Metabolites

17 pages, 4423 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Regulations of Smilax china L. against β-Amyloid Toxicity in Caenorhabditis elegans

by Lili Yan, Yuchan Deng, Yulan Du, Xutong Fang, Xin Fang and Qiang Zhang

Metabolites 2024, 14(1), 49; https://doi.org/10.3390/metabo14010049 - 13 Jan 2024

Viewed by 1790

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. [...] Read more.

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. china. roots using LC-HRMS and evaluated the neuroprotective effects and metabolic regulation of S. china on Caenorhabditis elegans. Chinaroot extract prolonged the life span of healthy nematodes, delayed the paralysis time of transgenic CL4176, and reduced the level of β-amyloid deposition in transgenic CL2006. The comprehensive analysis of metabolomics and qRT-PCR revealed that Chinaroot extract exerted neuroprotective effects through the valine, leucine and isoleucine degradation and fatty acid degradation pathways. Moreover, we first discovered that the expressions of T09B4.8, ech-7, and agxt-1 were linked to the neuroprotective effects of Chinaroot. The material exerted neuroprotective effects by modulating metabolic abnormalities in AD model C. elegans. Our study provides a new foundation for the development of functional food properties and functions. Full article

(This article belongs to the Section Cell Metabolism)

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20 pages, 4215 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Changes in Rat Serum after Chronic Exposure to Glyphosate-Based Herbicide

by Oluwatosin Daramola, Cristian D. Gutierrez Reyes, Jesús Chávez-Reyes, Bruno A. Marichal-Cancino, Judith Nwaiwu, Sherifdeen Onigbinde, Moyinoluwa Adeniyi, Joy Solomon, Md Mostofa Al Amin Bhuiyan and Yehia Mechref

Metabolites 2024, 14(1), 50; https://doi.org/10.3390/metabo14010050 - 13 Jan 2024

Cited by 6 | Viewed by 2382

Abstract

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that [...] Read more.

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that glyphosate may cause adverse health effects in humans via other mechanisms. In this study, we described the metabolomic changes in the serum of experimental rats exposed to chronic GBH using the highly sensitive LC-MS/MS technique. We investigated the possible relationship between chronic exposure to GBH and neurological disorders. Our findings suggest that chronic exposure to GBH can alter spatial learning memory and the expression of some important metabolites that are linked to neurophysiological disorders in young rats, with the female rats showing higher susceptibility compared to the males. This indicates that female rats are more likely to show early symptoms of the disorder on exposure to chronic GBH compared to male rats. We observed that four important metabolites (paraxanthine, epinephrine, L-(+)-arginine, and D-arginine) showed significant changes and involvement in neurological changes as suggested by ingenuity pathway analysis. In conclusion, our results indicate that chronic exposure to GBH can increase the risk of developing neurological disorders. Full article

(This article belongs to the Section Animal Metabolism)

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22 pages, 1737 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing Blood Collection: Innovations, Applications, and the Potential of Microsampling Technologies for Monitoring Metabolites and Lipids

by Eleonora Bossi, Elena Limo, Lisa Pagani, Nicole Monza, Simone Serrao, Vanna Denti, Giuseppe Astarita and Giuseppe Paglia

Metabolites 2024, 14(1), 46; https://doi.org/10.3390/metabo14010046 - 11 Jan 2024

Cited by 5 | Viewed by 3022

Abstract

Blood serves as the primary global biological matrix for health surveillance, disease diagnosis, and response to drug treatment, holding significant promise for personalized medicine. The diverse array of lipids and metabolites in the blood provides a snapshot of both physiological and pathological processes, [...] Read more.

Blood serves as the primary global biological matrix for health surveillance, disease diagnosis, and response to drug treatment, holding significant promise for personalized medicine. The diverse array of lipids and metabolites in the blood provides a snapshot of both physiological and pathological processes, with many routinely monitored during conventional wellness checks. The conventional method involves intravenous blood collection, extracting a few milliliters via venipuncture, a technique limited to clinical settings due to its dependence on trained personnel. Microsampling methods have evolved to be less invasive (collecting ≤150 µL of capillary blood), user-friendly (enabling self-collection), and suitable for remote collection in longitudinal studies. Dried blood spot (DBS), a pioneering microsampling technique, dominates clinical and research domains. Recent advancements in device technology address critical limitations of classical DBS, specifically variations in hematocrit and volume. This review presents a comprehensive overview of state-of-the-art microsampling devices, emphasizing their applications and potential for monitoring metabolites and lipids in blood. The scope extends to diverse areas, encompassing population studies, nutritional investigations, drug discovery, sports medicine, and multi-omics research. Full article

(This article belongs to the Special Issue Advances in Metabolic Profiling of Biological Samples 2nd Edition)

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19 pages, 1280 KiB

Open AccessEditor’s ChoiceArticle

The Urinary Metabolome of Newborns with Perinatal Complications

by Yamilé López-Hernández, Victoria Lima-Rogel, Rupasri Mandal, Jiamin Zheng, Lun Zhang, Eponine Oler, David Alejandro García-López, Claudia Torres-Calzada, Ana Ruth Mejía-Elizondo, Jenna Poelzer, Jesús Adrián López, Ashley Zubkowski and David S. Wishart

Metabolites 2024, 14(1), 41; https://doi.org/10.3390/metabo14010041 - 10 Jan 2024

Cited by 3 | Viewed by 3505

Abstract

Maternal pathological conditions such as infections and chronic diseases, along with unexpected events during labor, can lead to life-threatening perinatal outcomes. These outcomes can have irreversible consequences throughout an individual’s entire life. Urinary metabolomics can provide valuable insights into early physiological adaptations in [...] Read more.

Maternal pathological conditions such as infections and chronic diseases, along with unexpected events during labor, can lead to life-threatening perinatal outcomes. These outcomes can have irreversible consequences throughout an individual’s entire life. Urinary metabolomics can provide valuable insights into early physiological adaptations in healthy newborns, as well as metabolic disturbances in premature infants or infants with birth complications. In the present study, we measured 180 metabolites and metabolite ratios in the urine of 13 healthy (hospital-discharged) and 38 critically ill newborns (admitted to the neonatal intensive care unit (NICU)). We used an in-house-developed targeted tandem mass spectrometry (MS/MS)-based metabolomic assay (TMIC Mega) combining liquid chromatography (LC-MS/MS) and flow injection analysis (FIA-MS/MS) to quantitatively analyze up to 26 classes of compounds. Average urinary concentrations (and ranges) for 167 different metabolites from 38 critically ill NICU newborns during their first 24 h of life were determined. Similar sets of urinary values were determined for the 13 healthy newborns. These reference data have been uploaded to the Human Metabolome Database. Urinary concentrations and ranges of 37 metabolites are reported for the first time for newborns. Significant differences were found in the urinary levels of 44 metabolites between healthy newborns and those admitted at the NICU. Metabolites such as acylcarnitines, amino acids and derivatives, biogenic amines, sugars, and organic acids are dysregulated in newborns with bronchopulmonary dysplasia (BPD), asphyxia, or newborns exposed to SARS-CoV-2 during the intrauterine period. Urine can serve as a valuable source of information for understanding metabolic alterations associated with life-threatening perinatal outcomes. Full article

(This article belongs to the Special Issue Metabolomics in Pulmonary Diseases)

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23 pages, 2386 KiB

Open AccessEditor’s ChoiceReview

Obesity, Dietary Fats, and Gastrointestinal Cancer Risk-Potential Mechanisms Relating to Lipid Metabolism and Inflammation

by Kathleen A. J. Mitchelson, Fiona O’Connell, Jacintha O’Sullivan and Helen M. Roche

Metabolites 2024, 14(1), 42; https://doi.org/10.3390/metabo14010042 - 10 Jan 2024

Cited by 6 | Viewed by 2961

Abstract

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and [...] Read more.

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers. Full article

(This article belongs to the Section Nutrition and Metabolism)

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25 pages, 1170 KiB

Open AccessEditor’s ChoiceReview

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

by Amedeo Lonardo, Stefano Ballestri, Alessandro Mantovani, Giovanni Targher and Fernando Bril

Metabolites 2024, 14(1), 40; https://doi.org/10.3390/metabo14010040 - 8 Jan 2024

Cited by 6 | Viewed by 3108

Abstract

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments [...] Read more.

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone. Full article

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

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23 pages, 11632 KiB

Open AccessEditor’s ChoiceArticle

Conditional Vitamin D Receptor Deletion Induces Fungal and Archaeal Dysbiosis and Altered Metabolites

by Duncan J. Claypool, Yong-Guo Zhang, Yinglin Xia and Jun Sun

Metabolites 2024, 14(1), 32; https://doi.org/10.3390/metabo14010032 - 1 Jan 2024

Viewed by 2201

Abstract

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the [...] Read more.

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the VDR in Paneth cells (VDR^ΔPC), intestinal epithelial cells (VDR^ΔIEC), or myeloid cells (VDR^ΔLyz) in mice and collected feces for shotgun metagenomic sequencing and untargeted metabolomics. We found that fungi were significantly altered in each knockout (KO) group compared to the VDR^Loxp control. The VDR^ΔLyz mice had the most altered fungi species (three depleted and seven enriched), followed by the VDR^ΔPC mice (six depleted and two enriched), and the VDR^ΔIEC mice (one depleted and one enriched). The methanogen Methanofollis liminatans was enriched in the VDR^ΔPC and VDR^ΔLyz mice and two further archaeal species (Thermococcus piezophilus and Sulfolobus acidocaldarius) were enriched in the VDR^ΔLyz mice compared to the Loxp group. Significant correlations existed among altered fungi, archaea, bacteria, and viruses in the KO mice. Functional metagenomics showed changes in several biologic functions, including decreased sulfate reduction and increased biosynthesis of cobalamin (vitamin B12) in VDR^ΔLyz mice relative to VDR^Loxp mice. Fecal metabolites were analyzed to examine the involvement of sulfate reduction and other pathways. In conclusion, a VDR deficiency caused the formation of altered fungi and archaea in a tissue- and sex-dependent manner. These results provide a foundation about the impact of a host factor (e.g., VDR deficiency) on fungi and archaea. It opens the door for further studies to determine how mycobiome and cross-kingdom interactions in the microbiome community and metabolites contribute to the risk of certain diseases. Full article

(This article belongs to the Special Issue Impact of Microbiome Community Changes on Host Health through Metabolic Dysregulation)

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16 pages, 3418 KiB

Open AccessEditor’s ChoiceArticle

Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites

by Dhwani Patel, Iain A. Murray, Fangcong Dong, Andrew J. Annalora, Krishne Gowda, Denise M. Coslo, Jacek Krzeminski, Imhoi Koo, Fuhua Hao, Shantu G. Amin, Craig B. Marcus, Andrew D. Patterson and Gary H. Perdew

Metabolites 2023, 13(9), 985; https://doi.org/10.3390/metabo13090985 - 31 Aug 2023

