Metabolites

18 pages, 2699 KiB

Open AccessArticle

Effects of Water Stress, Defoliation and Crop Thinning on Vitis vinifera L. cv. Solaris Must and Wine Part II: ¹H NMR Metabolomics

by Violetta Aru, Andreas Paul Nittnaus, Klavs Martin Sørensen, Torben Bo Toldam-Andersen and Søren Balling Engelsen

Metabolites 2022, 12(7), 672; https://doi.org/10.3390/metabo12070672 - 21 Jul 2022

Cited by 4 | Viewed by 2016

Abstract

Proton nuclear magnetic resonance (¹H NMR) metabolomics was employed to investigate the impact of water deficit, defoliation, and crop thinning on the chemical composition of must and wines from the cool-climate white grape variety Solaris. The obtained results show that viticultural [...] Read more.

Proton nuclear magnetic resonance (¹H NMR) metabolomics was employed to investigate the impact of water deficit, defoliation, and crop thinning on the chemical composition of must and wines from the cool-climate white grape variety Solaris. The obtained results show that viticultural practices (defoliation and crop thinning) affected the amino acid and sugar content of Solaris must and thereby the quality of the final wine—mainly in terms of compounds normally related to fruity aroma (i.e., isopentanol), non-sugar sweetness (i.e., proline and glycerol), and alcohol content. The content of tyrosol, a natural phenolic antioxidant with a high bioavailability, was increased in the final wine by a combination of defoliation and crop thinning. The results of the metabolomics analysis performed on the must and wine samples from the water stress experiment showed that short-term water deficit significantly affected the concentration of several flavor-related compounds, including glutamate, butyrate and propanol, of the organic acids lactate and fumarate, and of the phenolic compounds caffeic acid and p-coumaric acid. ANOVA simultaneous component analysis showed that the effect of water deficit accounted for 11% (p < 0.001) and 8% (p < 0.001) of the variability in the metabolite concentrations in must and wines, respectively, while viticultural practices accounted for 38% (p < 0.001) and 30% (p < 0.001) of the metabolite variability in must and wines, respectively. Full article

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

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15 pages, 3194 KiB

Open AccessArticle

Imputation of Missing Values for Multi-Biospecimen Metabolomics Studies: Bias and Effects on Statistical Validity

by Machelle D. Wilson, Matthew D. Ponzini, Sandra L. Taylor and Kyoungmi Kim

Metabolites 2022, 12(7), 671; https://doi.org/10.3390/metabo12070671 - 21 Jul 2022

Cited by 5 | Viewed by 2013

Abstract

The analysis of high-throughput metabolomics mass spectrometry data across multiple biological sample types (biospecimens) poses challenges due to missing data. During differential abundance analysis, dropping samples with missing values can lead to severe loss of data as well as biased results in group [...] Read more.

The analysis of high-throughput metabolomics mass spectrometry data across multiple biological sample types (biospecimens) poses challenges due to missing data. During differential abundance analysis, dropping samples with missing values can lead to severe loss of data as well as biased results in group comparisons and effect size estimates. However, the imputation of missing data (the process of replacing missing data with estimated values such as a mean) may compromise the inherent intra-subject correlation of a metabolite across multiple biospecimens from the same subject, which in turn may compromise the efficacy of the statistical analysis of differential metabolites in biomarker discovery. We investigated imputation strategies when considering multiple biospecimens from the same subject. We compared a novel, but simple, approach that consists of combining the two biospecimen data matrices (rows and columns of subjects and metabolites) and imputes the two biospecimen data matrices together to an approach that imputes each biospecimen data matrix separately. We then compared the bias in the estimation of the intra-subject multi-specimen correlation and its effects on the validity of statistical significance tests between two approaches. The combined approach to multi-biospecimen studies has not been evaluated previously even though it is intuitive and easy to implement. We examine these two approaches for five imputation methods: random forest, k nearest neighbor, expectation-maximization with bootstrap, quantile regression, and half the minimum observed value. Combining the biospecimen data matrices for imputation did not greatly increase efficacy in conserving the correlation structure or improving accuracy in the statistical conclusions for most of the methods examined. Random forest tended to outperform the other methods in all performance metrics, except specificity. Full article

(This article belongs to the Special Issue Recent Advances in Computational Methods for Data Analysis in Untargeted Mass-Spectrometry Based Metabolomics)

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15 pages, 7012 KiB

Open AccessArticle

Hepatic Transcriptome Analysis Provides New Insight into the Lipid-Reducing Effect of Dietary Taurine in High–Fat Fed Groupers (Epinephelus coioides)

by Mingfan Chen, Fakai Bai, Tao Song, Xingjian Niu, Xuexi Wang, Kun Wang and Jidan Ye

Metabolites 2022, 12(7), 670; https://doi.org/10.3390/metabo12070670 - 20 Jul 2022

Cited by 8 | Viewed by 2558

Abstract

A transcriptome analysis was conducted to provide the first detailed overview of dietary taurine intervention on liver lipid accumulation caused by high–fat in groupers. After an eight-week feeding, the fish fed 15% fat diet (High–fat diet) had higher liver lipid contents vs. fish [...] Read more.

A transcriptome analysis was conducted to provide the first detailed overview of dietary taurine intervention on liver lipid accumulation caused by high–fat in groupers. After an eight-week feeding, the fish fed 15% fat diet (High–fat diet) had higher liver lipid contents vs. fish fed 10% fat diet (Control diet). 15% fat diet with 1% taurine (Taurine diet) improved weight gain and feed utilization, and decreased hepatosomatic index and liver lipid contents vs. the High–fat diet. In the comparison of the Control vs. High–fat groups, a total of 160 differentially expressed genes (DEGs) were identified, of which up- and down-regulated genes were 72 and 88, respectively. There were 49 identified DEGs with 26 and 23 of up- and down-regulated in the comparison to High–fat vs. Taurine. Several key genes, such as cysteine dioxygenase (CDO1), ADP–ribosylation factor 1/2 (ARF1_2), sodium/potassium–transporting ATPase subunit alpha (ATP1A), carnitine/acylcarnitine translocase (CACT), and calcium/calmodulin–dependent protein kinase II (CAMK) were obtained by enrichment for the above DEGs. These genes were enriched in taurine and hypotaurine metabolism, bile secretion, insulin secretion, phospholipase D signaling pathway, and thermogenesis pathways, respectively. The present study will also provide a new insight into the nutritional physiological function of taurine in farmed fish. Full article

(This article belongs to the Special Issue Regulation and Effect of Taurine on Metabolism)

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11 pages, 430 KiB

Open AccessEditor’s ChoiceArticle

Relationship between Fasting and Postprandial Glucose Levels and the Gut Microbiota

by Yui Mineshita, Hiroyuki Sasaki, Hyeon-ki Kim and Shigenobu Shibata

Metabolites 2022, 12(7), 669; https://doi.org/10.3390/metabo12070669 - 20 Jul 2022

Cited by 3 | Viewed by 2153

Abstract

Postprandial hyperglycemia increases the risk of mortality among patients with type 2 diabetes and cardiovascular diseases. Additionally, the gut microbiota and type 2 diabetes and cardio-vascular disease are known to be correlated. Currently, fasting blood glucose is the primary in-dex for the clinical [...] Read more.

