
Trillions of diverse microbes reside in the gut and are deeply interwoven with the human physiological process, from food digestion, immune system maturation, and fighting invading pathogens, to drug metabolism. Microbial drug metabolism has a profound impact on drug absorption, bioavailability, stability, efficacy, [...] Read more.
Trillions of diverse microbes reside in the gut and are deeply interwoven with the human physiological process, from food digestion, immune system maturation, and fighting invading pathogens, to drug metabolism. Microbial drug metabolism has a profound impact on drug absorption, bioavailability, stability, efficacy, and toxicity. However, our knowledge of specific gut microbial strains, and their genes that encode enzymes involved in the metabolism, is limited. The microbiome encodes over 3 million unique genes contributing to a huge enzymatic capacity, vastly expanding the traditional drug metabolic reactions that occur in the liver, manipulating their pharmacological effect, and, ultimately, leading to variation in drug response. For example, the microbial deactivation of anticancer drugs such as gemcitabine can lead to resistance to chemotherapeutics or the crucial role of microbes in modulating the efficacy of the anticancer drug, cyclophosphamide. On the other hand, recent findings show that many drugs can shape the composition, function, and gene expression of the gut microbial community, making it harder to predict the outcome of drug-microbiota interactions. In this review, we discuss the recent understanding of the multidirectional interaction between the host, oral medications, and gut microbiota, using traditional and machine-learning approaches. We analyze gaps, challenges, and future promises of personalized medicine that consider gut microbes as a crucial player in drug metabolism. This consideration will enable the development of personalized therapeutic regimes with an improved outcome, ultimately leading to precision medicine. Full article
(This article belongs to the Section Microbiology and Ecological Metabolomics)
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15 pages, 2999 KiB  
Article
Food Fingerprinting: LC-ESI-IM-QTOF-Based Identification of Blumeatin as a New Marker Metabolite for the Detection of Origanum majorana Admixtures to O. onites/vulgare
by Marina Creydt, Friedemann Flügge, Robin Dammann, Burkhard Schütze, Ulrich L. Günther and Markus Fischer
Metabolites 2023, 13(5), 673; https://doi.org/10.3390/metabo13050673 - 20 May 2023
Cited by 3 | Viewed by 1104
Abstract
Oregano (Origanum vulgare and O. onites) is one of the most frequently counterfeited herbs in the world and is diluted with the leaves of a wide variety of plants. In addition to olive leaves, marjoram (O. majorana) is often [...] Read more.
Oregano (Origanum vulgare and O. onites) is one of the most frequently counterfeited herbs in the world and is diluted with the leaves of a wide variety of plants. In addition to olive leaves, marjoram (O. majorana) is often used for this purpose in order to achieve a higher profit. However, apart from arbutin, no marker metabolites are known to reliably detect marjoram admixtures in oregano batches at low concentrations. In addition, arbutin is relatively widespread in the plant kingdom, which is why it is of great relevance to look for further marker metabolites in order to secure the analysis accordingly. Therefore, the aim of the present study was to use a metabolomics-based approach to identify additional marker metabolites with the aid of an ion mobility mass spectrometry instrument. The focus of the analysis was on the detection of non-polar metabolites, as this study was preceded by nuclear magnetic resonance spectroscopic investigations of the same samples based mainly on the detection of polar analytes. Using the MS-based approach, numerous marjoram specific features could be detected in admixtures of marjoram >10% in oregano. However, only one feature was detectable in admixtures of >5% marjoram. This feature was identified as blumeatin, which belongs to the class of flavonoid compounds. Initially, blumeatin was identified based on MS/MS spectra and collision cross section values using a database search. In addition, the identification of blumeatin was confirmed by a reference standard. Moreover, dried leaves of olive, myrtle, thyme, sage and peppermint, which are also known to be used to adulterate oregano, were measured. Blumeatin could not be detected in these plants, so this substance can be considered as an excellent marker compound for the detection of marjoram admixtures. Full article
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15 pages, 1460 KiB  
Article
Changes in the Carbohydrate Profile in Common Buckwheat (Fagopyrum esculentum Moench) Seedlings Induced by Cold Stress and Dehydration
by Lesław B. Lahuta, Ryszard J. Górecki, Joanna Szablińska-Piernik and Marcin Horbowicz
Metabolites 2023, 13(5), 672; https://doi.org/10.3390/metabo13050672 - 19 May 2023
Viewed by 1225
Abstract
Plant species are sensitive to stresses, especially at the seedling stage, and they respond to these conditions by making metabolic changes to counteract the negative effects of this. The objectives of this study were to determine carbohydrate profile in particular organs (roots, hypocotyl, [...] Read more.
Plant species are sensitive to stresses, especially at the seedling stage, and they respond to these conditions by making metabolic changes to counteract the negative effects of this. The objectives of this study were to determine carbohydrate profile in particular organs (roots, hypocotyl, and cotyledons) of common buckwheat seedlings and to verify whether carbohydrate accumulation is similar or not in the organs in response to cold stress and dehydration. Roots, hypocotyl, and cotyledons of common buckwheat seedlings have various saccharide compositions. The highest concentrations of cyclitols, raffinose, and stachyose were found in the hypocotyl, indicating that they may be transported from cotyledons, although this needs further studies. Accumulation of raffinose and stachyose is a strong indicator of the response of all buckwheat organs to introduced cold stress. Besides, cold conditions reduced d-chiro-inositol content, but did not affect d-pinitol level. Enhanced accumulation of raffinose and stachyose were also a distinct response of all organs against dehydration at ambient temperature. The process causes also a large decrease in the content of d-pinitol in buckwheat hypocotyl, which may indicate its transformation to d-chiro-inositol whose content increased at that time. In general, the sucrose and its galactosides in hypocotyl tissues were subject to the highest changes to the applied cold and dehydration conditions compared to the cotyledons and roots. This may indicate tissue differences in the functioning of the protective system(s) against such threats. Full article
(This article belongs to the Special Issue Metabolic Alterations and Gene Regulation in Plants under Stress)
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12 pages, 3714 KiB  
Article
Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites
by Jennifer Diaz-Espinosa, Kathleen A. Stringer and Gus R. Rosania
Metabolites 2023, 13(5), 671; https://doi.org/10.3390/metabo13050671 - 19 May 2023
Cited by 1 | Viewed by 1081
Abstract
Mitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measuring two metabolites, l-carnitine [...] Read more.
Mitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measuring two metabolites, l-carnitine and acetylcarnitine, to determine their effectiveness as candidate clinical biomarkers for age-related, drug-induced alterations in mitochondrial metabolism. To study age- and medication-related changes in mitochondrial metabolism, we administered the FDA-approved mitochondriotropic drug, clofazimine (CFZ), or vehicle for 8 weeks to young (4-week-old) and old (61-week-old) male C57BL/6J mice. At the end of treatment, whole blood and cardiac and skeletal muscle were analyzed for l-carnitine, acetylcarnitine, and CFZ levels; muscle function was measured via a treadmill test. No differences were found in blood or cardiac carnitine levels of CFZ-treated mice, but CFZ-treated mice displayed lost body mass and alterations in endurance and levels of skeletal muscle mitochondrial metabolites. These findings demonstrate the age-related susceptibility of the skeletal muscle to mitochondria drug toxicity. Since drug-induced alterations in mitochondrial metabolism in skeletal muscle were not reflected in the blood by l-carnitine or acetylcarnitine levels, drug-induced catabolism and changes in muscle function appear more relevant to stratifying individuals at increased risk for ADRs. Full article
(This article belongs to the Topic Biomarker Development and Application)
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11 pages, 1777 KiB  
Article
Non-Targeted Metabolic Profiling of Cerebellum in Spina Bifida Fetal Rats
by Evan Thielen, Marc Oria, Miki Watanabe-Chailland, Kristin Lampe, Lindsey Romick-Rosendale and Jose L. Peiro
Metabolites 2023, 13(5), 670; https://doi.org/10.3390/metabo13050670 - 19 May 2023
Viewed by 1407
Abstract
Spina bifida, known more commonly as myelomeningocele, is a neural tube defect that results in herniation of the cerebellum through the foramen magnum into the central canal as part of the Chiari II malformation. Effects stemming from the herniated cerebellum and its metabolic [...] Read more.