Cited by 2 | Viewed by 2413

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, [...] Read more.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, a novel set of mutagenic tryptophan metabolites named indolimines have been identified that are produced by M. morganii in the gastrointestinal tract. Here, we determined that indolimine-200, -214, and -248 are direct AHR ligands that can induce Cyp1a1 transcription and subsequent CYP1A1 enzymatic activity capable of metabolizing the carcinogen benzo(a)pyrene in microsomal assays. In addition, indolimines enhance IL6 expression in a colonic tumor cell line in combination with cytokine treatment. The concentration of indolimine-248 that induces AHR transcriptional activity failed to increase DNA damage. These observations reveal an additional aspect of how indolimines may alter colonic tumorigenesis beyond mutagenic activity. Full article

(This article belongs to the Special Issue Impact of Microbiome Community Changes on Host Health through Metabolic Dysregulation)

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17 pages, 3331 KiB

Open AccessEditor’s ChoiceArticle

The Integration of Metabolomics, Electronic Tongue, and Chromatic Difference Reveals the Correlations between the Critical Compounds and Flavor Characteristics of Two Grades of High-Quality Dianhong Congou Black Tea

by Shan Zhang, Xujiang Shan, Linchi Niu, Le Chen, Jinjin Wang, Qinghua Zhou, Haibo Yuan, Jia Li and Tian Wu

Metabolites 2023, 13(7), 864; https://doi.org/10.3390/metabo13070864 - 20 Jul 2023

Cited by 11 | Viewed by 1713

Abstract

Tea’s biochemical compounds and flavor quality vary depending on its grade ranking. Dianhong Congou black tea (DCT) is a unique tea category produced using the large-leaf tea varieties from Yunnan, China. To date, the flavor characteristics and critical components of two grades of [...] Read more.

Tea’s biochemical compounds and flavor quality vary depending on its grade ranking. Dianhong Congou black tea (DCT) is a unique tea category produced using the large-leaf tea varieties from Yunnan, China. To date, the flavor characteristics and critical components of two grades of high-quality DCT, single-bud-grade DCT (BDCT), and special-grade DCT (SDCT) manufactured mainly with single buds and buds with one leaf, respectively, are far from clear. Herein, comparisons of two grades were performed by the integration of human sensory evaluation, an electronic tongue, chromatic differences, the quantification of major components, and metabolomics. The BDCT possessed a brisk, umami taste and a brighter infusion color, while the SDCT presented a comprehensive taste and redder liquor color. Quantification analysis showed that the levels of total polyphenols, catechins, and theaflavins (TFs) were significantly higher in the BDCT. Fifty-six different key compounds were screened by metabolomics, including catechins, flavone/flavonol glycosides, amino acids, phenolic acids, etc. Correlation analysis revealed that the sensory features of the BDCT and SDCT were attributed to their higher contents of catechins, TFs, theogallin, digalloylglucose, and accumulations of thearubigins (TRs), flavone/flavonol glycosides, and soluble sugars, respectively. This report is the first to focus on the comprehensive evaluation of the biochemical compositions and sensory characteristics of two grades of high-quality DCT, advancing the understanding of DCT from a multi-dimensional perspective. Full article

(This article belongs to the Special Issue State-of-the-Art Metabolomics and Lipidomics in Life Sciences: Methods and Applications)

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17 pages, 1690 KiB

Open AccessEditor’s ChoiceArticle

Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro β-Cell Functions Critical for Metabolic Health

by Emily S. Krueger, Laura E. Griffin, Joseph L. Beales, Trevor S. Lloyd, Nathan J. Brown, Weston S. Elison, Colin D. Kay, Andrew P. Neilson and Jeffery S. Tessem

Metabolites 2023, 13(7), 801; https://doi.org/10.3390/metabo13070801 - 28 Jun 2023

Viewed by 1619

Abstract

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, [...] Read more.

Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 β-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices. Full article

(This article belongs to the Section Nutrition and Metabolism)

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17 pages, 14471 KiB

Open AccessEditor’s ChoiceArticle

Maternal Magnolol Supplementation during Pregnancy and Lactation Promotes Antioxidant Capacity, Improves Gut Health, and Alters Gut Microbiota and Metabolites of Weanling Piglets

by Qiwen Fan, Encun Du, Fang Chen, Wenjing Tao, Na Zhao, Shaowen Huang, Wanzheng Guo, Jing Huang and Jintao Wei

Metabolites 2023, 13(7), 797; https://doi.org/10.3390/metabo13070797 - 27 Jun 2023

Cited by 4 | Viewed by 1525

Abstract

Maternal nutrition exerts a profound effect on the postnatal performance of offspring, especially during the weaning period. The multifunctional bioactive component magnolol (MAG) has shown promise as a dietary supplement. This study aimed to explore the effects of maternal MAG supplementation on the [...] Read more.

Maternal nutrition exerts a profound effect on the postnatal performance of offspring, especially during the weaning period. The multifunctional bioactive component magnolol (MAG) has shown promise as a dietary supplement. This study aimed to explore the effects of maternal MAG supplementation on the antioxidant capacity, gut health, gut microbiome, and metabolome composition of weanling piglets. Fifty pregnant sows were randomly divided into two equally sized groups, the control group and the group supplemented with 100 g/t MAG during the gestation and lactation periods, and 7 days postweaning, the pups were euthanized. The microbiome and metabolome features of weanling piglet colons were compared. Our results revealed that maternal MAG supplementation modified the serum redox status of weanling piglets by decreasing malondialdehyde concentration and increasing superoxide dismutase activity and total antioxidant capacity. Moreover, the decreased indicators of diarrhea were accompanied by improved gut barrier function, in which serum diamine oxidase concentration was decreased, and expressions of zona occludens-1, claudin-1, and intestinal alkaline phosphatase were increased in the colon of weanling piglets from sows supplemented with MAG. Further analysis of the gut microbiota indicated that maternal MAG supplementation significantly increased the relative abundance of beneficial bacteria in the colon of weanling piglets, including Faecalibacterium prausnitzii and Oscillospira. Metabolome analysis identified 540 differential metabolites in the colon of piglets from MAG-fed dams, of which glycerophospholipid classes were highly correlated with progeny gut health and key beneficial bacteria. Our findings indicated that maternal MAG supplementation can improve the oxidative status and gut health of weanling piglets, possibly due to alterations in the gut microbiota and metabolites. Full article

(This article belongs to the Section Nutrition and Metabolism)

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27 pages, 3516 KiB

Open AccessEditor’s ChoiceReview

Dietary Patterns, Gut Microbiota Remodeling, and Cardiometabolic Disease

by Letizia Guiducci, Giuseppina Nicolini and Francesca Forini

Metabolites 2023, 13(6), 760; https://doi.org/10.3390/metabo13060760 - 17 Jun 2023

Cited by 6 | Viewed by 2992

Abstract

The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression [...] Read more.

The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression and treatment response is beginning to be deciphered, as is the mutualistic relation established between the GM and diet. In particular, dietary factors emerge as pivotal determinants shaping the architecture and function of resident microorganisms in the human gut. In turn, intestinal microbes influence the absorption, metabolism, and storage of ingested nutrients, with potentially profound effects on host physiology. Herein, we present an updated overview on major effects of dietary components on the GM, highlighting the beneficial and detrimental consequences of diet–microbiota crosstalk in the setting of CMD. We also discuss the promises and challenges of integrating microbiome data in dietary planning aimed at restraining CMD onset and progression with a more personalized nutritional approach. Full article

(This article belongs to the Special Issue Dietary–Microbiome–Metabolic Interactions in Cardiovascular Disease)

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11 pages, 1302 KiB

Open AccessEditor’s ChoiceReview

Metabolic Role of GABA in the Secretory Function of Pancreatic β-Cells: Its Hypothetical Implication in β-Cell Degradation in Type 2 Diabetes

by Jorge Tamarit-Rodriguez

Metabolites 2023, 13(6), 697; https://doi.org/10.3390/metabo13060697 - 27 May 2023

Cited by 4 | Viewed by 1956

Abstract

The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that [...] Read more.

The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K⁺-channel at the plasma membrane. The resultant depolarization of the β-cells opens voltage-dependent Ca²⁺-channels at the plasma membrane that triggers the exocytosis of insulin secretory granules. The secretory response is biphasic with a first and transient peak followed by a sustained phase. The first phase is reproduced by a depolarization of the β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide (triggering phase); the sustained phase (amplifying phase) depends on the participation of metabolic signals that remain to be determined. Our group has been investigating for several years the participation of the β-cell GABA metabolism in the stimulation of insulin secretion by three different secretagogues (glucose, a mixture of L-leucine plus L-glutamine, and some branched chain alpha-ketoacids, BCKAs). They stimulate a biphasic secretion of insulin accompanied by a strong suppression of the intracellular islet content of gamma-aminobutyric acid (GABA). As the islet GABA release simultaneously decreased, it was concluded that this resulted from an increased GABA shunt metabolism. The entrance of GABA into the shunt is catalyzed by GABA transaminase (GABAT) that transfers an amino group between GABA and alpha-ketoglutarate, resulting in succinic acid semialdehyde (SSA) and L-glutamate. SSA is oxidized to succinic acid that is further oxidized in the citric acid cycle. Inhibitors of GABAT (gamma-vinyl GABA, gabaculine) or glutamic acid decarboxylating activity (GAD), allylglycine, partially suppress the secretory response as well as GABA metabolism and islet ATP content and the ATP/ADP ratio. It is concluded that the GABA shunt metabolism contributes together with the own metabolism of metabolic secretagogues to increase islet mitochondrial oxidative phosphorylation. These experimental findings emphasize that the GABA shunt metabolism is a previously unrecognized anaplerotic mitochondrial pathway feeding the citric acid cycle with a β-cell endogenous substrate. It is therefore a postulated alternative to the proposed mitochondrial cataplerotic pathway(s) responsible for the amplification phase of insulin secretion. It is concluded the new postulated alternative suggests a possible new mechanism of β-cell degradation in type 2 (perhaps also in type 1) diabetes. Full article

(This article belongs to the Special Issue Biosynthesis, Metabolism, and Physiological Functions of Gamma-Aminobutyric Acid)

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15 pages, 297 KiB

Open AccessEditor’s ChoiceArticle

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids

by Qing Shen, Jun Yang, Daisy Zamora, Mark Horowitz, Keturah R. Faurot, Beth A. MacIntosh, J. Douglas Mann, Bruce D. Hammock, Christopher E. Ramsden and Ameer Y. Taha

Metabolites 2023, 13(6), 690; https://doi.org/10.3390/metabo13060690 - 25 May 2023

Viewed by 1919

Abstract

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA [...] Read more.