Postprandial hyperglycemia increases the risk of mortality among patients with type 2 diabetes and cardiovascular diseases. Additionally, the gut microbiota and type 2 diabetes and cardio-vascular disease are known to be correlated. Currently, fasting blood glucose is the primary in-dex for the clinical diagnosis of diabetes; however, postprandial blood glucose is associated with the risk of developing type 2 diabetes and cardiovascular disease and mortality. Therefore, the dynamic change in blood glucose levels under free-living conditions is considered an important and better marker than fasting glucose levels to study the relationship between glucose levels and microbiota. Here, we investigated the relationship between fasting and postprandial glucose levels and microbiota under free-living conditions for one week in older adults. In addition, in order to clarify the relationship between blood glucose level and intestinal bacteria, postprandial 4-h AUC was calculated and the correlation with gut bacteria was investigated. As a result of the present study, we observed many of the most significant correlations between the gut bacteria and the peak glucose levels after dinner and the 4-h AUC after dinner. Together, these findings suggest that the individual pattern of microbiota may help to predict post-dinner hyperglycemia and the risk of abnormal glucose metabolism, such as diabetes. Full article

(This article belongs to the Section Nutrition and Metabolism)

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18 pages, 3164 KiB

Open AccessArticle

Assessments of Ceanothanes Triterpenes as Cholinesterase Inhibitors: An Investigation of Potential Agents with Novel Inspiration for Drug Treatment of Neurodegenerative Diseases

by Evelyn Muñoz-Nuñez, Soledad Quiroz-Carreño, Edgar Pastene-Navarrete, David S. Seigler, Carlos Céspedes-Acuña, Ignacio Martínez Valenzuela, Martina Oppliger Muñoz, Alexis Salas-Burgos and Julio Alarcón-Enos

Metabolites 2022, 12(7), 668; https://doi.org/10.3390/metabo12070668 - 20 Jul 2022

Cited by 2 | Viewed by 1939

Abstract

The purpose of this study was to determine the inhibitory capacity of ceanothanes triterpenes isolate from Chilean Rhamnaceae on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Seven ceanothanes triterpenes were isolated from aerial parts of plant material by classical phytochemical methods or prepared by [...] Read more.

The purpose of this study was to determine the inhibitory capacity of ceanothanes triterpenes isolate from Chilean Rhamnaceae on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Seven ceanothanes triterpenes were isolated from aerial parts of plant material by classical phytochemical methods or prepared by the hemisynthetic method. Structures were determined by the spectroscopic method (¹H-NMR and ¹³C NMR) and mass spectrometry (MS). AChE and BChE activity were determined by the Ellmann method for all compounds. All tested compounds exerted a greater affinity to AChE than to BChE, where compound 3 has an IC₅₀ of 0.126 uM for AChE and of >500 uM to BChE. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compound 3 would be produced by interaction with the peripheral anionic site (PAS) of AChE. The compounds tested (1–7) showed an important inhibitory activity of AChE, binding to PAS. Therefore, inhibitors that bind to PAS would prevent the formation of the AChE-Aβ complex, constituting a new alternative in the treatment of Alzheimer’s disease (AD). Full article

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13 pages, 1328 KiB

Open AccessArticle

Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure

by Deepshikha Acharya, Ankita Mukherjea, Jiaming Cao, Alexander Ruesch, Samantha Schmitt, Jason Yang, Matthew A. Smith and Jana M. Kainerstorfer

Metabolites 2022, 12(7), 667; https://doi.org/10.3390/metabo12070667 - 20 Jul 2022

Cited by 6 | Viewed by 2265

Abstract

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO₂) and cerebral autoregulation (CA). However, current mathematical models for CMRO₂ estimation make assumptions that [...] Read more.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO₂) and cerebral autoregulation (CA). However, current mathematical models for CMRO₂ estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO₂ estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO₂ and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO₂/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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13 pages, 869 KiB

Open AccessArticle

Human In Vivo Metabolism and Elimination Behavior of Micro-Dosed Selective Androgen Receptor Modulator RAD140 for Doping Control Purposes

by Felicitas Wagener, Luisa Euler, Christian Görgens, Sven Guddat and Mario Thevis

Metabolites 2022, 12(7), 666; https://doi.org/10.3390/metabo12070666 - 20 Jul 2022

Cited by 9 | Viewed by 3209

Abstract

RAD140 is a selective androgen receptor modulator which has been abused in sporting competitions. Its use is prohibited by the World Anti-Doping Agency (WADA) for athletes at all times. In addition to its illicit use, adverse analytical findings of RAD140 in doping control [...] Read more.

RAD140 is a selective androgen receptor modulator which has been abused in sporting competitions. Its use is prohibited by the World Anti-Doping Agency (WADA) for athletes at all times. In addition to its illicit use, adverse analytical findings of RAD140 in doping control samples might result from other scenarios, e.g., the ingestion of contaminated dietary supplements. The differentiation between samples resulting from such contamination scenarios and intentional doping presents a considerable challenge, as little is known about the metabolism and elimination behavior of RAD140 in humans. In this study, six micro-dose excretion studies with five adult male volunteers each were conducted, and urine samples were analyzed by means of LC-HRMS/MS. Multiple metabolites, firstly detected in human urine, are described in this study. The sample preparation included an enzymatic hydrolysis step, which facilitated the estimation of RAD140 concentrations in urine. The elimination profiles and detection times for six metabolites as well as the intact drug are presented. The method was extensively characterized and deemed fit-for-purpose. The metabolite ratios were investigated for their predictive power in estimating the dose of RAD140 intake. The presented data will aid in better case result management in future doping cases involving RAD140. 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, 3008 KiB

Open AccessEditor’s ChoiceArticle

Molecular Network-Based Identification of Tramadol Metabolites in a Fatal Tramadol Poisoning

by Romain Magny, Nicolas Auzeil, Bertrand Lefrère, Bruno Mégarbane, Pascal Houzé and Laurence Labat

Metabolites 2022, 12(7), 665; https://doi.org/10.3390/metabo12070665 - 19 Jul 2022

Cited by 16 | Viewed by 2462

Abstract

Identification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass [...] Read more.