Spina bifida, known more commonly as myelomeningocele, is a neural tube defect that results in herniation of the cerebellum through the foramen magnum into the central canal as part of the Chiari II malformation. Effects stemming from the herniated cerebellum and its metabolic profile have not been extensively studied. The objective of this study is to examine the metabolic effects of this disease on the cerebellum in utero through the utilization of a retinoid acid-induced Spina bifida rat model. Analysis of this model at mid-late (day 15) and term (day 20) of gestation in comparison to both non-exposed and retinoic acid-exposed non-myelomeningocele controls, the observed metabolic changes suggest that mechanisms of oxidative stress and energy depletion are at play in this neuro tissue. These notable mechanisms are likely to result in further damage to neural tissue as the fetus grows and the compressed cerebellum develops and herniates more due to myelomeningocele. Full article
(This article belongs to the Section Metabolomic Profiling Technology)
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16 pages, 28615 KiB  
Article
Enhancement of Ambient Mass Spectrometry Imaging Data by Image Restoration
by Yuchen Xiang, Martin Metodiev, Meiqi Wang, Boxuan Cao, Josephine Bunch and Zoltan Takats
Metabolites 2023, 13(5), 669; https://doi.org/10.3390/metabo13050669 - 19 May 2023
Viewed by 1308
Abstract
Mass spectrometry imaging (MSI) has been a key driver of groundbreaking discoveries in a number of fields since its inception more than 50 years ago. Recently, MSI development trends have shifted towards ambient MSI (AMSI) as the removal of sample-preparation steps and the [...] Read more.
Mass spectrometry imaging (MSI) has been a key driver of groundbreaking discoveries in a number of fields since its inception more than 50 years ago. Recently, MSI development trends have shifted towards ambient MSI (AMSI) as the removal of sample-preparation steps and the possibility of analysing biological specimens in their natural state have drawn the attention of multiple groups across the world. Nevertheless, the lack of spatial resolution has been cited as one of the main limitations of AMSI. While significant research effort has presented hardware solutions for improving the resolution, software solutions are often overlooked, although they can usually be applied in a cost-effective manner after image acquisition. In this vein, we present two computational methods that we have developed to directly enhance the image resolution post-acquisition. Robust and quantitative resolution improvement is demonstrated for 12 cases of openly accessible datasets across laboratories around the globe. Using the same universally applicable Fourier imaging model, we discuss the possibility of true super-resolution by software for future studies. Full article
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20 pages, 2414 KiB  
Article
Changes in the Secretion of Melatonin and Selected Adipokines during the Progression of Parkinson’s Disease—Preliminary Studies
by Jan Milanowski, Kamil Kozerawski, Weronika Falęcka, Dominik Dudek, Beata Lisewska, Paweł Lisewski, Jarosław Nuszkiewicz, Roland Wesołowski, Jakub Wojtasik, Celestyna Mila-Kierzenkowska and Karolina Szewczyk-Golec
Metabolites 2023, 13(5), 668; https://doi.org/10.3390/metabo13050668 - 18 May 2023
Cited by 1 | Viewed by 1328
Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting elderly people. Considering the gap in the literature on melatonin and adipokine levels in PD patients at various stages of the disease, we conducted a study to investigate the levels of [...] Read more.
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting elderly people. Considering the gap in the literature on melatonin and adipokine levels in PD patients at various stages of the disease, we conducted a study to investigate the levels of selected parameters in PD patients at the disease’s early (ES) and advanced (AS) stages. Melatonin, leptin, adiponectin, and resistin concentrations were measured in the blood serum of 20 PD patients without dyskinesia (ES), 24 PD patients with dyskinesia (AS), and 20 healthy volunteers as a control group (CG). The data were analyzed using ANOVA. Melatonin was significantly lower in ES (p < 0.05) and higher in AS patients (p < 0.05) compared to CG. The level of leptin was increased both in ES (p < 0.001) and AS (p < 0.001) versus CG, while resistin was increased only in patients with dyskinesia (p < 0.05). Higher melatonin (p < 0.001) and resistin (p < 0.05) and lower leptin (p < 0.05) levels were found in AS versus ES. The main findings of the study include the changes in inflammatory markers’ levels during PD and a surprising increase in melatonin level in dyskinesia patients. Further research is necessary, which will be aimed at modulating the secretion of melatonin and adipokines as a treatment target for PD. Full article
(This article belongs to the Special Issue Roles of the Circadian Rhythms in Metabolic Disease and Health)
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16 pages, 2081 KiB  
Article
Shades of Fine Dark Chocolate Colors: Polyphenol Metabolomics and Molecular Networking to Enlighten the Brown from the Black
by Aecio Luís de Sousa Dias, Julie-Anne Fenger, Emmanuelle Meudec, Arnaud Verbaere, Pierre Costet, Clotilde Hue, Florent Coste, Sophie Lair, Véronique Cheynier, Jean-Claude Boulet and Nicolas Sommerer
Metabolites 2023, 13(5), 667; https://doi.org/10.3390/metabo13050667 - 17 May 2023
Viewed by 2209
Abstract
High-quality dark chocolates (70% cocoa content) can have shades from light to dark brown color. This work aimed at revealing compounds that discriminate black and brown chocolates. From 37 fine chocolate samples from years 2019 and 2020 provided by Valrhona,8 dark black samples [...] Read more.
High-quality dark chocolates (70% cocoa content) can have shades from light to dark brown color. This work aimed at revealing compounds that discriminate black and brown chocolates. From 37 fine chocolate samples from years 2019 and 2020 provided by Valrhona,8 dark black samples and 8 light brown samples were selected. A non-targeted metabolomics study was performed based on ultra-high performance liquid chromatography—high resolution mass spectrometry/mass spectrometry experiments, univariate, multivariate, and feature-based molecular networking analyses. Twenty-seven overaccumulated discriminating compounds were found for black chocolates. Among them, glycosylated flavanols including monomers and glycosylated A-type procyanidin dimers and trimers were highly representative. Fifty overaccumulated discriminating compounds were found for brown chocolates. Most of them were B-type procyanidins (from trimers to nonamers). These phenolic compounds may be partially related to the chocolate colors as precursors of colored compounds. This study increases the knowledge on the chemical diversity of dark chocolates by providing new information about the phenolic profiles of black and brown chocolates. Full article
(This article belongs to the Special Issue Proteomics and Metabolomics Studies of Food Plants)
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24 pages, 4590 KiB  
Article
Metabolic Reprogramming of Barley in Response to Foliar Application of Dichlorinated Functional Analogues of Salicylic Acid as Priming Agents and Inducers of Plant Defence
by Claude Y. Hamany Djande, Paul A. Steenkamp, Lizelle A. Piater, Fidele Tugizimana and Ian A. Dubery
Metabolites 2023, 13(5), 666; https://doi.org/10.3390/metabo13050666 - 17 May 2023
Cited by 2 | Viewed by 1130
Abstract
Designing innovative biological crop protection strategies to stimulate natural plant immunity is motivated by the growing need for eco-friendly alternatives to conventional biocidal agrochemicals. Salicylic acid (SA) and analogues are known chemical inducers of priming plant immunity against environmental stresses. The aim of [...] Read more.