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

16 pages, 987 KiB

Open AccessEditor’s ChoiceReview

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 10 | Viewed by 3605

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, 2720 KiB

Open AccessEditor’s ChoiceArticle

Optimization of Carob Products Preparation for Targeted LC-MS/MS Metabolomics Analysis

by Olga Deda, Olga Begou, Helen Gika, Georgios Theodoridis and Agapios Agapiou

Metabolites 2023, 13(5), 645; https://doi.org/10.3390/metabo13050645 - 9 May 2023

Cited by 3 | Viewed by 1954

Abstract

Carob (Ceratonia siliqua) is an exceptional source of significant bioactive compounds with great economic importance in the Mediterranean region, where it is widely cultivated. Carob fruit is used for the production of a variety of products and commodities such as powder, [...] Read more.

Carob (Ceratonia siliqua) is an exceptional source of significant bioactive compounds with great economic importance in the Mediterranean region, where it is widely cultivated. Carob fruit is used for the production of a variety of products and commodities such as powder, syrup, coffee, flour, cakes, and beverages. There is growing evidence of the beneficial effects of carob and the products made from it on a range of health problems. Therefore, metabolomics could be used to explore the nutrient-rich compounds of carob. Sample preparation is a crucial step in metabolomics-based analysis and has a great impact on the quality of the data obtained. Herein, sample preparation of carob syrup and powder was optimized, to enable highly efficient metabolomics-based HILIC-MS/MS analysis. Pooled powder and syrup samples were extracted under different conditions by adjusting pH, solvent type, and sample weight to solvent volume ratio (Wc/Vs). The metabolomics profiles obtained were evaluated using the established criteria of total area and number of maxima. It was observed that the Wc/Vs ratio of 1:2 resulted in the highest number of metabolites, regardless of solvent type or pH. Aqueous acetonitrile with a Wc/Vs ratio of 1:2 satisfied all established criteria for both carob syrup and powder samples. However, when the pH was adjusted, basic aqueous propanol 1:2 Wc/Vs and acidic aqueous acetonitrile 1:2 Wc/Vs provided the best results for syrup and powder, respectively. We strongly believe that the current study could support the standardization of the metabolomics sample preparation process to enable more efficient LC-MS/MS carob analysis. Full article

(This article belongs to the Special Issue Analytical Developments in Mapping the Polar Metabolome)

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22 pages, 12196 KiB

Open AccessEditor’s ChoiceReview

Benchtop NMR-Based Metabolomics: First Steps for Biomedical Application

by Pilar Alonso-Moreno, Ignacio Rodriguez and Jose Luis Izquierdo-Garcia

Metabolites 2023, 13(5), 614; https://doi.org/10.3390/metabo13050614 - 29 Apr 2023

Cited by 6 | Viewed by 3277

Abstract

Nuclear magnetic resonance (NMR)-based metabolomics is a valuable tool for identifying biomarkers and understanding the underlying metabolic changes associated with various diseases. However, the translation of metabolomics analysis to clinical practice has been limited by the high cost and large size of traditional [...] Read more.

Nuclear magnetic resonance (NMR)-based metabolomics is a valuable tool for identifying biomarkers and understanding the underlying metabolic changes associated with various diseases. However, the translation of metabolomics analysis to clinical practice has been limited by the high cost and large size of traditional high-resolution NMR spectrometers. Benchtop NMR, a compact and low-cost alternative, offers the potential to overcome these limitations and facilitate the wider use of NMR-based metabolomics in clinical settings. This review summarizes the current state of benchtop NMR for clinical applications where benchtop NMR has demonstrated the ability to reproducibly detect changes in metabolite levels associated with diseases such as type 2 diabetes and tuberculosis. Benchtop NMR has been used to identify metabolic biomarkers in a range of biofluids, including urine, blood plasma and saliva. However, further research is needed to optimize the use of benchtop NMR for clinical applications and to identify additional biomarkers that can be used to monitor and manage a range of diseases. Overall, benchtop NMR has the potential to revolutionize the way metabolomics is used in clinical practice, providing a more accessible and cost-effective way to study metabolism and identify biomarkers for disease diagnosis, prognosis, and treatment. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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11 pages, 1016 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Vitamin D Adequacy on Thyroid Hormones and Inflammatory Markers after Bariatric Surgery

by Roberta França, Adryana Cordeiro, Silvia Elaine Pereira, Carlos José Saboya and Andrea Ramalho

Metabolites 2023, 13(5), 603; https://doi.org/10.3390/metabo13050603 - 27 Apr 2023

Viewed by 1582

Abstract

Vitamin D status affects the clinical and corporal outcomes of postoperative patients who undergo a Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the effect of adequate vitamin D serum concentrations on thyroid hormones, body weight, blood cell count, [...] Read more.

Vitamin D status affects the clinical and corporal outcomes of postoperative patients who undergo a Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the effect of adequate vitamin D serum concentrations on thyroid hormones, body weight, blood cell count, and inflammation after an RYGB. A prospective observational study was conducted with eighty-eight patients from whom we collected blood samples before and 6 months after surgery to evaluate their levels of 25-hydroxyvitamin D 25(OH)D, thyroid hormones, and their blood cell count. Their body weight, body mass index (BMI), total weight loss, and excess weight loss were also evaluated 6 and 12 months after surgery. After 6 months, 58% of the patients achieved an adequate vitamin D nutritional status. Patients in the adequate group showed a decrease in the concentration of thyroid-stimulating hormone (TSH) (3.01 vs. 2.22 µUI/mL, p = 0.017) with lower concentrations than the inadequate group at 6 months (2.22 vs. 2.84 µUI/mL, p = 0.020). Six months after surgery, the group with vitamin D adequacy showed a significantly lower BMI compared with the inadequate group at 12 months (31.51 vs. 35.04 kg/m², p = 0.018). An adequate vitamin D nutritional status seems to favor a significant improvement in one’s thyroid hormone levels, immune inflammatory profile, and weight loss performance after an RYGB. Full article

(This article belongs to the Special Issue Metabolic and Functional Disorders of Essential Metals and Vitamin D)

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27 pages, 1696 KiB

Open AccessEditor’s ChoiceReview

Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States

by Pandichelvam Veeraiah and Jacobus F. A. Jansen

Metabolites 2023, 13(4), 577; https://doi.org/10.3390/metabo13040577 - 19 Apr 2023

Cited by 5 | Viewed by 2923

Abstract

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy [...] Read more.

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. ¹H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, ¹³C, ²H, ¹⁷O, and ³¹P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (¹H, ¹³C, ²H, ¹⁷O, and ³¹P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states. Full article

(This article belongs to the Special Issue Brain Substrate Metabolism in Health and Disease)

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16 pages, 1156 KiB

Open AccessEditor’s ChoiceArticle

A Machine-Learning Approach to Target Clinical and Biological Features Associated with Sarcopenia: Findings from Northern and Southern Italian Aging Populations

by Roberta Zupo, Alessia Moroni, Fabio Castellana, Clara Gasparri, Feliciana Catino, Luisa Lampignano, Simone Perna, Maria Lisa Clodoveo, Rodolfo Sardone and Mariangela Rondanelli

Metabolites 2023, 13(4), 565; https://doi.org/10.3390/metabo13040565 - 17 Apr 2023

Cited by 11 | Viewed by 2608

Abstract

Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia [...] Read more.

Epidemiological and public health resonance of sarcopenia in late life requires further research to identify better clinical markers useful for seeking proper care strategies in preventive medicine settings. Using a machine-learning approach, a search for clinical and fluid markers most associated with sarcopenia was carried out across older populations from northern and southern Italy. A dataset of adults >65 years of age (n = 1971) made up of clinical records and fluid markers from either a clinical-based subset from northern Italy (Pavia) and a population-based subset from southern Italy (Apulia) was employed (n = 1312 and n = 659, respectively). Body composition data obtained by dual-energy X-ray absorptiometry (DXA) were used for the diagnosis of sarcopenia, given by the presence of either low muscle mass (i.e., an SMI < 7.0 kg/m² for males or <5.5 kg/m² for females) and of low muscle strength (i.e., an HGS < 27 kg for males or <16 kg for females) or low physical performance (i.e., an SPPB ≤ 8), according to the EWGSOP2 panel guidelines. A machine-learning feature-selection approach, the random forest (RF), was used to identify the most predictive features of sarcopenia in the whole dataset, considering every possible interaction among variables and taking into account nonlinear relationships that classical models could not evaluate. Then, a logistic regression was performed for comparative purposes. Leading variables of association to sarcopenia overlapped in the two population subsets and included SMI, HGS, FFM of legs and arms, and sex. Using parametric and nonparametric whole-sample analysis to investigate the clinical variables and biological markers most associated with sarcopenia, we found that albumin, CRP, folate, and age ranked high according to RF selection, while sex, folate, and vitamin D were the most relevant according to logistics. Albumin, CRP, vitamin D, and serum folate should not be neglected in screening for sarcopenia in the aging population. Better preventive medicine settings in geriatrics are urgently needed to lessen the impact of sarcopenia on the general health, quality of life, and medical care delivery of the aging population. Full article

(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism)

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15 pages, 2495 KiB

Open AccessEditor’s ChoiceArticle

Amino Acid Profiles in Older Adults with Frailty: Secondary Analysis from MetaboFrail and BIOSPHERE Studies

by Riccardo Calvani, Anna Picca, Leocadio Rodriguez-Mañas, Matteo Tosato, Hélio José Coelho-Júnior, Alessandra Biancolillo, Olga Laosa, Jacopo Gervasoni, Aniello Primiano, Lavinia Santucci, Ottavia Giampaoli, Isabelle Bourdel-Marchasson, Sophie C. Regueme, Alan J. Sinclair, Andrea Urbani, Francesco Landi, Giovanni Gambassi, Federico Marini and Emanuele Marzetti

Metabolites 2023, 13(4), 542; https://doi.org/10.3390/metabo13040542 - 10 Apr 2023

Cited by 7 | Viewed by 2468

Abstract

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, [...] Read more.

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS–DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS–DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery. Full article

(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism)

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16 pages, 3518 KiB

Open AccessEditor’s ChoiceArticle

Deciphering Gut Microbiome Responses upon Microplastic Exposure via Integrating Metagenomics and Activity-Based Metabolomics

by Pengcheng Tu, Jingchuan Xue, Huixia Niu, Qiong Tang, Zhe Mo, Xiaodong Zheng, Lizhi Wu, Zhijian Chen, Yanpeng Cai and Xiaofeng Wang

Metabolites 2023, 13(4), 530; https://doi.org/10.3390/metabo13040530 - 7 Apr 2023

Cited by 7 | Viewed by 2872

Abstract

Perturbations of the gut microbiome are often intertwined with the onset and development of diverse metabolic diseases. It has been suggested that gut microbiome perturbation could be a potential mechanism through which environmental chemical exposure induces or exacerbates human diseases. Microplastic pollution, an [...] Read more.