Identification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass spectrometry with data processing based on a molecular network to identify tramadol metabolites in urine and plasma in poisoned patients. The generated molecular network from liquid chromatography coupled to high-resolution tandem mass spectrometry data acquired in both positive and negative ion modes allowed for the identification of 25 tramadol metabolites in urine and plasma, including four methylated metabolites that have not been previously reported in humans or in vitro models. While positive ion mode is reliable for generating a network of tramadol metabolites displaying a dimethylamino radical in their structure, negative ion mode was useful to cluster phase II metabolites. In conclusion, the combined use of molecular networks in positive and negative ion modes is a suitable and robust tool to identify a broad range of metabolites in poisoned patients, as shown in a fatal tramadol-poisoned patient. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics as Tools in Pharmaceutical and Biological Analysis)

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10 pages, 629 KiB

Open AccessFeature PaperArticle

Comparison of the Diagnostic Performance of Steatosis Indices for Discrimination of CT-Diagnosed Metabolic Dysfunction-Associated Fatty Liver Disease

by A. Lum Han and Hee Kyung Lee

Metabolites 2022, 12(7), 664; https://doi.org/10.3390/metabo12070664 - 19 Jul 2022

Cited by 19 | Viewed by 2365

Abstract

Non-alcoholic fatty liver disease (NAFLD) was redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020. Due to this, further validation of the non-invasive tests used in NAFLD diagnosis is required for MAFLD. There are five known steatosis indices for computed tomography (CT)-diagnosed [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) was redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020. Due to this, further validation of the non-invasive tests used in NAFLD diagnosis is required for MAFLD. There are five known steatosis indices for computed tomography (CT)-diagnosed MAFLD. These indices include the fatty liver index (FLI), the hepatic steatosis index (HSI), the lipid accumulation product (LAP), the visceral adiposity index (VAI), and the Zhejiang University index (ZJU). We aimed to analyze the diagnostic abilities of these five widely known steatosis indices for CT-diagnosed MAFLD. From March 2012 to October 2019, we retrospectively analyzed the clinical information and images of 1300 adults aged ≥19 years who underwent CT scans at our institution. To compare differences, the Chi-square test and independent t-test were used for categorical and continuous variables, respectively. The area under the receiver operating characteristic (AUROC) curve was used to validate the diagnostic accuracy of MAFLD. Of the five indices, FLI was the best at predicting MAFLD, with the highest AUROC (0.791). The sensitivity and specificity of FLI for diagnosing MAFLD were both 70.9%. The optimal cut-off value was 29.9. FLI is a useful surrogate index for screening MAFLD in clinical practice. Full article

(This article belongs to the Special Issue Fatty Liver Index and Progression to Diabetes in Patients with Metabolic Syndrome)

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17 pages, 2896 KiB

Open AccessArticle

Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice

by Alessio Torcinaro, Donato Cappetta, Francesca De Santa, Marialucia Telesca, Massimiliano Leigheb, Liberato Berrino, Konrad Urbanek, Antonella De Angelis and Elisabetta Ferraro

Metabolites 2022, 12(7), 663; https://doi.org/10.3390/metabo12070663 - 18 Jul 2022

Cited by 5 | Viewed by 2647

Abstract

Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate [...] Read more.

Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate with muscle mass loss. We chose to investigate the ability of the metabolic modulator Ranolazine to counteract skeletal muscle dysfunctions that occur with aging. For this purpose, we treated aged C57BL/6 mice with Ranolazine/vehicle for 14 days and collected the tibialis anterior and gastrocnemius muscles for histological and gene expression analyses, respectively. We found that Ranolazine treatment significantly increased the muscle strength of aged mice. At the histological level, we found an increase in centrally nucleated fibers associated with an up-regulation of genes encoding MyoD, Periostin and Osteopontin, thus suggesting a remodeling of the muscle even in the absence of physical exercise. Notably, these beneficial effects of Ranolazine were also accompanied by an up-regulation of antioxidant and mitochondrial genes as well as of NADH-dehydrogenase activity, together with a more efficient protection from oxidative damage in the skeletal muscle. These data indicate that the protection of muscle from oxidative stress by Ranolazine might represent a valuable approach to increase skeletal muscle strength in elderly populations. Full article

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

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24 pages, 8255 KiB

Open AccessArticle

A Comprehensive Study to Identify Major Metabolites of an Amoxicillin–Sulbactam Hybrid Molecule in Rats and Its Metabolic Pathway Using UPLC-Q-TOF-MS/MS

by Fei-Ke Zhao, Ren-Bin Shi, Yu-Bin Sun, Shuang-Yun Yang, Liang-Zhu Chen and Bing-Hu Fang

Metabolites 2022, 12(7), 662; https://doi.org/10.3390/metabo12070662 - 18 Jul 2022

Cited by 5 | Viewed by 2632

Abstract

Amoxicillin and sulbactam are widely used compound drugs in animal food. The amoxicillin–sulbactam hybrid molecule can achieve better curative effects through the combination of the two drugs. However, its pharmacokinetic behavior needs to be explored. In this study, a randomized crossover experiment was [...] Read more.

Amoxicillin and sulbactam are widely used compound drugs in animal food. The amoxicillin–sulbactam hybrid molecule can achieve better curative effects through the combination of the two drugs. However, its pharmacokinetic behavior needs to be explored. In this study, a randomized crossover experiment was performed to investigate the metabolism of the novel amoxicillin–sulbactam hybrid molecule in rats after gastric administration. Ultrahigh performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was used to isolate and to identify the metabolites in rats. Amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were eventually detected in the plasma, liver, urine, and kidneys; no hybrid molecules and their metabolites were detected in feces. The in vivo metabolism results showed that the hybrid molecule was absorbed into the body in the intestine, producing amoxicillin and sulbactam, then amoxicillin was partially metabolized to amoxicilloic acid and amoxicillin diketopiperazine, which are eventually excreted in the urine by the kidneys. In this study, four major metabolites of the amoxicillin–sulbactam hybrid molecule were identified and their metabolic pathways were speculated, which provided scientific data for understanding the metabolism of the hybrid molecule and for its clinical rational use. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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14 pages, 1419 KiB

Open AccessArticle

Circulating Metabolites in Relation to the Kidney Allograft Function in Posttransplant Patients

by Eva Baranovicova, Matej Vnucak, Karol Granak, Jan Lehotsky, Nina Kadasova, Juraj Miklusica and Ivana Dedinska

Metabolites 2022, 12(7), 661; https://doi.org/10.3390/metabo12070661 - 18 Jul 2022

Cited by 2 | Viewed by 2126

Abstract

End-stage kidney disease is preferably treated by kidney transplantation. The suboptimal function of the allograft often results in misbalances in kidney-controlled processes and requires long-term monitoring of allograft function and viability. As the kidneys are organs with a very high metabolomic rate, a [...] Read more.