Designing innovative biological crop protection strategies to stimulate natural plant immunity is motivated by the growing need for eco-friendly alternatives to conventional biocidal agrochemicals. Salicylic acid (SA) and analogues are known chemical inducers of priming plant immunity against environmental stresses. The aim of the study was to study the metabolic reprogramming in barley plants following an application of three proposed dichlorinated inducers of acquired resistance. 3,5-Dichloroanthranilic acid, 2,6-dichloropyridine-4-carboxylic acid, and 3,5-dichlorosalicylic acid were applied to barley at the third leaf stage of development and harvested at 12, 24, and 36 h post-treatment. Metabolites were extracted using methanol for untargeted metabolomics analyses. Samples were analysed by ultra-high performance liquid chromatography coupled to high-definition mass spectrometry (UHPLC-HDMS). Chemometric methods and bioinformatics tools were used to mine and interpret the generated data. Alterations in the levels of both primary and secondary metabolites were observed. The accumulation of barley-specific metabolites, hordatines, and precursors was observed from 24 h post-treatment. The phenylpropanoid pathway, a marker of induced resistance, was identified among the key mechanisms activated by the treatment with the three inducers. No salicylic acid or SA derivatives were annotated as signatory biomarkers; instead, jasmonic acid precursors and derivatives were found as discriminatory metabolites across treatments. The study highlights differences and similarities in the metabolomes of barley after treatment with the three inducers and points to the triggering chemical changes associated with defence and resistance. This report is the first of its kind, and the knowledge acquired provides deeper insight into the role of dichlorinated small molecules as inducers of plant immunity and can be used in metabolomics-guided plant improvement programmes. Full article
(This article belongs to the Special Issue Metabolomics and Plant Defence)
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16 pages, 987 KiB  
Review
Instrumental Drift in Untargeted Metabolomics: Optimizing Data Quality with Intrastudy QC Samples
by Andre Märtens, Johannes Holle, Brit Mollenhauer, Andre Wegner, Jennifer Kirwan and Karsten Hiller
Metabolites 2023, 13(5), 665; https://doi.org/10.3390/metabo13050665 - 16 May 2023
Cited by 1 | Viewed by 2147
Abstract
Untargeted metabolomics is an important tool in studying health and disease and is employed in fields such as biomarker discovery and drug development, as well as precision medicine. Although significant technical advances were made in the field of mass-spectrometry driven metabolomics, instrumental drifts, [...] Read more.
Untargeted metabolomics is an important tool in studying health and disease and is employed in fields such as biomarker discovery and drug development, as well as precision medicine. Although significant technical advances were made in the field of mass-spectrometry driven metabolomics, instrumental drifts, such as fluctuations in retention time and signal intensity, remain a challenge, particularly in large untargeted metabolomics studies. Therefore, it is crucial to consider these variations during data processing to ensure high-quality data. Here, we will provide recommendations for an optimal data processing workflow using intrastudy quality control (QC) samples that identifies errors resulting from instrumental drifts, such as shifts in retention time and metabolite intensities. Furthermore, we provide an in-depth comparison of the performance of three popular batch-effect correction methods of different complexity. By using different evaluation metrics based on QC samples and a machine learning approach based on biological samples, the performance of the batch-effect correction methods were evaluated. Here, the method TIGER demonstrated the overall best performance by reducing the relative standard deviation of the QCs and dispersion-ratio the most, as well as demonstrating the highest area under the receiver operating characteristic with three different probabilistic classifiers (Logistic regression, Random Forest, and Support Vector Machine). In summary, our recommendations will help to generate high-quality data that are suitable for further downstream processing, leading to more accurate and meaningful insights into the underlying biological processes. Full article
(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)
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12 pages, 1662 KiB  
Article
Certain Tomato Root Exudates Induced by Pseudomonas stutzeri NRCB010 Enhance Its Rhizosphere Colonization Capability
by Huanhuan Zhang, Donghui Zheng, Chun Hu, Wenwen Cheng, Peng Lei, Hong Xu and Nan Gao
Metabolites 2023, 13(5), 664; https://doi.org/10.3390/metabo13050664 - 16 May 2023
Cited by 1 | Viewed by 1192
Abstract
Plant growth-promoting rhizobacteria (PGPR) can colonize plant root surfaces or form biofilms to promote plant growth and enhance plant resistance to harsh external environments. However, plant–PGPR interactions, especially chemical signaling molecules, are poorly understood. This study aimed to gain an in-depth understanding of [...] Read more.
Plant growth-promoting rhizobacteria (PGPR) can colonize plant root surfaces or form biofilms to promote plant growth and enhance plant resistance to harsh external environments. However, plant–PGPR interactions, especially chemical signaling molecules, are poorly understood. This study aimed to gain an in-depth understanding of the rhizosphere interaction mechanisms between PGPR and tomato plants. This study found that inoculation with a certain concentration of Pseudomonas stutzeri significantly promoted tomato growth and induced significant changes in tomato root exudates. Furthermore, the root exudates significantly induced NRCB010 growth, swarming motility, and biofilm formation. In addition, the composition of the root exudates was analyzed, and four metabolites (methyl hexadecanoate, methyl stearate, 2,4-di-tert-butylphenol, and n-hexadecanoic acid) significantly related to the chemotaxis and biofilm formation of NRCB010 were screened. Further assessment showed that these metabolites positively affected the growth, swarming motility, chemotaxis, or biofilm formation of strain NRCB010. Among these, n-hexadecanoic acid induced the most remarkable growth, chemotactic response, biofilm formation, and rhizosphere colonization. This study will help develop effective PGPR-based bioformulations to improve PGPR colonization and crop yields. Full article
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11 pages, 451 KiB  
Article
The Relationship between Maternal Antibodies to Fetal Brain and Prenatal Stress Exposure in Autism Spectrum Disorder
by Amy N. Costa, Bradley J. Ferguson, Emily Hawkins, Adriana Coman, Joseph Schauer, Alex Ramirez-Celis, Patrick M. Hecht, Danielle Bruce, Michael Tilley, Zohreh Talebizadeh, Judy Van de Water and David Q. Beversdorf
Metabolites 2023, 13(5), 663; https://doi.org/10.3390/metabo13050663 - 16 May 2023
Cited by 1 | Viewed by 1672
Abstract
Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to [...] Read more.
Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to stress during pregnancy. Additionally, the presence of maternal antibodies for the fetal brain is associated with a diagnosis of ASD in children. However, the relationship between prenatal stress exposure and maternal antibodies in the mothers of children diagnosed with ASD has not yet been addressed. This exploratory study examined the association of maternal antibody response with prenatal stress and a diagnosis of ASD in children. Blood samples from 53 mothers with at least one child diagnosed with ASD were examined by ELISA. Maternal antibody presence, perceived stress levels during pregnancy (high or low), and maternal 5-HTTLPR polymorphisms were examined for their interrelationship in ASD. While high incidences of prenatal stress and maternal antibodies were found in the sample, they were not associated with each other (p = 0.709, Cramér’s V = 0.051). Furthermore, the results revealed no significant association between maternal antibody presence and the interaction between 5-HTTLPR genotype and stress (p = 0.729, Cramér’s V = 0.157). Prenatal stress was not found to be associated with the presence of maternal antibodies in the context of ASD, at least in this initial exploratory sample. Despite the known relationship between stress and changes in immune function, these results suggest that prenatal stress and immune dysregulation are independently associated with a diagnosis of ASD in this study population, rather than acting through a convergent mechanism. However, this would need to be confirmed in a larger sample. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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17 pages, 2388 KiB  
Article
Bone Metabolite Profile Differs between Normal and Femur Head Necrosis (FHN/BCO)-Affected Broilers: Implications for Dysregulated Metabolic Cascades in FHN Pathophysiology
by Alison Ramser, Rachel Hawken, Elizabeth Greene, Ron Okimoto, Brenda Flack, Courtney J. Christopher, Shawn R. Campagna and Sami Dridi
Metabolites 2023, 13(5), 662; https://doi.org/10.3390/metabo13050662 - 16 May 2023
Viewed by 1117
Abstract
Femur head necrosis (FHN), also known as bacterial chondronecrosis with osteomyelitis (BCO), has remained an animal welfare and production concern for modern broilers regardless of efforts to select against it in primary breeder flocks. Characterized by the bacterial infection of weak bone, FHN [...] Read more.
Femur head necrosis (FHN), also known as bacterial chondronecrosis with osteomyelitis (BCO), has remained an animal welfare and production concern for modern broilers regardless of efforts to select against it in primary breeder flocks. Characterized by the bacterial infection of weak bone, FHN has been found in birds without clinical lameness and remains only detectable via necropsy. This presents an opportunity to utilize untargeted metabolomics to elucidate potential non-invasive biomarkers and key causative pathways involved in FHN pathology. The current study used ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS) and identified a total of 152 metabolites. Mean intensity differences at p < 0.05 were found in 44 metabolites, with 3 significantly down-regulated and 41 up-regulated in FHN-affected bone. Multivariate analysis and a partial least squares discriminant analysis (PLS-DA) scores plot showed the distinct clustering of metabolite profiles from FHN-affected vs. normal bone. Biologically related molecular networks were predicted using an ingenuity pathway analysis (IPA) knowledge base. Using a fold-change cut off of −1.5 and 1.5, top canonical pathways, networks, diseases, molecular functions, and upstream regulators were generated using the 44 differentially abundant metabolites. The results showed the metabolites NAD+, NADP+, and NADH to be downregulated, while 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and histamine were significantly increased in FHN. Ascorbate recycling and purine nucleotides degradation were the top canonical pathways, indicating the potential dysregulation of redox homeostasis and osteogenesis. Lipid metabolism and cellular growth and proliferation were some of the top molecular functions predicted based on the metabolite profile in FHN-affected bone. Network analysis showed significant overlap across metabolites and predicted upstream and downstream complexes, including AMP-activated protein kinase (AMPK), insulin, collagen type IV, mitochondrial complex, c-Jun N-terminal kinase (Jnk), extracellular signal-regulated kinase (ERK), and 3β-hydroxysteroid dehydrogenase (3β HSD). The qPCR analysis of relevant factors showed a significant decrease in AMPKα2 mRNA expression in FHN-affected bone, supporting the predicted downregulation found in the IPA network analysis. Taken as a whole, these results demonstrate a shift in energy production, bone homeostasis, and bone cell differentiation that is distinct in FHN-affected bone, with implications for how metabolites drive the pathology of FHN. Full article
(This article belongs to the Special Issue Manipulation of Metabolic Pathways by Transcription Factors)
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15 pages, 480 KiB  
Article
The Evaluation of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 Phenoconversion in Post-Mortem Casework: The Challenge of Forensic Toxicogenetics
by Arianna Giorgetti, Sara Amurri, Giulia Fazio, Carla Bini, Laura Anniballi, Filippo Pirani, Guido Pelletti and Susi Pelotti
Metabolites 2023, 13(5), 661; https://doi.org/10.3390/metabo13050661 - 16 May 2023
Cited by 2 | Viewed by 1569
Abstract
In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between [...] Read more.
In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between the phenotype based on the genotype and the metabolic profile actually observed after phenoconversion. The aim of our study was to evaluate the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolising enzymes in a series of autopsy cases tested positive for drugs that are substrates, inducers, or inhibitors of these enzymes. Our results showed a high rate of phenoconversion for all enzymes and a statistically significant higher frequency of poor and intermediate metabolisers for CYP2D6, CYP2C9, and CYP2C19 after phenoconversion. No association was found between phenotypes and CoD or MoD, suggesting that, although phenoconversion might be useful for a forensic toxicogenetics approach, more research is needed to overcome the challenges arising from the post-mortem setting. Full article
(This article belongs to the Special Issue Biochemical Activation and Functions of Drug-Metabolizing Enzymes)
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17 pages, 4454 KiB  
Article
Longitudinal Characterization of the Gut Microbiota in the Diabetic ZDSD Rat Model and Therapeutic Potential of Oligofructose
by Savanna N. Weninger, Angela Ding, Elizabeth N. Browne, Morgan L. Frost, Gabriele Schiro, Daniel Laubitz and Frank A. Duca
Metabolites 2023, 13(5), 660; https://doi.org/10.3390/metabo13050660 - 16 May 2023
Cited by 2 | Viewed by 1263
Abstract
The complex development of type 2 diabetes (T2D) creates challenges for studying the progression and treatment of the disease in animal models. A newly developed rat model of diabetes, the Zucker Diabetic Sprague Dawley (ZDSD) rat, closely parallels the progression of T2D in [...] Read more.
The complex development of type 2 diabetes (T2D) creates challenges for studying the progression and treatment of the disease in animal models. A newly developed rat model of diabetes, the Zucker Diabetic Sprague Dawley (ZDSD) rat, closely parallels the progression of T2D in humans. Here, we examine the progression of T2D and associated changes in the gut microbiota in male ZDSD rats and test whether the model can be used to examine the efficacy of potential therapeutics such as prebiotics, specifically oligofructose, that target the gut microbiota. Bodyweight, adiposity, and fed/fasting blood glucose and insulin were recorded over the course of the study. Glucose and insulin tolerance tests were performed, and feces collected at 8, 16, and 24 weeks of age for short-chain fatty acids and microbiota analysis using 16s rRNA gene sequencing. At the end of 24 weeks of age, half of the rats were supplemented with 10% oligofructose and tests were repeated. We observed a transition from healthy/nondiabetic to prediabetic and overtly diabetic states, via worsened insulin and glucose tolerance and significant increases in fed/fasted glucose, followed by a significant decrease in circulating insulin. Acetate and propionate levels were significantly increased in the overt diabetic state compared to healthy and prediabetic. Microbiota analysis demonstrated alterations in the gut microbiota with shifts in alpha and beta diversity as well as alterations in specific bacterial genera in healthy compared to prediabetic and diabetic states. Oligofructose treatment improved glucose tolerance and shifted the cecal microbiota of the ZDSD rats during late-stage diabetes. These findings underscore the translational potential of ZDSD rats as a model of T2D and highlight potential gut bacteria that could impact the development of the disease or serve as a biomarker for T2D. Additionally, oligofructose treatment was able to moderately improve glucose homeostasis. Full article
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31 pages, 5326 KiB  
Article
A Holistic Approach from Systems Biology Reveals the Direct Influence of the Quorum-Sensing Phenomenon on Pseudomonas aeruginosa Metabolism to Pyoverdine Biosynthesis
by Diana Carolina Clavijo-Buriticá, Catalina Arévalo-Ferro and Andrés Fernando González Barrios
Metabolites 2023, 13(5), 659; https://doi.org/10.3390/metabo13050659 - 16 May 2023
Viewed by 2332
Abstract
Computational modeling and simulation of biological systems have become valuable tools for understanding and predicting cellular performance and phenotype generation. This work aimed to construct, model, and dynamically simulate the virulence factor pyoverdine (PVD) biosynthesis in Pseudomonas aeruginosa through a systemic approach, considering [...] Read more.