Perturbations of the gut microbiome are often intertwined with the onset and development of diverse metabolic diseases. It has been suggested that gut microbiome perturbation could be a potential mechanism through which environmental chemical exposure induces or exacerbates human diseases. Microplastic pollution, an emerging environmental issue, has received ever increasing attention in recent years. However, interactions between microplastic exposure and the gut microbiota remain elusive. This study aimed to decipher the responses of the gut microbiome upon microplastic polystyrene (MP) exposure by integrating 16S rRNA high-throughput sequencing with metabolomic profiling techniques using a C57BL/6 mouse model. The results indicated that MP exposure significantly perturbed aspects of the gut microbiota, including its composition, diversity, and functional pathways that are involved in xenobiotic metabolism. A distinct metabolite profile was observed in mice with MP exposure, which probably resulted from changes in gut bacterial composition. Specifically, untargeted metabolomics revealed that levels of metabolites associated with cholesterol metabolism, primary and secondary bile acid biosynthesis, and taurine and hypotaurine metabolism were changed significantly. Targeted approaches indicated significant perturbation with respect to the levels of short-chain fatty acids derived from the gut microbiota. This study can provide evidence for the missing link in understanding the mechanisms behind the toxic effects of microplastics. Full article

(This article belongs to the Special Issue Effects of Environmental Exposure on Host and Microbial Metabolism)

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14 pages, 2838 KiB

Open AccessEditor’s ChoiceArticle

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

by Yaoxiang Li, Shivani Bansal, Vijayalakshmi Sridharan, Sunil Bansal, Meth M. Jayatilake, Jose A. Fernández, John H. Griffin, Marjan Boerma and Amrita K. Cheema

Metabolites 2023, 13(4), 525; https://doi.org/10.3390/metabo13040525 - 6 Apr 2023

Cited by 3 | Viewed by 1828

Abstract

Survivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed [...] Read more.

Survivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed to identify urinary metabolites indicative of radiation-induced cardiac damage by analyzing previously collected urine samples from a published study. The samples were collected from male and female wild-type (C57BL/6N) and transgenic mice constitutively expressing activated protein C (APCHi), a circulating protein with potential cardiac protective properties, who were exposed to 9.5 Gy of γ-rays. We utilized LC-MS-based metabolomics and lipidomics for the analysis of urine samples collected at 24 h, 1 week, 1 month, 3 months, and 6 months post-irradiation. Radiation caused perturbations in the TCA cycle, glycosphingolipid metabolism, fatty acid oxidation, purine catabolism, and amino acid metabolites, which were more prominent in the wild-type (WT) mice compared to the APCHi mice, suggesting a differential response between the two genotypes. After combining the genotypes and sexes, we identified a multi-analyte urinary panel at early post-irradiation time points that predicted heart dysfunction using a logistic regression model with a discovery validation study design. These studies demonstrate the utility of a molecular phenotyping approach to develop a urinary biomarker panel predictive of the delayed effects of ionizing radia-tion. It is important to note that no live mice were used or assessed in this study; instead, we focused solely on analyzing previously collected urine samples. Full article

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

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18 pages, 2206 KiB

Open AccessEditor’s ChoiceArticle

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort

by Brooke Gleason, Alan Kuang, James R. Bain, Michael J. Muehlbauer, Olga R. Ilkayeva, Denise M. Scholtens and William L. Lowe, Jr.

Metabolites 2023, 13(4), 505; https://doi.org/10.3390/metabo13040505 - 31 Mar 2023

Cited by 4 | Viewed by 2383

Abstract

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn [...] Read more.

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24–32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity. Full article

(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)

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14 pages, 2405 KiB

Open AccessEditor’s ChoiceArticle

Effects of Different Storage Conditions on Lipid Stability in Mice Tissue Homogenates

by Erika Dorochow, Robert Gurke, Samuel Rischke, Gerd Geisslinger and Lisa Hahnefeld

Metabolites 2023, 13(4), 504; https://doi.org/10.3390/metabo13040504 - 31 Mar 2023

Cited by 4 | Viewed by 2206

Abstract

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the [...] Read more.

Lipids are biomolecules involved in numerous (patho-)physiological processes and their elucidation in tissue samples is of particular interest. However, tissue analysis goes hand in hand with many challenges and the influence of pre-analytical factors can intensively change lipid concentrations ex vivo, compromising the results of the whole research project. Here, we study the influence of pre-analytical factors on lipid profiles during the processing of homogenized tissues. Homogenates from four different mice tissues (liver, kidney, heart, spleen) were stored at room temperature as well as in ice water for up to 120 min and analyzed via ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Lipid class ratios were calculated since their suitability as indicators for sample stability has been previously illustrated. Only approx. 40% of lipid class ratios were unchanged after 35 min, which was further reduced to 25% after 120 min during storage at room temperature. In contrast, lipids in tissue homogenates were generally stable when samples were kept in ice water, as more than 90% of investigated lipid class ratios remained unchanged after 35 min. Ultimately, swift processing of tissue homogenates under cooled conditions represents a viable option for lipid analysis and pre-analytical factors require more attention to achieve reliable results. Full article

(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)

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14 pages, 821 KiB

Open AccessEditor’s ChoiceArticle

Chronometabolism: The Timing of the Consumption of Meals Has a Greater Influence Than Glycemic Index (GI) on the Postprandial Metabolome

by Yi Ning Yong, Jiangwen Dong, Leroy Sivappiragasam Pakkiri, Christiani Jeyakumar Henry, Sumanto Haldar and Chester Lee Drum

Metabolites 2023, 13(4), 490; https://doi.org/10.3390/metabo13040490 - 29 Mar 2023

Cited by 2 | Viewed by 2480

Abstract

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover [...] Read more.

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine and ornithine levels during DI, indicating a worse metabolic state during the evening DI period. Greater reductions (δAUC) in postprandial creatine and ornithine were also observed during HI compared with LO (both p < 0.05). These metabolomic changes may indicate potential molecular signatures and/or pathways linking metabolic responses with cardiometabolic disease risk between different meal intake timings and/or meals with variable GI. Full article

(This article belongs to the Special Issue Roles of the Circadian Rhythms in Metabolic Disease and Health)

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11 pages, 927 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Carotid Plaque Echolucency Is Associated with Reduced Cognitive Performance in Elderly Patients with Atherosclerotic Disease Independently on Metabolic Profile

by Daniela Mastroiacovo, Alessandro Mengozzi, Francesco Dentali, Fulvio Pomero, Agostino Virdis, Antonio Camerota, Mario Muselli, Stefano Necozione, Raffaella Bocale, Claudio Ferri and Giovambattista Desideri

Metabolites 2023, 13(4), 478; https://doi.org/10.3390/metabo13040478 - 27 Mar 2023

Cited by 6 | Viewed by 1673

Abstract

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled [...] Read more.

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled 113 patients aged 65 years or more (72.4 ± 5.9 years) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by grey-scale median (GSM) and neuropsychological tests to assess cognitive function. The GSM values at baseline were inversely correlated with the number of seconds required to complete Trail Makin Test (TMT) A (rho: −0.442; p < 0.0001), TMT B (rho: −0.460; p < 0.0001) and TMT B-A (rho: −0.333; p < 0.0001) and directly correlated with Mini Mental State Examination (MMSE) and Verbal Fluency Test (VFT) score (rho: 0.217; p = 0.021 and rho: 0.375; p < 0.0001, respectively) and the composite cognitive z-score (rho: 0.464; p < 0.0001). After a mean period of 3.5 ± 0.5 years, 55 patients were reevaluated according to the same baseline study protocol. Patients with baseline GSM value higher than the median value of 29 did not show any significant variation in the z-score. Instead, those with GSM ≤ 29 showed a significant worsening of z-score (−1.2; p = 0.0258). In conclusion, this study demonstrates the existence of an inverse relationship between the echolucency of carotid plaques and cognitive function in elderly patients with atherosclerotic carotid disease. These data suggest that the assessment of plaque echogenicity if used appropriately, might aid in identifying subjects at increased risk for cognitive dysfunction. Full article

(This article belongs to the Special Issue Lipid Metabolism Regulation and Obesity Treatment)

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27 pages, 1713 KiB

Open AccessEditor’s ChoiceReview

Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target

by Allison B. Reiss, Saba Ahmed, Maryann Johnson, Usman Saeedullah and Joshua De Leon

Metabolites 2023, 13(4), 479; https://doi.org/10.3390/metabo13040479 - 27 Mar 2023

Cited by 14 | Viewed by 4691

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an [...] Read more.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described. Full article

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

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14 pages, 2245 KiB

Open AccessEditor’s ChoiceArticle

The Effect of 75 Grams of Glucose during OGTT on Plasma Markers of Lipid and Lipoprotein Peroxidation, Oxidized LDL and Thiobarbituric Acid Reactive Substances, in People with Increased Body Mass

by Lena Bielawska, Ewa Wysocka, Aleksandra Baszczuk, Anna Dżumak, Aleksandra Ludziejewska, Maciej Cymerys and Alicja Płóciniczak

Metabolites 2023, 13(4), 483; https://doi.org/10.3390/metabo13040483 - 27 Mar 2023

Viewed by 1378

Abstract

Obesity, currently defined as a disease, is associated with a number of metabolic disorders, and oxidative stress is discussed as the link between them. The aim of this study was to analyze the plasma markers reflecting oxidative modification of lipids and lipoproteins, oxidized [...] Read more.

Obesity, currently defined as a disease, is associated with a number of metabolic disorders, and oxidative stress is discussed as the link between them. The aim of this study was to analyze the plasma markers reflecting oxidative modification of lipids and lipoproteins, oxidized LDL (oxLDL) and thiobarbituric acid reactive substances (TBARS), under the influence of the 75 g of oral glucose during oral glucose tolerance test (OGTT), in patients with increased body mass. One hundred twenty individuals of both genders (46 women and 74 men) aged 26 to 75 years with increased body mass (BMI > 25 kg/m²) were recruited for the study. OGTT was performed in each of the qualified persons, and glycemia, insulinemia, and concentrations of oxLDL and TBARS were measured fasting and at 120 min of OGTT. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to assess the degree of insulin resistance (IR). In order to assess the changes of the investigated parameters under the influence of 75 g glucose, the index R_OGTT = [120’]/[0’] was calculated to obtain oxLDL-R_OGTT and TBARS-R_OGTT. The statistical analysis was performed in the entire study population and subsequent groups from H1 to H4, defined by HOMA-IR quartiles. In the entire study population and the subgroups, oxidative stress markers changed during OGTT. From H1 to H4 group, increasing oxLDL and TBARS were observed both in the fasting state and at 120 min of OGTT, and the oxLDL-R_OGTT index decreased from the H2 to the H4 group. The intensification of IR in people with increased body mass may predispose them to enhanced oxidative modification of lipoproteins. Individual reduction in the concentration of oxLDL during OGTT, in reference to fasting value (decreased oxLDL-R_OGTT), suggests increased uptake of modified lipoproteins by scavenger receptor-presenting cells or increased migration to the vascular wall. Full article

(This article belongs to the Special Issue Prooxidant–Antioxidant and Inflammation Markers in Metabolic Syndrome and Its Complications)

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13 pages, 2634 KiB

Open AccessEditor’s ChoiceArticle

A Strategy for Uncovering the Serum Metabolome by Direct-Infusion High-Resolution Mass Spectrometry

by Xiaoshan Sun, Zhen Jia, Yuqing Zhang, Xinjie Zhao, Chunxia Zhao, Xin Lu and Guowang Xu

Metabolites 2023, 13(3), 460; https://doi.org/10.3390/metabo13030460 - 22 Mar 2023

Cited by 3 | Viewed by 1893

Abstract

Direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) is a promising tool for high-throughput metabolomics analysis. However, metabolite assignment is limited by the inadequate mass accuracy and chemical space of the metabolome database. Here, a serum metabolome characterization method was proposed to make full [...] Read more.

Direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) is a promising tool for high-throughput metabolomics analysis. However, metabolite assignment is limited by the inadequate mass accuracy and chemical space of the metabolome database. Here, a serum metabolome characterization method was proposed to make full use of the potential of DI-nESI-HRMS. Different from the widely used database search approach, unambiguous formula assignments were achieved by a reaction network combined with mass accuracy and isotopic patterns filter. To provide enough initial known nodes, an initial network was directly constructed by known metabolite formulas. Then experimental formula candidates were screened by the predefined reaction with the network. The effects of sources and scales of networks on assignment performance were investigated. Further, a scoring rule for filtering unambiguous formula candidates was proposed. The developed approach was validated by a pooled serum sample spiked with reference standards. The coverage and accuracy rates for the spiked standards were 98.9% and 93.6%, respectively. A total of 1958 monoisotopic features were assigned with unique formula candidates for the pooled serum, which is twice more than the database search. Finally, a case study of serum metabolomics in diabetes was carried out using the developed method. Full article

(This article belongs to the Special Issue State-of-the-Art Metabolomics and Lipidomics in Life Sciences: Methods and Applications)

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34 pages, 1476 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Maternal Diet-Induced Obesity Affecting the Offspring Brain and Development of Affective Disorders

by Daniel E. Radford-Smith and Daniel C. Anthony

Metabolites 2023, 13(3), 455; https://doi.org/10.3390/metabo13030455 - 20 Mar 2023

Cited by 12 | Viewed by 4179

Abstract

Depression and metabolic disease are common disorders that share a bidirectional relationship and continue to increase in prevalence. Maternal diet and maternal behaviour both profoundly influence the developmental trajectory of offspring during the perinatal period. At an epidemiological level, both maternal depression and [...] Read more.

Depression and metabolic disease are common disorders that share a bidirectional relationship and continue to increase in prevalence. Maternal diet and maternal behaviour both profoundly influence the developmental trajectory of offspring during the perinatal period. At an epidemiological level, both maternal depression and obesity during pregnancy have been shown to increase the risk of neuropsychiatric disease in the subsequent generation. Considerable progress has been made to understand the mechanisms by which maternal obesity disrupts the developing offspring gut–brain axis, priming offspring for the development of affective disorders. This review outlines such mechanisms in detail, including altered maternal care, the maternal microbiome, inflammation, breast milk composition, and maternal and placental metabolites. Subsequently, offspring may be prone to developing gut–brain interaction disorders with concomitant changes to brain energy metabolism, neurotransmission, and behaviour, alongside gut dysbiosis. The gut microbiome may act as a key modifiable, and therefore treatable, feature of the relationship between maternal obesity and the offspring brain function. Further studies examining the relationship between maternal nutrition, the maternal microbiome and metabolites, and offspring neurodevelopment are warranted to identify novel therapeutic targets. Full article

(This article belongs to the Special Issue Obesity and Associated Comorbidities: Implications for Neural and Immune Regulation of Energy Metabolism)

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14 pages, 279 KiB

Open AccessEditor’s ChoiceReview

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives

by Marcello Cossu, Roberta Pintus, Marco Zaffanello, Michele Mussap, Fabiola Serra, Maria Antonietta Marcialis and Vassilios Fanos

Metabolites 2023, 13(3), 447; https://doi.org/10.3390/metabo13030447 - 18 Mar 2023

Cited by 8 | Viewed by 3399

Abstract

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are [...] Read more.

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022. Full article

(This article belongs to the Special Issue Metabolic Profiles and Biomarkers in Pregnancy)

18 pages, 1756 KiB

Open AccessEditor’s ChoiceReview

Detecting and Profiling of Milk Thistle Metabolites in Food Supplements: A Safety-Oriented Approach by Advanced Analytics

by Ancuța Cristina Raclariu-Manolică and Carmen Socaciu

Metabolites 2023, 13(3), 440; https://doi.org/10.3390/metabo13030440 - 17 Mar 2023

Cited by 5 | Viewed by 3302

Abstract

Milk thistle (Silybum marianum (L.) Gaertn.) is among the top-selling botanicals used as a supportive treatment for liver diseases. Silymarin, a mixture of unique flavonolignan metabolites, is the main bioactive component of milk thistle. The biological activities of silymarin have been well [...] Read more.

Milk thistle (Silybum marianum (L.) Gaertn.) is among the top-selling botanicals used as a supportive treatment for liver diseases. Silymarin, a mixture of unique flavonolignan metabolites, is the main bioactive component of milk thistle. The biological activities of silymarin have been well described in the literature, and its use is considered safe and well-tolerated in appropriate doses. However, commercial preparations do not always contain the recommended concentrations of silymarin, failing to provide the expected therapeutic effect. While the poor quality of raw material may explain the low concentrations of silymarin, its deliberate removal is suspected to be an adulteration. Toxic contaminants and foreign matters were also detected in milk thistle preparations, raising serious health concerns. Standard methods for determination of silymarin components include thin-layer chromatography (TLC), high-performance thin-layer chromatography (HPTLC), and high-performance liquid chromatography (HPLC) with various detectors, but nuclear magnetic resonance (NMR) and ultra-high-performance liquid chromatography (UHPLC) have also been applied. This review surveys the extraction techniques of main milk thistle metabolites and the quality, efficacy, and safety of the derived food supplements. Advanced analytical authentication approaches are discussed with a focus on DNA barcoding and metabarcoding to complement orthogonal chemical characterization and fingerprinting of herbal products. Full article

(This article belongs to the Special Issue Plant, Food and Nutritional Metabolomics)

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15 pages, 2322 KiB

Open AccessEditor’s ChoiceArticle

Primary Treatment Effects for High-Grade Serous Ovarian Carcinoma Evaluated by Changes in Serum Metabolites and Lipoproteins

by Cecilie Fredvik Torkildsen, Marie Austdal, Ann-Charlotte Iversen, Tone Frost Bathen, Guro Fanneløb Giskeødegård, Elisabeth Berge Nilsen, Grete Alræk Iversen, Ragnar Kvie Sande, Line Bjørge and Liv Cecilie Vestrheim Thomsen

Metabolites 2023, 13(3), 417; https://doi.org/10.3390/metabo13030417 - 12 Mar 2023

Cited by 2 | Viewed by 2760

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most common and deadliest ovarian cancer subtype. Despite advances in treatment, the overall prognosis remains poor. Regardless of efforts to develop biomarkers to predict surgical outcome and recurrence risk and resistance, reproducible indicators are scarce. Exploring [...] Read more.

High-grade serous ovarian carcinoma (HGSOC) is the most common and deadliest ovarian cancer subtype. Despite advances in treatment, the overall prognosis remains poor. Regardless of efforts to develop biomarkers to predict surgical outcome and recurrence risk and resistance, reproducible indicators are scarce. Exploring the complex tumor heterogeneity, serum profiling of metabolites and lipoprotein subfractions that reflect both systemic and local biological processes were utilized. Furthermore, the overall impact on the patient from the tumor and the treatment was investigated. The aim was to characterize the systemic metabolic effects of primary treatment in patients with advanced HGSOC. In total 28 metabolites and 112 lipoproteins were analyzed by nuclear magnetic resonance (NMR) spectroscopy in longitudinal serum samples (n = 112) from patients with advanced HGSOC (n = 24) from the IMPACT trial with linear mixed effect models and repeated measures ANOVA simultaneous component analysis. The serum profiling revealed treatment-induced changes in both lipoprotein subfractions and circulating metabolites. The development of a more atherogenic lipid profile throughout the treatment, which was more evident in patients with short time to recurrence, indicates an enhanced systemic inflammation and increased risk of cardiovascular disease after treatment. The findings suggest that treatment-induced changes in the metabolome reflect mechanisms behind the diversity in disease-related outcomes. Full article

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

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15 pages, 3081 KiB

Open AccessEditor’s ChoiceArticle

Adult Triploid Rainbow Trout Can Adapt to Various Dietary Lipid Levels by Coordinating Metabolism in Different Tissues

by Gege Liu, Lixia Chen, Haining Tian, Guoliang Sun, Fulei Wei, Yuqiong Meng and Rui Ma

Metabolites 2023, 13(3), 396; https://doi.org/10.3390/metabo13030396 - 8 Mar 2023

Cited by 4 | Viewed by 1713

Abstract

Triploid rainbow trout can adapt to various dietary lipid levels; however, the mechanisms of systematic adaptation are not well understood. To investigate how adult triploid rainbow trout maintains lipid hemostasis under different exogenous lipid intake, a 77-day feeding trial was conducted. Diets with [...] Read more.

Triploid rainbow trout can adapt to various dietary lipid levels; however, the mechanisms of systematic adaptation are not well understood. To investigate how adult triploid rainbow trout maintains lipid hemostasis under different exogenous lipid intake, a 77-day feeding trial was conducted. Diets with lipid contents of 20%, 25%, and 30% were formulated and fed to triploid rainbow trout with an initial weight of 3 ± 0.02 kg, and they were named L20, L25, and L30 group, respectively. Results showed that the condition factor, hepatosomatic index, liver color, and plasma triglyceride were comparable among three groups (p > 0.05), whereas the value of specific growth rate, viscerosomatic index, and liver glycogen content gradually increased with increasing dietary lipid level (p < 0.05). A significantly highest value of plasma glucose and nonesterified fatty acids were found in the L30 group (p < 0.05), whereas the significantly higher content of plasma total cholesterol, high-density lipoprotein–cholesterol, and low-density lipoprotein–cholesterol was found in the L25 group compared with those in L20 group (p < 0.05). As for lipid deposition, abdominal adipose tissue, and muscle were the main lipid storage place for triploid rainbow trout when tissues’ weight is taken into consideration. Overall quantitative PCR showed that the lipid transport and glycolysis were upregulated, and fatty acids oxidative was downregulated in liver when fish were fed low lipid diets. It meant that the liver was the primary lipid metabolizing organ to low lipid diet feeding, which could switch energy supply between glycolysis and fatty acids oxidation. Fish fed with a moderate dietary lipid level diet could increase lipid uptake and promote lipogenesis in muscle. Abdominal adipose tissue could efficiently uptake excess exogenous free fatty acid through upregulating fatty acid uptake and synthesis de novo and then storing it in the form of triglyceride. Excess lipid uptake is preferentially stored in abdominal adipose tissue through coordinated fatty acid uptake and fatty acid synthesis de novo as dietary lipid levels increased. In summary, triploid rainbow trout can adapt to various dietary lipid levels by coordinating metabolism in different tissues. Full article

(This article belongs to the Special Issue Glycolipid Metabolism and Health of Aquatic Animals)

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16 pages, 2234 KiB

Open AccessEditor’s ChoiceArticle

Cross-Platform Comparison of Amino Acid Metabolic Profiling in Three Model Organisms Used in Environmental Metabolomics

by Jessica C. D’eon, Brian P. Lankadurai, André J. Simpson, Eric J. Reiner, David G. Poirier, Greg C. Vanlerberghe and Myrna J. Simpson

Metabolites 2023, 13(3), 402; https://doi.org/10.3390/metabo13030402 - 8 Mar 2023

Cited by 1 | Viewed by 2016

Abstract

Environmental metabolomics is a promising approach to study pollutant impacts to target organisms in both terrestrial and aquatic environments. To this end, both nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based methods are used to profile amino acids in different environmental metabolomic studies. [...] Read more.