End-stage kidney disease is preferably treated by kidney transplantation. The suboptimal function of the allograft often results in misbalances in kidney-controlled processes and requires long-term monitoring of allograft function and viability. As the kidneys are organs with a very high metabolomic rate, a metabolomics approach is suitable to describe systematic changes in post-transplant patients and has great potential for monitoring allograft function, which has not been described yet. In this study, we used blood plasma samples from 55 patients after primary kidney transplantation identically treated with immunosuppressants with follow-up 50 months in the mean after surgery and evaluated relative levels of basal plasma metabolites detectable by NMR spectroscopy. We were looking for the correlations between circulating metabolites levels and allograft performance and allograft rejection features. Our results imply a quantitative relationship between restricted renal function, insufficient hydroxylation of phenylalanine to tyrosine, lowered renal glutamine utilization, shifted nitrogen balance, and other alterations that are not related exclusively to the metabolism of the kidney. No link between allograft function and energy metabolism can be concluded, as no changes were found for glucose, glycolytic intermediates, and 3-hydroxybutyrate as a ketone body representative. The observed changes are to be seen as a superposition of changes in the comprehensive inter-organ metabolic exchange, when the restricted function of one organ may induce compensatory effects or cause secondary alterations. Particular differences in plasma metabolite levels in patients with acute cellular and antibody-mediated allograft rejection were considered rather to be related to the loss of kidney function than to the molecular mechanism of graft rejection since they largely follow the alterations observed by restricted allograft function. In the end, we showed using a simple mathematical model, multilinear regression, that the basal plasmatic metabolites correlated with allograft function expressed by the level of glomerular filtration rate (with creatinine: p-value = 4.0 × 10⁻²⁶ and r = 0.94, without creatinine: p-value = 3.2 × 10⁻²² and r = 0.91) make the noninvasive estimation of the allograft function feasible. Full article

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

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9 pages, 2102 KiB

Open AccessArticle

Long-Term Mastication Changed Salivary Metabolomic Profiles

by Yoji Saeki, Akane Takenouchi, Etsuyo Otani, Minji Kim, Yumi Aizawa, Yasuko Aita, Atsumi Tomita, Masahiro Sugimoto and Takashi Matsukubo

Metabolites 2022, 12(7), 660; https://doi.org/10.3390/metabo12070660 - 18 Jul 2022

Cited by 3 | Viewed by 2168

Abstract

Saliva is an ideal biofluid for monitoring oral and systemic health. Repeated mastication is a typical physical stimulus that improves salivary flow and oral hygiene. Recent metabolomic studies have shown the potential of salivary metabolomic components for various disease monitoring systems. Here, we [...] Read more.

Saliva is an ideal biofluid for monitoring oral and systemic health. Repeated mastication is a typical physical stimulus that improves salivary flow and oral hygiene. Recent metabolomic studies have shown the potential of salivary metabolomic components for various disease monitoring systems. Here, we evaluated the effect of long-term mastication on salivary metabolomic profiles. Young women with good oral hygiene (20.8 ± 0.3 years, n = 17) participated. They were prohibited from chewing gum during control periods (4 weeks each) and were instructed to chew a piece of gum base seven times a day for 10 min each time during the intervention period. Paired samples of unstimulated whole saliva collected on the last day of the control and intervention period were compared. Liquid chromatography–time-of-flight mass spectrometry successfully quantified 85 metabolites, of which 41 showed significant differences (p < 0.05, Wilcoxon paired test corrected by false discovery rate). Except for a few metabolites, such as citrate, most metabolites showed lower concentrations after the intervention. The pathways related to glycogenic amino acids, such as alanine, arginine, and glutamine, altered considerably. This study suggests that long-term mastication induces unstimulated salivary component-level changes. Full article

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

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11 pages, 2420 KiB

Open AccessArticle

Lithocholic Acid Alleviates Deoxynivalenol-Induced Lethal Cholesterol Metabolic Abnormalities in IPI-2I Cells

by Yanwei Li, Fang Gu, Haotian Gu, Ping Hu, Hui-Xin Liu and Demin Cai

Metabolites 2022, 12(7), 659; https://doi.org/10.3390/metabo12070659 - 17 Jul 2022

Cited by 4 | Viewed by 2282

Abstract

Deoxynivalenol (DON) is a secondary metabolite of fungi. Ingestion of feed containing DON causes severe intestinal damage in humans and animals, possibly due to cholesterol-enriched lipid raft abnormalities. Cholic acid (CA) and lithocholic acid (LCA) are metabolites of cholesterol transformation, which have been [...] Read more.

Deoxynivalenol (DON) is a secondary metabolite of fungi. Ingestion of feed containing DON causes severe intestinal damage in humans and animals, possibly due to cholesterol-enriched lipid raft abnormalities. Cholic acid (CA) and lithocholic acid (LCA) are metabolites of cholesterol transformation, which have been proven to benefit epithelial cell proliferation and reduce intestinal inflammation and lesions. Therefore, we aimed to study the protective roles of CA and LCA administration on the DON-exposed intestinal epithelial cells (IPI-2I) and the underlying mechanisms involved in cholesterol metabolism. We found that LCA pretreatment, but not CA, alleviated the reduction of cell numbers caused by DON exposure. Furthermore, we demonstrate that LCA restored the DON-induced cell apoptosis by reducing the cleaved caspase 3 and cleaved PARP-1 expression. DON-increased cellular cholesterol and bile acid contents were significantly reduced when LCA was co-treated. Further transcriptomic analysis revealed that the aberrant cholesterol homeostasis genes profile was observed in the cells exposed to DON or pretreated with LCA. We also validated that the key genes involved in cholesterol biosynthesis and transformation (cholesterol to bile acids) were strongly inhibited by the LCA treatment in the DON-exposed cells. Together, this study demonstrated that LCA ameliorated DON-caused toxic apoptosis in IPI-2I cells by maintaining cholesterol metabolism. We suggest that as an endogenous metabolite, LCA may be used as a therapeutic and/or integrated into a dietary intervention against mycotoxin toxicity. Full article

(This article belongs to the Special Issue Dietary Effects on Gut Microbial Metabolism and Intestinal Inflammation in Mammals)

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21 pages, 3638 KiB

Open AccessArticle

Sustained Endurance Training Leads to Metabolomic Adaptation

by Astrid Weiss, Katharina Alack, Stephan Klatt, Sven Zukunft, Ralph Schermuly, Torsten Frech, Frank-Christoph Mooren and Karsten Krüger

Metabolites 2022, 12(7), 658; https://doi.org/10.3390/metabo12070658 - 16 Jul 2022

Cited by 3 | Viewed by 2558

Abstract

Endurance training induces several adaptations in substrate metabolism, especially in relation to glycogen conservation. The study aimed to investigate differences in the metabolism of lipids, lipid-like substances, and amino acids between highly trained and untrained subjects using targeted metabolomics. Depending on their maximum [...] Read more.