Computational modeling and simulation of biological systems have become valuable tools for understanding and predicting cellular performance and phenotype generation. This work aimed to construct, model, and dynamically simulate the virulence factor pyoverdine (PVD) biosynthesis in Pseudomonas aeruginosa through a systemic approach, considering that the metabolic pathway of PVD synthesis is regulated by the quorum-sensing (QS) phenomenon. The methodology comprised three main stages: (i) Construction, modeling, and validation of the QS gene regulatory network that controls PVD synthesis in P. aeruginosa strain PAO1; (ii) construction, curating, and modeling of the metabolic network of P. aeruginosa using the flux balance analysis (FBA) approach; (iii) integration and modeling of these two networks into an integrative model using the dynamic flux balance analysis (DFBA) approximation, followed, finally, by an in vitro validation of the integrated model for PVD synthesis in P. aeruginosa as a function of QS signaling. The QS gene network, constructed using the standard System Biology Markup Language, comprised 114 chemical species and 103 reactions and was modeled as a deterministic system following the kinetic based on mass action law. This model showed that the higher the bacterial growth, the higher the extracellular concentration of QS signal molecules, thus emulating the natural behavior of P. aeruginosa PAO1. The P. aeruginosa metabolic network model was constructed based on the iMO1056 model, the P. aeruginosa PAO1 strain genomic annotation, and the metabolic pathway of PVD synthesis. The metabolic network model included the PVD synthesis, transport, exchange reactions, and the QS signal molecules. This metabolic network model was curated and then modeled under the FBA approximation, using biomass maximization as the objective function (optimization problem, a term borrowed from the engineering field). Next, chemical reactions shared by both network models were chosen to combine them into an integrative model. To this end, the fluxes of these reactions, obtained from the QS network model, were fixed in the metabolic network model as constraints of the optimization problem using the DFBA approximation. Finally, simulations of the integrative model (CCBM1146, comprising 1123 reactions and 880 metabolites) were run using the DFBA approximation to get (i) the flux profile for each reaction, (ii) the bacterial growth profile, (iii) the biomass profile, and (iv) the concentration profiles of metabolites of interest such as glucose, PVD, and QS signal molecules. The CCBM1146 model showed that the QS phenomenon directly influences the P. aeruginosa metabolism to PVD biosynthesis as a function of the change in QS signal intensity. The CCBM1146 model made it possible to characterize and explain the complex and emergent behavior generated by the interactions between the two networks, which would have been impossible to do by studying each system’s individual components or scales separately. This work is the first in silico report of an integrative model comprising the QS gene regulatory network and the metabolic network of P. aeruginosa. Full article
(This article belongs to the Section Bioinformatics and Data Analysis)
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16 pages, 9232 KiB  
Article
Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation
by Abdulrahim A. Alzain, Rua M. Mukhtar, Nihal Abdelmoniem, Fatima A. Elbadwi, Amira Hussien, Elrashied A. E. Garelnabi, Wadah Osman, Asmaa E. Sherif, Amgad I. M. Khedr, Kholoud F. Ghazawi, Waad A. Samman, Sabrin R. M. Ibrahim, Gamal A. Mohamed and Ahmed Ashour
Metabolites 2023, 13(5), 658; https://doi.org/10.3390/metabo13050658 - 15 May 2023
Cited by 6 | Viewed by 1510
Abstract
Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it [...] Read more.
Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8. Full article
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11 pages, 1293 KiB  
Article
Effects of Ecologically Relevant Concentrations of Cadmium on the Microbiota, Short-Chain Fatty Acids, and FFAR2 Expression in Zebrafish
by Jian Yang, Junyi Li, Xiaoshun Zhang, Qin Zhou, Junyi Wang, Qingsong Chen, Xiaojing Meng and Yuan Xia
Metabolites 2023, 13(5), 657; https://doi.org/10.3390/metabo13050657 - 15 May 2023
Cited by 3 | Viewed by 1188
Abstract
Exposure to cadmium (Cd) can affect neurodevelopment and results in increased potential of developing neurodegenerative diseases during the early developmental stage of organisms, but the mechanisms through which exposure to environmentally relevant concentrations of Cd lead to developmental neurotoxicity remain unclear. Although we [...] Read more.
Exposure to cadmium (Cd) can affect neurodevelopment and results in increased potential of developing neurodegenerative diseases during the early developmental stage of organisms, but the mechanisms through which exposure to environmentally relevant concentrations of Cd lead to developmental neurotoxicity remain unclear. Although we know that microbial community fixations overlap with the neurodevelopmental window during early development and that Cd-induced neurodevelopmental toxicity may be related to the disruption of microorganisms during early development, information on the effects of exposure to environmentally relevant Cd concentrations on gut microbiota disruption and neurodevelopment is scarce. Therefore, we established a model of zebrafish exposed to Cd (5 µg/L) to observe the changes in the gut microbiota, SCFAs, and free fatty acid receptor 2 (FFAR2) in zebrafish larvae exposed to Cd for 7 days. Our results indicated that there were significant changes in the gut microbial composition due to the exposure to Cd in zebrafish larvae. At the genus level, there were decreases in the relative abundances of Phascolarctobacterium, Candidatus Saccharimonas, and Blautia in the Cd group. Our analysis revealed that the acetic acid concentration was decreased (p > 0.05) while the isobutyric acid concentration was increased (p < 0.05). Further correlation analysis indicated a positive correlation between the content of acetic acid and the relative abundances of Phascolarctobacterium and Candidatus Saccharimonas (R = 0.842, p < 0.01; R = 0.767, p < 0.01), and a negative correlation between that of isobutyric acid and the relative abundance of Blautia glucerasea (R = −0.673, p < 0.05). FFAR2 needs to be activated by SCFAs to exert physiological effects, and acetic acid is its main ligand. The FFAR2 expression and the acetic acid concentration were decreased in the Cd group. We speculate that FFAR2 may be implicated in the regulatory mechanism of the gut–brain axis in Cd-induced neurodevelopmental toxicity. Full article
(This article belongs to the Special Issue Environmental Toxicology and Metabolism)
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24 pages, 4687 KiB  
Article
20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells
by Oleg Shuvalov, Yulia Kirdeeva, Elizaveta Fefilova, Sofia Netsvetay, Mark Zorin, Yulia Vlasova, Olga Fedorova, Alexandra Daks, Sergey Parfenyev and Nickolai Barlev
Metabolites 2023, 13(5), 656; https://doi.org/10.3390/metabo13050656 - 15 May 2023
Cited by 4 | Viewed by 1825
Abstract
20-Hydroxyecdysone (20E) is an arthropod hormone which is synthesized by some plants as part of their defense mechanism. In humans, 20E has no hormonal activity but possesses a number of beneficial pharmacological properties including anabolic, adaptogenic, hypoglycemic, and antioxidant properties, as well as [...] Read more.