Environmental metabolomics is a promising approach to study pollutant impacts to target organisms in both terrestrial and aquatic environments. To this end, both nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based methods are used to profile amino acids in different environmental metabolomic studies. However, these two methods have not been compared directly which is an important consideration for broader comparisons in the environmental metabolomics field. We compared the quantification of 18 amino acids in the tissue extracts of Daphnia magna, a common model organism used in both ecotoxicology and ecology, using both ¹H NMR spectroscopy and liquid chromatography with tandem MS (LC-MS/MS). ¹H NMR quantification of amino acids agreed with the LC-MS/MS quantification for 17 of 18 amino acids measured. We also tested both quantitative methods in a D. magna sub-lethal exposure study to copper and lithium. Again, both NMR and LC-MS/MS measurements showed agreement. We extended our analyses with extracts from the earthworm Eisenia fetida and the plant model Nicotiana tabacum. The concentrations of amino acids by both ¹H NMR and LC-MS/MS, agreed and demonstrated the robustness of both techniques for quantitative metabolomics. These findings demonstrate the compatibility of these two analytical platforms for amino acid profiling in environmentally relevant model organisms and emphasizes that data from either method is robust for comparisons across studies to further build the knowledge base related to pollutant exposure impacts and toxic responses of diverse environmental organisms. Full article

(This article belongs to the Section Environmental Metabolomics)

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15 pages, 2094 KiB

Open AccessEditor’s ChoiceArticle

Capsicum baccatum Red Pepper Prevents Cardiometabolic Risk in Rats Fed with an Ultra-Processed Diet

by Aline Rigon Zimmer, Bianca Franco Leonardi, Eduardo Rigon Zimmer, Alexandre Pastoris Muller, Grace Gosmann and Luis Valmor Cruz Portela

Metabolites 2023, 13(3), 385; https://doi.org/10.3390/metabo13030385 - 5 Mar 2023

Cited by 1 | Viewed by 1900

Abstract

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. [...] Read more.

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome. Full article

(This article belongs to the Special Issue Effects of Dietary Supplementation in Metabolic Syndrome)

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15 pages, 2673 KiB

Open AccessEditor’s ChoiceArticle

Microbial Virulence Factors, Antimicrobial Resistance Genes, Metabolites, and Synthetic Chemicals in Cabins of Commercial Aircraft

by Xi Fu, Mei Zhang, Yiwen Yuan, Yang Chen, Zheyuan Ou, Zailina Hashim, Jamal Hisham Hashim, Xin Zhang, Zhuohui Zhao, Dan Norbäck and Yu Sun

Metabolites 2023, 13(3), 343; https://doi.org/10.3390/metabo13030343 - 24 Feb 2023

Cited by 1 | Viewed by 2136

Abstract

Passengers are at a higher risk of respiratory infections and chronic diseases due to microbial exposure in airline cabins. However, the presence of virulence factors (VFs), antimicrobial resistance genes (ARGs), metabolites, and chemicals are yet to be studied. To address this gap, we [...] Read more.

Passengers are at a higher risk of respiratory infections and chronic diseases due to microbial exposure in airline cabins. However, the presence of virulence factors (VFs), antimicrobial resistance genes (ARGs), metabolites, and chemicals are yet to be studied. To address this gap, we collected dust samples from the cabins of two airlines, one with textile seats (TSC) and one with leather seats (LSC), and analyzed the exposure using shotgun metagenomics and LC/MS. Results showed that the abundances of 17 VFs and 11 risk chemicals were significantly higher in TSC than LSC (p < 0.01). The predominant VFs in TSC were related to adherence, biofilm formation, and immune modulation, mainly derived from facultative pathogens such as Haemophilus parainfluenzae and Streptococcus pneumoniae. The predominant risk chemicals in TSC included pesticides/herbicides (carbofuran, bromacil, and propazine) and detergents (triethanolamine, diethanolamine, and diethyl phthalate). The abundances of these VFs and detergents followed the trend of TSC > LSC > school classrooms (p < 0.01), potentially explaining the higher incidence of infectious and chronic inflammatory diseases in aircraft. The level of ARGs in aircraft was similar to that in school environments. This is the first multi-omic survey in commercial aircraft, highlighting that surface material choice is a potential intervention strategy for improving passenger health. Full article

(This article belongs to the Special Issue Environmental Toxicology and Metabolism)

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18 pages, 3022 KiB

Open AccessEditor’s ChoiceArticle

Expression Silencing of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 Conferred Its Role in Pancreatic β-Cell Physiology and Insulin Secretion

by Rania Saeed, Abdul Khader Mohammed, Sarra E. Saleh, Khaled M. Aboshanab, Mohammad M. Aboulwafa and Jalal Taneera

Metabolites 2023, 13(2), 307; https://doi.org/10.3390/metabo13020307 - 20 Feb 2023

Cited by 1 | Viewed by 2267

Abstract

Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) gene has been recognized as a susceptibility gene for diabetes. However, its action in the physiology of pancreatic β-cells is not fully understood. Herein, bioinformatics and genetic analyses on the publicly available database were performed to [...] Read more.

Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) gene has been recognized as a susceptibility gene for diabetes. However, its action in the physiology of pancreatic β-cells is not fully understood. Herein, bioinformatics and genetic analyses on the publicly available database were performed to map the expression of the MAPK8IP1 gene in human pancreatic islets and to explore whether this gene contains any genetic variants associated with type 2 diabetes (T2D). Moreover, a series of functional experiments were executed in a rat insulinoma cell line (INS-1 832/13) to investigate the role of the Mapk8ip1 gene in β-cell function. Metabolic engineering using RNA-sequencing (RNA-seq) data confirmed higher expression levels of MAPK8IP1 in human islets compared to other metabolic tissues. Additionally, comparable expression of MAPK8IP1 expression was detected in sorted human endocrine cells. However, β-cells exhibited higher expression of MAPK8IP1 than ductal and PSC cells. Notably, MAPK8IP1 expression was reduced in diabetic islets, and the expression was positively correlated with insulin and the β-cell transcription factor PDX1 and MAFA. Using the TIGER portal, we found that one genetic variant, “rs7115753,” in the proximity of MAPK8IP1, passes the genome-wide significance for the association with T2D. Expression silencing of Mapk8ip1 by small interfering RNA (siRNA) in INS-1 cells reduced insulin secretion, glucose uptake rate, and reactive oxygen species (ROS) production. In contrast, insulin content, cell viability, and apoptosis without cytokines were unaffected. However, silencing of Mapk8ip1 reduced cytokines-induced apoptosis and downregulated the expression of several pancreatic β-cell functional markers including, Ins1, Ins2, Pdx1, MafA, Glut2, Gck, Insr, Vamp2, Syt5, and Cacna1a at mRNA and/or protein levels. Finally, we reported that siRNA silencing of Pdx1 resulted in the downregulation of MAPK8IP1 expression in INS-1 cells. In conclusion, our findings confirmed that MAPK8IP1 is an important component of pancreatic β-cell physiology and insulin secretion. Full article

(This article belongs to the Special Issue Construction of High-Efficiency Production Strains by Synthetic Biology and Metabolic Engineering)

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12 pages, 1308 KiB

Open AccessEditor’s ChoiceArticle

Concentrations of Plasma Amino Acids and Neurotransmitters in Participants with Functional Gut Disorders and Healthy Controls

by Shanalee C. James, Karl Fraser, Janine Cooney, Catrin S. Günther, Wayne Young, Richard B. Gearry, Phoebe E. Heenan, Tania Trower, Jacqueline I. Keenan, Nicholas J. Talley, Warren C. McNabb and Nicole C. Roy

Metabolites 2023, 13(2), 313; https://doi.org/10.3390/metabo13020313 - 20 Feb 2023

Cited by 2 | Viewed by 2310

Abstract

Amino acids are important in several biochemical pathways as precursors to neurotransmitters which impact biological processes previously linked to functional gastrointestinal disorders (FGIDs). Dietary protein consumption, metabolic host processes, and the gut microbiome can influence the plasma concentration of amino acids and neurotransmitters, [...] Read more.

Amino acids are important in several biochemical pathways as precursors to neurotransmitters which impact biological processes previously linked to functional gastrointestinal disorders (FGIDs). Dietary protein consumption, metabolic host processes, and the gut microbiome can influence the plasma concentration of amino acids and neurotransmitters, and their uptake by tissues. The aim of this analysis was to quantify 19 proteogenic and 4 non-proteogenic amino acids and 19 neurotransmitters (including precursors and catabolites, herein referred to as neurotransmitters) to ascertain if their circulating concentrations differed between healthy participants and those with FGIDs. Plasma proteogenic and non-proteogenic amino acids and neurotransmitters were measured using ultra-performance liquid chromatography and liquid chromatography–mass spectrometry, respectively, from 165 participants (Rome IV: irritable bowel syndrome (IBS-constipation, IBS-diarrhea), functional constipation, functional diarrhea, and healthy controls). There were significant differences (p < 0.05) in pairwise comparisons between healthy controls and specific FGID groups for branched-chain amino acids (BCAAs), ornithine, and alpha-aminobutyric acid. No other significant differences were observed for the neurotransmitters or any other amino acids analyzed. Multivariate and bivariate correlation analyses between proteogenic and non-proteogenic amino acids and neurotransmitters for constipation (constipation (IBS-C and functional constipation) and phenotypes diarrhea (IBS-D and functional diarrhea)) and healthy controls suggested that associations between BCAAs, 5-hydroxytryptophan, and kynurenine in combination with tyrosine, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylacetic acid and associations with gamma-aminobutyric acid, glutamate, asparagine, and serine are likely disrupted in FGID phenotypes. In conclusion, although correlations were evident between some proteogenic and non-proteogenic amino acids and neurotransmitters, the results showed minor concentration differences in plasma proteogenic and non-proteogenic amino acids, amino acid-derived metabolites, and neurotransmitters between FGID phenotypes and healthy controls. Full article

(This article belongs to the Section Nutrition and Metabolism)

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10 pages, 266 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Deregulations in Patients with Polycystic Ovary Syndrome

by Marzena Jabczyk, Justyna Nowak, Paweł Jagielski, Bartosz Hudzik, Karolina Kulik-Kupka, Aleksander Włodarczyk, Katarzyna Lar and Barbara Zubelewicz-Szkodzińska

Metabolites 2023, 13(2), 302; https://doi.org/10.3390/metabo13020302 - 17 Feb 2023

Cited by 7 | Viewed by 3489

Abstract

Polycystic ovary syndrome (PCOS) contributes to endocrine and metabolic complications for women worldwide. The aim of this study was to establish the usefulness of new anthropometric indices and atherogenic indices in the evaluation of metabolic disorders, in particular, glucose and insulin abnormalities in [...] Read more.