Endurance training induces several adaptations in substrate metabolism, especially in relation to glycogen conservation. The study aimed to investigate differences in the metabolism of lipids, lipid-like substances, and amino acids between highly trained and untrained subjects using targeted metabolomics. Depending on their maximum relative oxygen uptake (VO_2max), subjects were categorized as either endurance-trained (ET) or untrained (UT). Resting blood was taken and plasma isolated. It was screened for changes of 345 metabolites, including amino acids and biogenic amines, acylcarnitines, glycerophosphocholines (GPCs), sphingolipids, hexoses, bile acids, and polyunsaturated fatty acids (PUFAs) by using liquid chromatography coupled to tandem mass spectrometry. Acylcarnitine (C14:1, down in ET) and five GPCs (lysoPC a C18:2, up in ET; PC aa C42:0, up in ET; PC ae C38:2, up in ET; PC aa C38:5, down in ET; lysoPC a C26:0, down in ET) were differently regulated in ET compared to UT. TCDCA was down-regulated in athletes, while for three ratios of bile acids CA/CDCA, CA/(GCA+TCA), and DCA/(GDCA+TDCA) an up-regulation was found. TXB2 and 5,6-EET were down-regulated in the ET group and 18S-HEPE, a PUFA, showed higher levels in 18S-HEPE in endurance-trained subjects. For PC ae C38:2, TCDCA, and the ratio of cholic acid to chenodeoxycholic acid, an association with VO_2max was found. Numerous phospholipids, acylcarnitines, glycerophosphocholines, bile acids, and PUFAs are present in varying concentrations at rest in ET. These results might represent an adaptation of lipid metabolism and account for the lowered cardiovascular risk profile of endurance athletes. Full article

(This article belongs to the Topic Metabolism and Health)

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21 pages, 3314 KiB

Open AccessArticle

Multi-Tissue Time-Domain NMR Metabolomics Investigation of Time-Restricted Feeding in Male and Female Nile Grass Rats

by Hayden Johnson, Thomas Yates, Gary Leedom, Chidambaram Ramanathan, Melissa Puppa, Marie van der Merwe and Aaryani Tipirneni-Sajja

Metabolites 2022, 12(7), 657; https://doi.org/10.3390/metabo12070657 - 16 Jul 2022

Cited by 2 | Viewed by 3031

Abstract

Metabolic disease resulting from overnutrition is prevalent and rapidly increasing in incidence in modern society. Time restricted feeding (TRF) dietary regimens have recently shown promise in attenuating some of the negative metabolic effects associated with chronic nutrient stress. The purpose of this study [...] Read more.

Metabolic disease resulting from overnutrition is prevalent and rapidly increasing in incidence in modern society. Time restricted feeding (TRF) dietary regimens have recently shown promise in attenuating some of the negative metabolic effects associated with chronic nutrient stress. The purpose of this study is to utilize a multi-tissue metabolomics approach using nuclear magnetic resonance (NMR) spectroscopy to investigate TRF and sex-specific effects of high-fat diet in a diurnal Nile grass rat model. Animals followed a six-week dietary protocol on one of four diets: chow ad libitum, high-fat ad libitum (HF-AD), high-fat early TRF (HF-AM), or high-fat late TRF (HF-PM), and their liver, heart, and white adipose tissues were harvested at the end of the study and were analyzed by NMR. Time-domain complete reduction to amplitude–frequency table (CRAFT) was used to semi-automate and systematically quantify metabolites in liver, heart, and adipose tissues while minimizing operator bias. Metabolite profiling and statistical analysis revealed lipid remodeling in all three tissues and ectopic accumulation of cardiac and hepatic lipids for HF-AD feeding compared to a standard chow diet. Animals on TRF high-fat diet had lower lipid levels in the heart and liver compared to the ad libitum group; however, no significant differences were noted for adipose tissue. Regardless of diet, females exhibited greater amounts of hepatic lipids compared to males, while no consistent differences were shown in adipose and heart. In conclusion, this study demonstrates the feasibility of performing systematic and time-efficient multi-tissue NMR metabolomics to elucidate metabolites involved in the crosstalk between different metabolic tissues and provides a more holistic approach to better understand the etiology of metabolic disease and the effects of TRF on metabolic profiles. Full article

(This article belongs to the Section Bioinformatics and Data Analysis)

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14 pages, 2368 KiB

Open AccessArticle

HS-SPME-GC/MS Analysis for Revealing Carob’s Ripening

by Panagiota Fella, Kyriaki Kaikiti, Marinos Stylianou and Agapios Agapiou

Metabolites 2022, 12(7), 656; https://doi.org/10.3390/metabo12070656 - 15 Jul 2022

Cited by 6 | Viewed by 2157

Abstract

Carob’s recognized nutritional and medicinal value next to its unique agriculture importance is associated with an array of social, economic, and cultural activities. The carob fruit is popular for its intense aroma due to the emitted volatile organic compounds (VOCs). The composition of [...] Read more.

Carob’s recognized nutritional and medicinal value next to its unique agriculture importance is associated with an array of social, economic, and cultural activities. The carob fruit is popular for its intense aroma due to the emitted volatile organic compounds (VOCs). The composition of VOCs released from carob fruits changes during ripening, rendering it a non-invasive tool for the determination of the ripening period and freshness of the fruit. Therefore, headspace solid-phase microextraction gas chromatography/mass spectrometry (HS-SPME-GC/MS) was applied to reveal the respective gaseous signal molecules related to fruit maturity. The sampling was implemented during weeks 26–36 from five different locations in Cyprus. Additionally, the gaseous emissions of total VOCs (TVOCs) and carbon dioxide (CO₂) were recorded next to the moisture content of the fruit. The major chemical classes in the ripening are acids, followed by esters, and ketones. More specifically, the most abundant VOCs during ripening are propanoic acid, 2-methyl-(isobutyric acid), 2-heptanone, propanoic acid, 2-methyl-, 2-methylbutyl ester, acetic acid, methyl isobutyrate, propanoic acid, 2-methyl-, 3-methylbutyl ester, 2-pentanone, butanoic acid and propanoic acid, 2-methyl-ethyl ester. Finally, CO₂ emissions and moisture content showed a rapid decline until the 31st week and then stabilized for all examined areas. The methodology revealed variations in VOCs’ profile during the ripening process. Full article