20-Hydroxyecdysone (20E) is an arthropod hormone which is synthesized by some plants as part of their defense mechanism. In humans, 20E has no hormonal activity but possesses a number of beneficial pharmacological properties including anabolic, adaptogenic, hypoglycemic, and antioxidant properties, as well as cardio-, hepato-, and neuroprotective features. Recent studies have shown that 20E may also possess antineoplastic activity. In the present study, we reveal the anticancer properties of 20E in Non-Small Cell Lung Cancer (NSCLC) cell lines. 20E displayed significant antioxidant capacities and induced the expression of antioxidative stress response genes. The RNA-seq analysis of 20E-treated lung cancer cells revealed the attenuation of genes involved in different metabolic processes. Indeed, 20E suppressed several enzymes of glycolysis and one-carbon metabolism, as well as their key transcriptional regulators—c-Myc and ATF4, respectively. Accordingly, using the SeaHorse energy profiling approach, we observed the inhibition of glycolysis and respiration mediated by 20E treatment. Furthermore, 20E sensibilized lung cancer cells to metabolic inhibitors and markedly suppressed the expression of Cancer Stem Cells (CSCs) markers. Thus, in addition to the known beneficial pharmacological activities of 20E, our data uncovered novel antineoplastic properties of 20E in NSCLC cells. Full article
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12 pages, 4504 KiB  
Article
Resveratrol Alleviates Advanced Glycation End-Products-Related Renal Dysfunction in D-Galactose-Induced Aging Mice
by Kuo-Cheng Lan, Pei-Jin Peng, Ting-Yu Chang and Shing-Hwa Liu
Metabolites 2023, 13(5), 655; https://doi.org/10.3390/metabo13050655 - 13 May 2023
Cited by 3 | Viewed by 8095
Abstract
The elderly have higher concentrations of advanced glycation end-products (AGEs). AGEs are considered risk factors that accelerate aging and cause diabetic nephropathy. The effects of AGEs on renal function in the elderly remain to be clarified. This study aimed to explore the role [...] Read more.
The elderly have higher concentrations of advanced glycation end-products (AGEs). AGEs are considered risk factors that accelerate aging and cause diabetic nephropathy. The effects of AGEs on renal function in the elderly remain to be clarified. This study aimed to explore the role of AGEs in renal function decline in the elderly and the protective effect of resveratrol, a stilbenoid polyphenol, comparing it with aminoguanidine (an AGEs inhibitor). A D-galactose-induced aging mouse model was used to explore the role of AGEs in the process of renal aging. The mice were administered D-galactose subcutaneously for eight weeks in the presence or absence of orally administered aminoguanidine or resveratrol. The results showed that the serum levels of AGEs and renal function markers BUN, creatinine, and cystatin C in the mice significantly increased after the administration of D-galactose, and this outcome could be significantly reversed by treatment with aminoguanidine or resveratrol. The protein expression levels for apoptosis, fibrosis, and aging-related indicators in the kidneys were significantly increased, which could also be reversed by treatment with aminoguanidine or resveratrol. These findings suggest that resveratrol could alleviate AGEs-related renal dysfunction through the improvement of renal cellular senescence, apoptosis, and fibrosis in D-galactose-induced aging in mice. Full article
(This article belongs to the Special Issue Functional Foods and Diabetes II)
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17 pages, 8673 KiB  
Article
Dynamic Changes in Plant Secondary Metabolites Induced by Botrytis cinerea Infection
by Zhaochen Wu, Tuqiang Gao, Zhengya Liang, Jianjun Hao, Pengfei Liu and Xili Liu
Metabolites 2023, 13(5), 654; https://doi.org/10.3390/metabo13050654 - 13 May 2023
Cited by 6 | Viewed by 1352
Abstract
In response to pathogen infection, some plants increase production of secondary metabolites, which not only enhance plant defense but also induce fungicide resistance, especially multidrug resistance (MDR) in the pathogen through preadaptation. To investigate the cause of MDR in Botrytis cinerea, grapes ‘Victoria’ [...] Read more.
In response to pathogen infection, some plants increase production of secondary metabolites, which not only enhance plant defense but also induce fungicide resistance, especially multidrug resistance (MDR) in the pathogen through preadaptation. To investigate the cause of MDR in Botrytis cinerea, grapes ‘Victoria’ (susceptible to B. cinerea) and ‘Shine Muscat’ (resistant to B. cinerea) were inoculated into seedling leaves with B. cinerea, followed by extraction of metabolites from the leaves on days 3, 6, and 9 after inoculation. The extract was analyzed using gas chromatography/quadrupole time-of-flight mass (GC/QTOF) combined with solid-phase microextraction (SPME) for volatile and nonvolatile metabolomic components. Nonvolatile metabolites γ-aminobutyric acid (GABA), resveratrol, piceid, and some carbohydrates or amino acids, coupled with volatile metabolites β-ocimene, α-farnesene, caryophyllene, germacrene D, β-copaene, and alkanes, accumulated at a higher level in grape leaves infected with B. cinerea compared to in noninoculated leaves. Among the established metabolic pathways, seven had greater impacts, including aminoacyl-tRNA biosynthesis, galactose metabolism, valine, leucine, and isoleucine biosynthesis. Furthermore, isoquinoline alkaloid biosynthesis; phenylpropanoid biosynthesis; monobactam biosynthesis; tropane, piperidine, and pyridine alkaloid biosynthesis; phenylalanine metabolism; and glucosinolate biosynthesis were related to antifungal activities. Based on liquid chromatography/quadrupole time-of-flight mass (LC/QTOF) detection and bioassay, B. cinerea infection induced production of plant secondary metabolites (PSMs) including eugenol, flavanone, reserpine, resveratrol, and salicylic acid, which all have inhibitory activity against B. cinerea. These compounds also promoted overexpression of ATP-binding cassette (ABC) transporter genes, which are involved in induction of MDR in B. cinerea. Full article
(This article belongs to the Section Plant Metabolism)
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18 pages, 2382 KiB  
Article
Differences Due to Sex and Sweetener on the Bioavailability of (Poly)phenols in Urine Samples: A Machine Learning Approach
by Diego Hernández-Prieto, Alberto Garre, Vicente Agulló, Cristina García-Viguera and Jose A. Egea
Metabolites 2023, 13(5), 653; https://doi.org/10.3390/metabo13050653 - 11 May 2023
Cited by 1 | Viewed by 1369
Abstract
Metabolic diseases have been related to the overdrinking of high-sugar content beverages. As a result, the demand for alternative formulations based on plant-based ingredients with health-promoting properties has increased during the last few years. Nonetheless, the design and production of effective formulations requires [...] Read more.