Polycystic ovary syndrome (PCOS) contributes to endocrine and metabolic complications for women worldwide. The aim of this study was to establish the usefulness of new anthropometric indices and atherogenic indices in the evaluation of metabolic disorders, in particular, glucose and insulin abnormalities in the profiles of women with polycystic ovary syndrome (PCOS). In the study, a total of 49 women with PCOS aged between 18 and 39 years were recruited. All patients were tested for fasting glucose and insulin, lipid parameters, oral-glucose administration, and biochemical parameters. All of them underwent anthropometric measurements, such as BMI (body mass index), WHR (waist-to-hip ratio), WHtR (waist-to-height ratio), BAI (body adiposity index), VAI (visceral adiposity index), LAP (lipid accumulation product), BRI (body roundness index), ABSI (A body shape index), AIP (atherogenic risk of plasma), AC (atherogenic coefficient), Castelli risk index-I, Castelli risk index-II and (LCI) lipoprotein combine index, TG/HDL-C ratio, METS-IR (The metabolic score of insulin resistance), triglyceride glucose index (TyG index), triglyceride glucose-body mass index (TyG-BMI index) and triglyceride glucose-waist circumference index (TyG-WC index) were calculated. The analyzed anthropometric measurements/indices and atherogenic indices demonstrated significant correlations in PCOS women. T A strong relationship was found between fasting glucose, fasting insulin, glucose after 60 min, HOMA-IR index in the patients with PCOS. There was no significant relationship between HbA1c and other analyzed parameters and indices. Most of the analyzed anthropometric and atherogenic indices may be useful tools in evaluating metabolic disorders, and, in particular, glucose and insulin abnormalities in PCOS women. Full article

(This article belongs to the Special Issue Prooxidant–Antioxidant and Inflammation Markers in Metabolic Syndrome and Its Complications)

27 pages, 2580 KiB

Open AccessEditor’s ChoiceReview

Crucial Regulatory Role of Organokines in Relation to Metabolic Changes in Non-Diabetic Obesity

by Hajnalka Lőrincz, Sándor Somodi, Balázs Ratku, Mariann Harangi and György Paragh

Metabolites 2023, 13(2), 270; https://doi.org/10.3390/metabo13020270 - 14 Feb 2023

Cited by 12 | Viewed by 3290

Abstract

Obesity is characterized by an excessive accumulation of fat leading to a plethora of medical complications, including coronary artery disease, hypertension, type 2 diabetes mellitus or impaired glucose tolerance and dyslipidemia. Formerly, several physiological roles of organokines, including adipokines, hepatokines, myokines and gut [...] Read more.

Obesity is characterized by an excessive accumulation of fat leading to a plethora of medical complications, including coronary artery disease, hypertension, type 2 diabetes mellitus or impaired glucose tolerance and dyslipidemia. Formerly, several physiological roles of organokines, including adipokines, hepatokines, myokines and gut hormones have been described in obesity, especially in the regulation of glucose and lipid metabolism, insulin sensitivity, oxidative stress, and low-grade inflammation. The canonical effect of these biologically active peptides and proteins may serve as an intermediate regulatory level that connects the central nervous system and the endocrine, autocrine, and paracrine actions of organs responsible for metabolic and inflammatory processes. Better understanding of the function of this delicately tuned network may provide an explanation for the wide range of obesity phenotypes with remarkable inter-individual differences regarding comorbidities and therapeutic responses. The aim of this review is to demonstrate the role of organokines in the lipid and glucose metabolism focusing on the obese non-diabetic subgroup. We also discuss the latest findings about sarcopenic obesity, which has recently become one of the most relevant metabolic disturbances in the aging population. Full article

(This article belongs to the Special Issue Effects of Cardiovascular Risk Factors on Patients with Metabolic Syndrome)

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14 pages, 1834 KiB

Open AccessEditor’s ChoiceArticle

Placental Metabolomics of Fetal Growth Restriction

by Jacopo Troisi, Steven J. K. Symes, Martina Lombardi, Pierpaolo Cavallo, Angelo Colucci, Giovanni Scala, David C. Adair, Maurizio Guida and Sean M. Richards

Metabolites 2023, 13(2), 235; https://doi.org/10.3390/metabo13020235 - 4 Feb 2023

Cited by 5 | Viewed by 3700

Abstract

Fetal growth restriction is an obstetrical pathological condition that causes high neonatal mortality and morbidity. The mechanisms of its onset are not completely understood. Metabolites were extracted from 493 placentas from non-complicated pregnancies in Hamilton Country, TN (USA), and analyzed by gas chromatography–mass [...] Read more.

Fetal growth restriction is an obstetrical pathological condition that causes high neonatal mortality and morbidity. The mechanisms of its onset are not completely understood. Metabolites were extracted from 493 placentas from non-complicated pregnancies in Hamilton Country, TN (USA), and analyzed by gas chromatography–mass spectrometry (GC–MS). Newborns were classified according to raw fetal weight (low birth weight (LBW; <2500 g) and non-low birth weight (Non-LBW; >2500 g)), and according to the calculated birth weight centile as it relates to gestational age (small for gestational age (SGA), large for gestational age (LGA), and adequate for gestational age (AGA)). Mothers of LBW infants had a lower pre-pregnancy weight (66.2 ± 17.9 kg vs. 73.4 ± 21.3 kg, p < 0.0001), a lower body mass index (BMI) (25.27 ± 6.58 vs. 27.73 ± 7.83, p < 0.001), and a shorter gestation age (246.4 ± 24.0 days vs. 267.2 ± 19.4 days p < 0.001) compared with non-LBW. Marital status, tobacco use, and fetus sex affected birth weight centile classification according to gestational age. Multivariate statistical comparisons of the extracted metabolomes revealed that asparagine, aspartic acid, deoxyribose, erythritol, glycerophosphocholine, tyrosine, isoleucine, serine, and lactic acid were higher in both SGA and LBW placentas, while taurine, ethanolamine, β-hydroxybutyrate, and glycine were lower in both SGA and LBW. Several metabolic pathways are implicated in fetal growth restriction, including those related to the hypoxia response and amino-acid uptake and metabolism. Inflammatory pathways are also involved, suggesting that fetal growth restriction might share some mechanisms with preeclampsia. Full article

(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)

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12 pages, 3064 KiB

Open AccessEditor’s ChoiceArticle

Mass-Spectrometry-Based Lipidomics Discriminates Specific Changes in Lipid Classes in Healthy and Dyslipidemic Adults

by Salvador Sánchez-Vinces, Pedro Henrique Dias Garcia, Alex Ap. Rosini Silva, Anna Maria Alves de Piloto Fernandes, Joyce Aparecida Barreto, Gustavo Henrique Bueno Duarte, Marcia Aparecida Antonio, Alexander Birbrair, Andreia M. Porcari and Patricia de Oliveira Carvalho

Metabolites 2023, 13(2), 222; https://doi.org/10.3390/metabo13020222 - 3 Feb 2023

Cited by 4 | Viewed by 2079

Abstract

Triacylglycerols (TAGs) and cholesterol lipoprotein levels are widely used to predict cardiovascular risk and metabolic disorders. The aim of this study is to determine how the comprehensive lipidome (individual molecular lipid species) determined by mass spectrometry is correlated to the serum whole-lipidic profile [...] Read more.

Triacylglycerols (TAGs) and cholesterol lipoprotein levels are widely used to predict cardiovascular risk and metabolic disorders. The aim of this study is to determine how the comprehensive lipidome (individual molecular lipid species) determined by mass spectrometry is correlated to the serum whole-lipidic profile of adults with different lipidemic conditions. The study included samples from 128 adults of both sexes, and they were separated into four groups according to their lipid profile: Group I—normolipidemic (TAG < 150 mg/dL, LDL-C < 160 mg/dL and HDL-c > 40 mg/dL); Group II—isolated hypertriglyceridemia (TAG ≥ 150 mg/dL); Group III—isolated hypercholesterolemia (LDL-C ≥ 160 mg/dL) and Group IV—mixed dyslipidemia. An untargeted mass spectrometry (MS)-based approach was applied to determine the lipidomic signature of 32 healthy and 96 dyslipidemic adults. Limma linear regression was used to predict the correlation of serum TAGs and cholesterol lipoprotein levels with the abundance of the identified MS-annotated lipids found in the subgroups of subjects. Serum TAG levels of dyslipidemic adults have a positive correlation with some of the MS-annotated specific TAGs and ceramides (Cer) and a negative correlation with sphingomyelins (SMs). High-density lipoprotein-cholesterol (HDL-C) levels are positively correlated with some groups of glycerophosphocholine, while low-density lipoprotein-cholesterol (LDL-C) has a positive correlation with SMs. Full article

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

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18 pages, 38737 KiB

Open AccessEditor’s ChoiceArticle

Projections from the Rostral Zona Incerta to the Thalamic Paraventricular Nucleus Mediate Nociceptive Neurotransmission in Mice

by Feng-Ling Wu, Si-Hai Chen, Jia-Ni Li, Liu-Jie Zhao, Xue-Mei Wu, Jie Hong, Ke-Hua Zhu, Han-Xue Sun, Su-Juan Shi, E Mao, Wei-Dong Zang, Jing Cao, Zhen-Zhen Kou and Yun-Qing Li

Metabolites 2023, 13(2), 226; https://doi.org/10.3390/metabo13020226 - 3 Feb 2023

Cited by 7 | Viewed by 2533

Abstract

Zona incerta (ZI) is an integrative subthalamic region in nociceptive neurotransmission. Previous studies demonstrated that the rostral ZI (ZIR) is an important gamma–aminobutyric acid-ergic (GABAergic) source to the thalamic paraventricular nucleus (PVT), but whether the ZIR–PVT pathway participates in nociceptive modulation is still [...] Read more.