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17 pages, 2523 KiB

Open AccessArticle

Differential Protein Expression among Two Different Ovine ARDS Phenotypes—A Preclinical Randomized Study

by Karin Wildi, Mahe Bouquet, Carmen Ainola, Samantha Livingstone, Sebastiano Maria Colombo, Silver Heinsar, Noriko Sato, Kei Sato, Emily Wilson, Gabriella Abbate, Margaret R. Passmore, Kieran Hyslop, Keibun Liu, Gianluigi Li Bassi, Jacky Y. Suen and John F. Fraser

Metabolites 2022, 12(7), 655; https://doi.org/10.3390/metabo12070655 - 15 Jul 2022

Cited by 1 | Viewed by 1858

Abstract

Despite decades of comprehensive research, Acute Respiratory Distress Syndrome (ARDS) remains a disease with high mortality and morbidity worldwide. The discovery of inflammatory subphenotypes in human ARDS provides a new approach to study the disease. In two different ovine ARDS lung injury models, [...] Read more.

Despite decades of comprehensive research, Acute Respiratory Distress Syndrome (ARDS) remains a disease with high mortality and morbidity worldwide. The discovery of inflammatory subphenotypes in human ARDS provides a new approach to study the disease. In two different ovine ARDS lung injury models, one induced by additional endotoxin infusion (phenotype 2), mimicking some key features as described in the human hyperinflammatory group, we aim to describe protein expression among the two different ovine models. Nine animals on mechanical ventilation were included in this study and were randomized into (a) phenotype 1, n = 5 (Ph1) and (b) phenotype 2, n = 4 (Ph2). Plasma was collected at baseline, 2, 6, 12, and 24 h. After protein extraction, data-independent SWATH-MS was applied to inspect protein abundance at baseline, 2, 6, 12, and 24 h. Cluster analysis revealed protein patterns emerging over the study observation time, more pronounced by the factor of time than different injury models of ARDS. A protein signature consisting of 33 proteins differentiated among Ph1/2 with high diagnostic accuracy. Applying network analysis, proteins involved in the inflammatory and defense response, complement and coagulation cascade, oxygen binding, and regulation of lipid metabolism were activated over time. Five proteins, namely LUM, CA2, KNG1, AGT, and IGJ, were more expressed in Ph2. Full article

(This article belongs to the Special Issue Using Metabolomics to Subphenotype Disease and Therapeutic Response)

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15 pages, 1142 KiB

Open AccessSystematic Review

Coffee Drinking and Adverse Physical Outcomes in the Aging Adult Population: A Systematic Review

by Simon Mazeaud, Fabio Castellana, Hélio José Coelho-Junior, Francesco Panza, Mariangela Rondanelli, Federico Fassio, Giovanni De Pergola, Roberta Zupo and Rodolfo Sardone

Metabolites 2022, 12(7), 654; https://doi.org/10.3390/metabo12070654 - 15 Jul 2022

Cited by 6 | Viewed by 3234

Abstract

Declining physical functioning covers a prominent span of later life and, as a modifiable driver to be leveraged, lifestyle plays a critical role. This research aimed to undertake a systematic review investigating the association between levels of coffee consumption and declining conditions of [...] Read more.

Declining physical functioning covers a prominent span of later life and, as a modifiable driver to be leveraged, lifestyle plays a critical role. This research aimed to undertake a systematic review investigating the association between levels of coffee consumption and declining conditions of physical functioning during aging, such as sarcopenia, frailty, weakness, falls, and disability, while trying to explain the underlying mechanisms, both from a metabolic and social angle. The literature was reviewed from inception to May 2022 using different electronic databases, not excluding the grey literature. Two independent researchers assessed the eligibility of 28 retrieved articles based on inclusion criteria; only 10 met the eligibility requirements. Different levels of coffee consumption were considered as exposure(s) and comparator(s) according to PECO concepts, while middle age was an inclusion criterion (40+ years). No limitations were set on the tool(s) assessing physical functioning, type of dietary assessment(s), study setting, general health status, country, and observational study design (cohort, cross-sectional). The cross-sectional design outnumbered the longitudinal (90%, n = 9/10). The overall quality rating was judged poor (70%) to good (30%). It was found that higher exposure to coffee drinking is strongly associated with better physical functioning outcomes, and the findings showed consistency in the direction of association across selected reports. Countering physical decline is a considerable challenge in easing the burden of population aging. For preventive models that aim to allow a better lifestyle, it has to be kept in mind that increased coffee consumption does not lead to poor physical functioning. Full article

(This article belongs to the Section Nutrition and Metabolism)

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16 pages, 5288 KiB

Open AccessArticle

Puerarin Induces Molecular Details of Ferroptosis-Associated Anti-Inflammatory on RAW264.7 Macrophages

by Jinzi Zeng, Ning Zhao, Jiajia Yang, Weiyang Kuang, Xuewei Xia, Xiaodan Chen, Zhiyuan Liu and Riming Huang

Metabolites 2022, 12(7), 653; https://doi.org/10.3390/metabo12070653 - 15 Jul 2022

Cited by 15 | Viewed by 3985

Abstract

Puerarin is a natural flavonoid with significant anti-inflammatory effects. Recent studies have suggested that ferroptosis may involve puerarin countering inflammation. However, the mechanism of ferroptosis mediated by the anti-inflammatory process of puerarin has not been widely explored. Herein, puerarin at a concentration of [...] Read more.

Puerarin is a natural flavonoid with significant anti-inflammatory effects. Recent studies have suggested that ferroptosis may involve puerarin countering inflammation. However, the mechanism of ferroptosis mediated by the anti-inflammatory process of puerarin has not been widely explored. Herein, puerarin at a concentration of 40 μM showed an anti-inflammatory effect on lipopolysaccharide (LPS)-induced macrophages RAW264.7. The analysis of network pharmacology indicated that 51 common targets were enriched in 136 pathways, and most of the pathways were associated with ferroptosis. Subsequently, the analysis of metabolomics obtained 61 differential metabolites that were enriched in 30 metabolic pathways. Furthermore, integrated network pharmacology and metabolomics revealed that puerarin exerted an excellent effect on anti-inflammatory in RAW264.7 via regulating ferroptosis-related arachidonic acid metabolism, tryptophan metabolism, and glutathione metabolism pathways, and metabolites such as 20-hydroxyeicosatetraenoic acid (20-HETE), serotonin, kynurenine, oxidized glutathione (GSSG), gamma-glutamylcysteine and cysteinylglycine were involved. In addition, the possible active binding sites of the potential targeted proteins such as acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 15-lipoxygenase (ALOX15) and glutathione peroxidase 4 (GPX4) with puerarin were further revealed by molecular docking. Thus, we suggested that ferroptosis mediated the anti-inflammatory effects of puerarin in macrophages RAW264.7 induced by LPS. Full article

(This article belongs to the Special Issue Metabolism of Immune System in Inflammatory and Infectious Diseases)

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15 pages, 2164 KiB

Open AccessArticle

Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma

by Yuchan Li, Omar Elakad, Sha Yao, Alexander von Hammerstein-Equord, Marc Hinterthaner, Bernhard C. Danner, Carmelo Ferrai, Philipp Ströbel, Stefan Küffer and Hanibal Bohnenberger

Metabolites 2022, 12(7), 652; https://doi.org/10.3390/metabo12070652 - 15 Jul 2022

Cited by 3 | Viewed by 2584

Abstract

Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients [...] Read more.

Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS G12C mutation, the overall response rate only reaches about 40% and mutations other than G12C still cannot be targeted. Despite the fact that one-carbon metabolism (1CM) and epigenetic regulation are known to be dysregulated by aberrant KRAS activity, we still lack evidence that co-treatment with drugs that regulate these factors might ameliorate response rates and patient prognosis. In this study, we show a direct dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on mutationally activated KRAS and their prognostic relevance in KRAS-mutated AC. We show that aberrant KRAS activity generates a vulnerability of AC cancer cell lines to both MTHFD2 and EZH2 inhibitors. Importantly, co-inhibition of both factors was synergistically effective and comparable to KRASG12C inhibition alone, paving the way for their use in a therapeutic approach for NSCLC cancer patients. Full article

(This article belongs to the Special Issue One Carbon Metabolism in Human Cancer)

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14 pages, 1360 KiB

Open AccessReview

Succinate as a New Actor in Pluripotency and Early Development?

by Damien Detraux and Patricia Renard

Metabolites 2022, 12(7), 651; https://doi.org/10.3390/metabo12070651 - 15 Jul 2022

Cited by 2 | Viewed by 3476

Abstract

Pluripotent cells have been stabilized from pre- and post-implantation blastocysts, representing respectively naïve and primed stages of embryonic stem cells (ESCs) with distinct epigenetic, metabolic and transcriptomic features. Beside these two well characterized pluripotent stages, several intermediate states have been reported, as well [...] Read more.

Pluripotent cells have been stabilized from pre- and post-implantation blastocysts, representing respectively naïve and primed stages of embryonic stem cells (ESCs) with distinct epigenetic, metabolic and transcriptomic features. Beside these two well characterized pluripotent stages, several intermediate states have been reported, as well as a small subpopulation of cells that have reacquired features of the 2C-embryo (2C-like cells) in naïve mouse ESC culture. Altogether, these represent a continuum of distinct pluripotency stages, characterized by metabolic transitions, for which we propose a new role for a long-known metabolite: succinate. Mostly seen as the metabolite of the TCA, succinate is also at the crossroad of several mitochondrial biochemical pathways. Its role also extends far beyond the mitochondrion, as it can be secreted, modify proteins by lysine succinylation and inhibit the activity of alpha-ketoglutarate-dependent dioxygenases, such as prolyl hydroxylase (PHDs) or histone and DNA demethylases. When released in the extracellular compartment, succinate can trigger several key transduction pathways after binding to SUCNR1, a G-Protein Coupled Receptor. In this review, we highlight the different intra- and extracellular roles that succinate might play in the fields of early pluripotency and embryo development. Full article

(This article belongs to the Special Issue The Factors Governing Cell Fate and Metabolism)

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17 pages, 27395 KiB

Open AccessArticle

Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition

by Susama Chokesuwattanaskul, Michele Fresneda Alarcon, Sangeetha Mangalakumaran, Rudi Grosman, Andrew L. Cross, Elinor A. Chapman, David Mason, Robert J. Moots, Marie M. Phelan and Helen L. Wright

Metabolites 2022, 12(7), 650; https://doi.org/10.3390/metabo12070650 - 15 Jul 2022

Cited by 5 | Viewed by 2689

Abstract

Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically [...] Read more.

Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However, clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors have been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n = 6) and people with RA (n = 7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200 ng/mL) for 2 h. Metabolites were extracted, and ¹H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0 h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p < 0.05). Bacterial killing was not impaired by JAK inhibitors, indicating that the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease. Full article

(This article belongs to the Section Cell Metabolism)

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9 pages, 679 KiB

Open AccessArticle

Higher Levels of Serum Uric Acid Have a Significant Association with Lower Incidence of Lower Urinary Tract Symptoms in Healthy Korean Men

by Jiwon Hwang, Seungho Ryu and Joong Kyong Ahn

Metabolites 2022, 12(7), 649; https://doi.org/10.3390/metabo12070649 - 14 Jul 2022

Cited by 7 | Viewed by 1770

Abstract

Gout has been correlated with the risk of incident benign prostatic hyperplasia. In line with increasing prevalence of hyperuricemia, the aim of this study was to investigate the relationship between serum uric acid (SUA) level and the incidence of lower urinary tract symptoms [...] Read more.

Gout has been correlated with the risk of incident benign prostatic hyperplasia. In line with increasing prevalence of hyperuricemia, the aim of this study was to investigate the relationship between serum uric acid (SUA) level and the incidence of lower urinary tract symptoms (LUTS) among clinically healthy middle-aged men. We performed a cohort study in 101,091 Korean men without LUTS at baseline who completed health checkups between 2011 and 2016. LUTS were evaluated using the International Prostate Symptom Score, where a score ≥ 8 was defined as significant LUTS. Men were divided into six groups according to their SUA levels in mg/dL (<5.5, 5.5–6.4, 6.5–7.4, 7.5–8.4, 8.5–9.4, and ≥9.5). Throughout the follow-up—encompassing a total of 358,982.6 person years—13,424 people had significant LUTS (37.3 per 1000 person years for incidence rate). The multivariable models demonstrated that the highest level of SUA (≥9.5 mg/dL) was related to the lowest risk of significant LUTS compared with the reference category (<5.5 mg/dL) (0.77 (95% CI 0.59–0.99) for adjusted HR). In this large cohort composed of middle-aged men, higher SUA levels were related to a reduced risk of LUTS. This result suggests another potential role of SUA in restraining LUTS. Additional studies are needed to explain the underlying biological mechanisms of this phenomenological relationship. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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14 pages, 29682 KiB

Open AccessArticle

Upregulation of Nrf2/HO-1 Signaling and Attenuation of Oxidative Stress, Inflammation, and Cell Death Mediate the Protective Effect of Apigenin against Cyclophosphamide Hepatotoxicity

by Wesam Al-Amarat, Mohammad H. Abukhalil, Reem S. Alruhaimi, Haifa A. Alqhtani, Nouf Aldawood, Manal A. Alfwuaires, Osama Y. Althunibat, Saleem H. Aladaileh, Abdulmohsen I. Algefare, Abdulkareem A. Alanezi, Ali M. AbouEl-ezz, Ahmad F. Ahmeda and Ayman M. Mahmoud

Metabolites 2022, 12(7), 648; https://doi.org/10.3390/metabo12070648 - 14 Jul 2022

Cited by 24 | Viewed by 2930

Abstract

Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 [...] Read more.

Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling. Full article

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

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10 pages, 875 KiB

Open AccessReview

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

by Hideki Mori, Gianluca Svegliati Baroni, Marco Marzioni, Francesca Di Nicola, Pierangelo Santori, Luca Maroni, Ludovico Abenavoli and Emidio Scarpellini

Metabolites 2022, 12(7), 647; https://doi.org/10.3390/metabo12070647 - 14 Jul 2022

Cited by 27 | Viewed by 3810

Abstract

Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in [...] Read more.

Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new “actor” that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut–liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM. Full article

(This article belongs to the Special Issue Bile Acid Metabolism and Gut Microbiota)

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13 pages, 1561 KiB

Open AccessArticle

Isotope Calculation Gadgets: A Series of Software for Isotope-Tracing Experiments in Garuda Platform

by Nobuyuki Okahashi, Yuki Yamada, Junko Iida and Fumio Matsuda

Metabolites 2022, 12(7), 646; https://doi.org/10.3390/metabo12070646 - 14 Jul 2022

Cited by 7 | Viewed by 2326

Abstract

Isotope tracing is a powerful technique for elucidating intracellular metabolism. Experiments utilizing this technique involve various processes, such as the correction of natural isotopes. Although some previously developed software are available for these procedures, there are still time-consuming steps in isotope tracing including [...] Read more.

Isotope tracing is a powerful technique for elucidating intracellular metabolism. Experiments utilizing this technique involve various processes, such as the correction of natural isotopes. Although some previously developed software are available for these procedures, there are still time-consuming steps in isotope tracing including the creation of an isotope measurement method in mass spectrometry (MS) and the interpretation of obtained labeling data. Additionally, these multi-step tasks often require data format conversion, which is also time-consuming. In this study, the Isotope Calculation Gadgets, a series of software that supports an entire workflow of isotope-tracing experiments, was developed in the Garuda platform, an open community. Garuda is a graphical user interface-based platform that allows individual operations to be sequentially performed, without data format conversion, which significantly reduces the required time and effort. The developed software includes new features that construct channels for isotopomer measurements, as well as conventional functions such as natural isotope correction, the calculation of fractional labeling and split ratio, and data mapping, thus facilitating an overall workflow of isotope-tracing experiments through smooth functional integration. Full article

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15 pages, 2223 KiB

Open AccessArticle

Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression

by Carlos Guijas, Lucy E. Horton, Linh Hoang, Xavier Domingo-Almenara, Elizabeth M. Billings, Brian C. Ware, Brian Sullivan and Gary Siuzdak

Metabolites 2022, 12(7), 645; https://doi.org/10.3390/metabo12070645 - 14 Jul 2022

Cited by 7 | Viewed by 3079

Abstract

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8⁺ T cells, reveal [...] Read more.

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8⁺ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection. Full article

(This article belongs to the Special Issue Application of Metabolomics in Characterization of Novel Bioactive Natural Products)

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12 pages, 1205 KiB

Open AccessSystematic Review

Dysregulated Metabolism in EGFR-TKI Drug Resistant Non-Small-Cell Lung Cancer: A Systematic Review

by Julia Babuta, Zoe Hall and Toby Athersuch

Metabolites 2022, 12(7), 644; https://doi.org/10.3390/metabo12070644 - 14 Jul 2022

Cited by 5 | Viewed by 3301

Abstract

Drug resistance is a common barrier to continued effective treatment in cancer. In non-small-cell lung cancer (NSCLC), tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR-TKIs) exhibit good efficacy in cancer treatment until acquired resistance occurs. It has been observed that [...] Read more.

Drug resistance is a common barrier to continued effective treatment in cancer. In non-small-cell lung cancer (NSCLC), tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR-TKIs) exhibit good efficacy in cancer treatment until acquired resistance occurs. It has been observed that drug resistance is accompanied by numerous molecular-level changes, including significant shifts in cellular metabolism. The purpose of this study was to critically and systematically review the published literature with respect to how metabolism differs in drug-resistant compared to drug-sensitive NSCLC. Understanding the differences between resistant and sensitive cells is vital and has the potential to allow interventions that enable the re-sensitisation of resistant cells to treatment, and consequently reinitiate the therapeutic effect of EGFR-TKIs. The main literature search was performed using relevant keywords in PubMed and Ovid (Medline) and reviewed using the Covidence platform. Of the 1331 potentially relevant literature records retrieved, 27 studies were subsequently selected for comprehensive analysis. Collectively, the literature revealed that NSCLC cell lines resistant to EGFR-TKI treatment possess characteristic metabolic and lipidomic phenotypic signatures that differentiate them from sensitive lines. Further exploration of these reported differences suggests that drug-resistant cell lines are differentially reliant on cellular energy sources and that modulation of relative energy production pathways may lead to the reversal of drug resistance. Full article

(This article belongs to the Topic Cancer Cell Metabolism)

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15 pages, 719 KiB

Open AccessReview

Metabolomics of Breast Cancer: A Review

by Ramadevi Subramani, Seeta Poudel, Kenneth D. Smith, Adriana Estrada and Rajkumar Lakshmanaswamy

Metabolites 2022, 12(7), 643; https://doi.org/10.3390/metabo12070643 - 13 Jul 2022

Cited by 23 | Viewed by 3895

Abstract

Breast cancer is the most commonly diagnosed cancer in women worldwide. Major advances have been made towards breast cancer prevention and treatment. Unfortunately, the incidence of breast cancer is still increasing globally. Metabolomics is the field of science which studies all the metabolites [...] Read more.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Major advances have been made towards breast cancer prevention and treatment. Unfortunately, the incidence of breast cancer is still increasing globally. Metabolomics is the field of science which studies all the metabolites in a cell, tissue, system, or organism. Metabolomics can provide information on dynamic changes occurring during cancer development and progression. The metabolites identified using cutting-edge metabolomics techniques will result in the identification of biomarkers for the early detection, diagnosis, and treatment of cancers. This review briefly introduces the metabolic changes in cancer with particular focus on breast cancer. Full article

(This article belongs to the Topic Cancer Cell Metabolism)

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