Metabolic diseases have been related to the overdrinking of high-sugar content beverages. As a result, the demand for alternative formulations based on plant-based ingredients with health-promoting properties has increased during the last few years. Nonetheless, the design and production of effective formulations requires understanding the bioavailability of these compounds. For this purpose, a two-month longitudinal trial with 140 volunteers was conducted to measure the beneficial effects of a maqui–citrus beverage, rich in (poly)phenols. From data obtained by quantifying metabolites present in urine samples, biostatistical and machine learning (data imputation, feature selection, and clustering) methods were applied to assess whether a volunteer’s sex and the sweetener added to the beverage (sucrose, sucralose, or stevia) affected the bioavailability of (poly)phenol metabolites. Several metabolites have been described as being differentially influenced: 3,4-dihydroxyphenylacetic acid and naringenin with its derivatives were positively influenced by stevia and men, while eriodictyol sulfate and homoeridictyol glucunoride concentrations were enhanced with stevia and women. By examining groups of volunteers created by clustering analysis, patterns in metabolites’ bioavailability distribution as a function of sex and/or sweeteners (or even due to an uncontrolled factor) were also discovered. These results underline the potential of stevia as a (poly)phenol bioavailability enhancer. Furthermore, they also evidence sex affects the bioavailability of (poly)phenols, pointing at a sex-dependent metabolic pathway regulation. Full article
(This article belongs to the Special Issue Plant, Food and Nutritional Metabolomics)
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13 pages, 334 KiB  
Article
Effects of Metabolic Syndrome and Sex on Stress Coping Strategies in Individuals with Depressive Disorder
by Eva Puchner, Martina Platzer, Nina Dalkner, Karin Schwalsberger, Melanie Lenger, Frederike T. Fellendorf, Human-Friedrich Unterrainer, Andreas Schwerdtfeger, Bernd Reininghaus and Eva Z. Reininghaus
Metabolites 2023, 13(5), 652; https://doi.org/10.3390/metabo13050652 - 11 May 2023
Viewed by 1413
Abstract
Metabolic syndrome (MetS) is related to depression and contributes to reduced life expectancy in individuals with mental disorders. Stress coping strategies are important factors in the development and maintenance of depressive disorders and have been related to metabolic disturbances. The aim of this [...] Read more.
Metabolic syndrome (MetS) is related to depression and contributes to reduced life expectancy in individuals with mental disorders. Stress coping strategies are important factors in the development and maintenance of depressive disorders and have been related to metabolic disturbances. The aim of this study was to determine whether there is a difference in the use of positive (re- and devaluation, distraction, and control) and negative stress coping strategies in relation to patients’ MetS. A sample of 363 individuals (n female = 204, n male = 159) with a diagnosis of depression was measured with the Stress Coping Style Questionnaire and the Beck Depression Inventory. In addition, we collected data on MetS (waist circumference, triglycerides, high-density lipoprotein, fasting glucose/diabetes, blood pressure/hypertonia) according to the International Diabetes Federation. A 2 × 2 design including Mets (with vs. without) and sex (female vs. male) was performed to test for differences in stress coping strategies. Individuals with depression and MetS scored higher on distraction strategies than depressed individuals without MetS (p < 0.01, corrected with false discovery rate). In addition, we found sex differences in stress coping strategies indicating that women with depression scored higher on distraction strategies (p < 0.001, FDR corrected), as well as negative strategies (p < 0.001, FDR corrected), than men. No significant interaction between MetS and sex was found regarding the higher value of stress coping strategies. Findings suggest that individuals with depression and MetS used distraction strategies to a higher amount to cope with stress, which could be stress eating in some cases, than those without MetS. Women with depressive disorders had higher values than men on other coping strategies in our sample of individuals with depression. A better understanding of MetS and sex-specific differences in stress coping strategies might help to plan more effective preventive strategies and personalized treatment options for depression. Full article
(This article belongs to the Topic Metabolism and Health)
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17 pages, 2197 KiB  
Article
Exploring Volatile Organic Compounds in Rhizomes and Leaves of Kaempferia parviflora Wall. Ex Baker Using HS-SPME and GC–TOF/MS Combined with Multivariate Analysis
by May San Thawtar, Miyako Kusano, Li Yingtao, Wunna, Min San Thein, Keisuke Tanaka, Marlon Rivera, Miao Shi and Kazuo N. Watanabe
Metabolites 2023, 13(5), 651; https://doi.org/10.3390/metabo13050651 - 11 May 2023
Viewed by 1954
Abstract
Volatile organic compounds (VOCs) play an important role in the biological activities of the medicinal Zingiberaceae species. In commercial preparations of VOCs from Kaempferia parviflora rhizomes, its leaves are wasted as by-products. The foliage could be an alternative source to rhizome, but its [...] Read more.
Volatile organic compounds (VOCs) play an important role in the biological activities of the medicinal Zingiberaceae species. In commercial preparations of VOCs from Kaempferia parviflora rhizomes, its leaves are wasted as by-products. The foliage could be an alternative source to rhizome, but its VOCs composition has not been explored previously. In this study, the VOCs in the leaves and rhizomes of K. parviflora plants grown in a growth room and in the field were analyzed using the headspace solid-phase microextraction (HS-SPME) method coupled with gas chromatography and time-of-flight mass spectrometry (GC-TOF-MS). The results showed a total of 75 and 78 VOCs identified from the leaves and rhizomes, respectively, of plants grown in the growth room. In the field samples, 96 VOCs were detected from the leaves and 98 from the rhizomes. These numbers are higher compared to the previous reports, which can be attributed to the analytical techniques used. It was also observed that monoterpenes were dominant in leaves, whereas sesquiterpenes were more abundant in rhizomes. Principal component analysis (PCA) revealed significantly higher abundance and diversity of VOCs in plants grown in the field than in the growth room. A high level of similarity of identified VOCs between the two tissues was also observed, as they shared 68 and 94 VOCs in the growth room and field samples, respectively. The difference lies in the relative abundance of VOCs, as most of them are abundant in rhizomes. Overall, the current study showed that the leaves of K. parviflora, grown in any growth conditions, can be further utilized as an alternative source of VOCs for rhizomes. Full article
(This article belongs to the Section Plant Metabolism)
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16 pages, 5316 KiB  
Article
Dietary Coated Sodium Butyrate Ameliorates Hepatic Lipid Accumulation and Inflammation via Enhancing Antioxidative Function in Post-Peaking Laying Hens
by Sasa Miao, Yan Li, Tianming Mu, Xiaoming Wang, Wenyan Zhao, Ru Li, Xinyang Dong and Xiaoting Zou
Metabolites 2023, 13(5), 650; https://doi.org/10.3390/metabo13050650 - 10 May 2023
Cited by 7 | Viewed by 1741
Abstract
During the aging process of laying hens, hepatic oxidative stress damage and lipid accumulation are prone to occur, leading to the deterioration of egg quality and a decline in production properties. This research was designed to explore the effects of different levels of [...] Read more.
During the aging process of laying hens, hepatic oxidative stress damage and lipid accumulation are prone to occur, leading to the deterioration of egg quality and a decline in production properties. This research was designed to explore the effects of different levels of coated sodium butyrate (CSB) addition on oxidation resistance, inflammatory reaction, lipid metabolism and hepatic oxidative damage-related gene expression in aged laying hens. A total of 720 healthy 52 weeks old Huafeng laying hens were arbitrarily divided into 5 groups of 6 replicates with 24 birds each and fed a basal diet supplemented with 0, 250, 500, 750 and 1000 mg/kg CSB for 8 weeks, respectively. The CSB quadratically upgraded GSH-Px activities and downgraded MDA content in the liver and serum. The LDL-C, NEFA and TG contents decreased quadratically in CSB groups and significantly reduced the fatty vacuoles as well as the formation of fat granules in the liver (p < 0.05). Meanwhile, the CSB quadratically upregulated the gene expression of IL-10, Nrf2 and HO1, but downregulated the gene expression of IFN-γ, TNF-α and Keap1 in a quadratic manner (p < 0.05). Moreover, the CSB quadratically degraded the mRNA level of fatty acid synthesis but increased the gene level of key enzymes of fatty acid catabolism (p < 0.05). In conclusion, dietary CSB supplementation has a favorable effect in protecting against liver injury and alleviating lipid accumulation and inflammation by enhancing hepatic antioxidative function in aged laying hens. Full article
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16 pages, 2597 KiB  
Article
Untargeted UHPLC-TOF/MS Lipidomic Analysis for the Investigation of Egg Yolks after Xylanase Supplementation of the Diet of Laying Hens
by Artemis Lioupi, Georgios A. Papadopoulos, Domniki Gallou, Christina Virgiliou, Georgios I. Arsenos, Paschalis Fortomaris, Veerle Van Hoeck, Dany Morisset and Georgios Theodoridis
Metabolites 2023, 13(5), 649; https://doi.org/10.3390/metabo13050649 - 10 May 2023
Viewed by 1455
Abstract
Xylanase supplementation of diets is used to enhance nutrient digestibility in monogastrics which lack necessary enzymes for non-starch polysaccharide degradation. The effects of enzymatic treatment in the nutritional value of the feed are typically not comprehensively studied. Though the fundamental effects of xylanase [...] Read more.
Xylanase supplementation of diets is used to enhance nutrient digestibility in monogastrics which lack necessary enzymes for non-starch polysaccharide degradation. The effects of enzymatic treatment in the nutritional value of the feed are typically not comprehensively studied. Though the fundamental effects of xylanase on performance are well studied, limited data is available on the complex interactions between xylanase supplementation and hen physiology; therefore, the aim of this study was to develop a new, simple UPLC-TOF/MS lipidomics method for the analysis of hen egg yolks after supplementation with different amounts of xylanase. Sample preparation for the extraction of lipids was optimized and different sample preparation modes and solvent mixtures were tested. Optimal results for the extraction of total lipids were obtained by using the solvent mixture MTBE: MeOH (5:1, v/v). Multivariate statistical analysis of the signals of hundreds of lipids in positive and negative ionisation modes highlighted differences in several egg yolk lipid species-classes. Four lipid species-classes, phosphatidylcholines (PC and PC O), phosphatidylethanolamines (PE and PE O), phosphatidylinositols (PI), and fatty acids (FA), were among those contributing to the separation of the experimental groups (control-treated) in negative ionisation mode. In positive ionisation mode, principal beneficial lipid compounds such as phosphatidylcholines (PC and PC O), phosphatidylethanolamines (PE and PE O), triacylglycerols (TG), diacylglycerols (DG), and ceramides (Cer) were found to be increased in treated groups. Overall, supplementation of laying hens’ diets with xylanase significantly changed the lipid profile of egg yolks compared to the control diet. The association between the lipid profiles of egg yolks and hens’ diets, as well as the underlying mechanisms, require further investigation. These findings are of practical significance for the food industry. Full article
(This article belongs to the Section Animal Metabolism)
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18 pages, 1917 KiB  
Review
Simultaneous Quantitation and Discovery (SQUAD) Analysis: Combining the Best of Targeted and Untargeted Mass Spectrometry-Based Metabolomics
by Bashar Amer, Rahul R. Deshpande and Susan S. Bird
Metabolites 2023, 13(5), 648; https://doi.org/10.3390/metabo13050648 - 10 May 2023
Cited by 4 | Viewed by 4317
Abstract
Untargeted and targeted approaches are the traditional metabolomics workflows acquired for a wider understanding of the metabolome under focus. Both approaches have their strengths and weaknesses. The untargeted, for example, is maximizing the detection and accurate identification of thousands of metabolites, while the [...] Read more.
Untargeted and targeted approaches are the traditional metabolomics workflows acquired for a wider understanding of the metabolome under focus. Both approaches have their strengths and weaknesses. The untargeted, for example, is maximizing the detection and accurate identification of thousands of metabolites, while the targeted is maximizing the linear dynamic range and quantification sensitivity. These workflows, however, are acquired separately, so researchers compromise either a low-accuracy overview of total molecular changes (i.e., untargeted analysis) or a detailed yet blinkered snapshot of a selected group of metabolites (i.e., targeted analysis) by selecting one of the workflows over the other. In this review, we present a novel single injection simultaneous quantitation and discovery (SQUAD) metabolomics that combines targeted and untargeted workflows. It is used to identify and accurately quantify a targeted set of metabolites. It also allows data retro-mining to look for global metabolic changes that were not part of the original focus. This offers a way to strike the balance between targeted and untargeted approaches in one single experiment and address the two approaches’ limitations. This simultaneous acquisition of hypothesis-led and discovery-led datasets allows scientists to gain more knowledge about biological systems in a single experiment. Full article
(This article belongs to the Section Advances in Metabolomics)
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16 pages, 5423 KiB  
Article
High-Intensity Interval Training Induces Protein Lactylation in Different Tissues of Mice with Specificity and Time Dependence
by Wenhua Huang, Jie Su, Xuefei Chen, Yanjun Li, Zheng Xing, Lanlan Guo, Shitian Li and Jing Zhang
Metabolites 2023, 13(5), 647; https://doi.org/10.3390/metabo13050647 - 09 May 2023
Cited by 4 | Viewed by 2020
Abstract
Protein lysine lactylation (Kla) is a novel protein acylation reported in recent years, which plays an important role in the development of several diseases with pathologically elevated lactate levels, such as tumors. The concentration of lactate as a donor is directly related to [...] Read more.
Protein lysine lactylation (Kla) is a novel protein acylation reported in recent years, which plays an important role in the development of several diseases with pathologically elevated lactate levels, such as tumors. The concentration of lactate as a donor is directly related to the Kla level. High-intensity interval training (HIIT) is a workout pattern that has positive effects in many metabolic diseases, but the mechanisms by which HIIT promotes health are not yet clear. Lactate is the main metabolite of HIIT, and it is unknown as to whether high lactate during HIIT can induce changes in Kla levels, as well as whether Kla levels differ in different tissues and how time-dependent Kla levels are. In this study, we observed the specificity and time-dependent effects of a single HIIT on the regulation of Kla in mouse tissues. In addition, we aimed to select tissues with high Kla specificity and obvious time dependence for lactylation quantitative omics and analyze the possible biological targets of HIIT-induced Kla regulation. A single HIIT induces Kla in tissues with high lactate uptake and metabolism, such as iWAT, BAT, soleus muscle and liver proteins, and Kla levels peak at 24 h after HIIT and return to steady state at 72 h. Kla proteins in iWAT may affect pathways related to glycolipid metabolism and are highly associated with de novo synthesis. It is speculated that the changes in energy expenditure, lipolytic effects and metabolic characteristics during the recovery period after HIIT may be related to the regulation of Kla in iWAT. Full article
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