Zona incerta (ZI) is an integrative subthalamic region in nociceptive neurotransmission. Previous studies demonstrated that the rostral ZI (ZIR) is an important gamma–aminobutyric acid-ergic (GABAergic) source to the thalamic paraventricular nucleus (PVT), but whether the ZIR–PVT pathway participates in nociceptive modulation is still unclear. Therefore, our investigation utilized anatomical tracing, fiber photometry, chemogenetic, optogenetic and local pharmacological approaches to investigate the roles of the ZIR^GABA+–PVT pathway in nociceptive neurotransmission in mice. We found that projections from the GABAergic neurons in ZIR to PVT were involved in nociceptive neurotransmission. Furthermore, chemogenetic and optogenetic activation of the ZIR^GABA+–PVT pathway alleviates pain, whereas inhibiting the activities of the ZIR^GABA+-PVT circuit induces mechanical hypersensitivity and partial heat hyperalgesia. Importantly, in vivo pharmacology combined with optogenetics revealed that the GABA-A receptor (GABA_AR) is crucial for GABAergic inhibition from ZIR to PVT. Our data suggest that the ZIR^GABA+–PVT pathway acts through GABA_AR-expressing glutamatergic neurons in PVT mediates nociceptive neurotransmission. Full article

(This article belongs to the Special Issue Biosynthesis, Metabolism, and Physiological Functions of Gamma-Aminobutyric Acid)

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21 pages, 887 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Signatures Elucidate the Effect of Body Mass Index on Type 2 Diabetes

by Qiuling Dong, Sidra Sidra, Christian Gieger, Rui Wang-Sattler, Wolfgang Rathmann, Cornelia Prehn, Jerzy Adamski, Wolfgang Koenig, Annette Peters, Harald Grallert and Sapna Sharma

Metabolites 2023, 13(2), 227; https://doi.org/10.3390/metabo13020227 - 3 Feb 2023

Cited by 13 | Viewed by 2974

Abstract

Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA FF4 cohort consisting of 1715 [...] Read more.

Obesity plays an important role in the development of insulin resistance and diabetes, but the molecular mechanism that links obesity and diabetes is still not completely understood. Here, we used 146 targeted metabolomic profiles from the German KORA FF4 cohort consisting of 1715 participants and associated them with obesity and type 2 diabetes. In the basic model, 83 and 51 metabolites were significantly associated with body mass index (BMI) and T2D, respectively. Those metabolites are branched-chain amino acids, acylcarnitines, lysophospholipids, or phosphatidylcholines. In the full model, 42 and 3 metabolites were significantly associated with BMI and T2D, respectively, and replicate findings in the previous studies. Sobel mediation testing suggests that the effect of BMI on T2D might be mediated via lipids such as sphingomyelin (SM) C16:1, SM C18:1 and diacylphosphatidylcholine (PC aa) C38:3. Moreover, mendelian randomization suggests a causal relationship that BMI causes the change of SM C16:1 and PC aa C38:3, and the change of SM C16:1, SM C18:1, and PC aa C38:3 contribute to T2D incident. Biological pathway analysis in combination with genetics and mice experiments indicate that downregulation of sphingolipid or upregulation of phosphatidylcholine metabolism is a causal factor in early-stage T2D pathophysiology. Our findings indicate that metabolites like SM C16:1, SM C18:1, and PC aa C38:3 mediate the effect of BMI on T2D and elucidate their role in obesity related T2D pathologies. Full article

(This article belongs to the Special Issue Advances in Cardiometabolic Research)

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10 pages, 2338 KiB

Open AccessEditor’s ChoiceCommunication

Surface-Coated Acupuncture Needles as Solid-Phase Microextraction Probes for In Vivo Analysis of Bioactive Molecules in Living Plants by Mass Spectrometry

by Huiyun Cheng, Xu Zhao, Lin Zhang, Mingying Ma and Xiaoxiao Ma

Metabolites 2023, 13(2), 220; https://doi.org/10.3390/metabo13020220 - 2 Feb 2023

Cited by 3 | Viewed by 1783

Abstract

In this work, we report the coupling of solid-phase microextraction (SPME) enabled by surface-coated acupuncture needles with nano-electrospray mass spectrometry (nanoESI-MS) for the analysis of bioactive molecules in living plants. The needle tip was oxidized by a mixture of nitric acid and hydrogen [...] Read more.

In this work, we report the coupling of solid-phase microextraction (SPME) enabled by surface-coated acupuncture needles with nano-electrospray mass spectrometry (nanoESI-MS) for the analysis of bioactive molecules in living plants. The needle tip was oxidized by a mixture of nitric acid and hydrogen peroxide solution and then subject to surface coating via carbonization of paraffin. A combination of oxidation and surface coating resulted in a thin coating of carbon film, whereby the significantly increased surface area promoted both analyte enrichment and ionization for MS analysis. The analytical performances were evaluated through the characterization of small molecules, peptides and proteins. Compared with conventional nanoESI, our new strategy of employing surface-coated needles had a high salt tolerance. The streamlined experimental workflow could be completed within one minute. The linear dynamic ranges for L-histidine and L-lysine, as two representatives, were over two orders of magnitude with a limit of detection (LOD) of 3.0~5.0 ng/mL. A mark is made on the needle at 2 mm from the tip, the needle is then kept in the sample for 30 s. In vivo sampling and identification of α-tomatine and organic acids from the stem of a living tomato plant were demonstrated as a practical application, while the physiological activities of the plant were not disrupted due to the minimally invasive sampling. We anticipate that the developed strategy may be of potential use for real-time clinical and other on-site analyses. Full article

(This article belongs to the Special Issue Application of Mass Spectrometry Analysis in Metabolomics)

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13 pages, 3423 KiB

Open AccessEditor’s ChoiceReview

Metabolic Contributions to Pathobiology of Asthma

by Tamanna Roshan Lal, Laura Reck Cechinel, Robert Freishtat and Deepa Rastogi

Metabolites 2023, 13(2), 212; https://doi.org/10.3390/metabo13020212 - 31 Jan 2023

Cited by 7 | Viewed by 3191

Abstract

Asthma is a heterogenous disorder driven by inflammatory mechanisms that result in multiple phenotypes. Given the complex nature of this condition, metabolomics is being used to delineate the pathobiology of asthma. Metabolomics is the study of metabolites in biology, which includes biofluids, cells, [...] Read more.

Asthma is a heterogenous disorder driven by inflammatory mechanisms that result in multiple phenotypes. Given the complex nature of this condition, metabolomics is being used to delineate the pathobiology of asthma. Metabolomics is the study of metabolites in biology, which includes biofluids, cells, and tissues. These metabolites have a vital role in a disease as they contribute to the pathogenesis of said condition. This review describes how macrometabolic and micrometabolic studies pertaining to these metabolites have contributed to our current understanding of asthma, as well as its many phenotypes. One of the main phenotypes this review will discuss in further detail is obesity as well as diabetes. Distinct roles of metabolites in endotyping asthma and their translation to potential therapy development for asthma is also discussed in this review. Full article

(This article belongs to the Special Issue Metabolomics in the Prevention and Management of Asthma)

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18 pages, 1852 KiB

Open AccessEditor’s ChoiceArticle

Efficient SABRE-SHEATH Hyperpolarization of Potent Branched-Chain-Amino-Acid Metabolic Probe [1-¹³C]ketoisocaproate

by Isaiah Adelabu, Md Raduanul H. Chowdhury, Shiraz Nantogma, Clementinah Oladun, Firoz Ahmed, Lukas Stilgenbauer, Marianna Sadagurski, Thomas Theis, Boyd M. Goodson and Eduard Y. Chekmenev

Metabolites 2023, 13(2), 200; https://doi.org/10.3390/metabo13020200 - 29 Jan 2023

Cited by 9 | Viewed by 3708

Abstract

Efficient ¹³C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-¹³C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous [...] Read more.

Efficient ¹³C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-¹³C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous chemical exchange with an Ir-IMes-based hexacoordinate complex in CD₃OD. SABRE-SHEATH enables spontaneous polarization transfer from parahydrogen-derived hydrides to the ¹³C nucleus of transiently bound ketoisocaproate. ¹³C polarization values of up to 18% are achieved at the 1-¹³C site in 1 min in the liquid state at 30 mM substrate concentration. The efficient polarization build-up becomes possible due to favorable relaxation dynamics. Specifically, the exponential build-up time constant (14.3 ± 0.6 s) is substantially lower than the corresponding polarization decay time constant (22.8 ± 1.2 s) at the optimum polarization transfer field (0.4 microtesla) and temperature (10 °C). The experiments with natural abundance ketoisocaproate revealed polarization level on the ¹³C-2 site of less than 1%—i.e., one order of magnitude lower than that of the 1-¹³C site—which is only partially due to more-efficient relaxation dynamics in sub-microtesla fields. We rationalize the overall much lower ¹³C-2 polarization efficiency in part by less favorable catalyst-binding dynamics of the C-2 site. Pilot SABRE experiments at pH 4.0 (acidified sample) versus pH 6.1 (unaltered sodium [1-¹³C]ketoisocaproate) reveal substantial modulation of SABRE-SHEATH processes by pH, warranting future systematic pH titration studies of ketoisocaproate, as well as other structurally similar ketocarboxylate motifs including pyruvate and alpha-ketoglutarate, with the overarching goal of maximizing ¹³C polarization levels in these potent molecular probes. Finally, we also report on the pilot post-mortem use of HP [1-¹³C]ketoisocaproate in a euthanized mouse, demonstrating that SABRE-hyperpolarized ¹³C contrast agents hold promise for future metabolic studies. Full article

(This article belongs to the Special Issue Interrogation of Tumor Metabolism Employing Magnetic Resonance Spectroscopy and Imaging)

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29 pages, 370 KiB

Open AccessEditor’s ChoiceArticle

Fetal Hepatic Lipidome Is More Greatly Affected by Maternal Rate of Gain Compared with Vitamin and Mineral Supplementation at day 83 of Gestation

by Ana Clara B. Menezes, Carl R. Dahlen, Kacie L. McCarthy, Cierrah J. Kassetas, Friederike Baumgaertner, James D. Kirsch, Sheri T. Dorsam, Tammi L. Neville, Alison K. Ward, Pawel P. Borowicz, Lawrence P. Reynolds, Kevin K. Sedivec, J. Chris Forcherio, Ronald Scott, Joel S. Caton and Matthew S. Crouse

Metabolites 2023, 13(2), 175; https://doi.org/10.3390/metabo13020175 - 25 Jan 2023

Cited by 13 | Viewed by 2290

Abstract

Herein, we evaluated the hepatic lipid metabolic profiles of bovine fetuses in response to maternal vitamin and mineral supplementation (VMSUP; supplemented (VTM) or not (NoVTM)) and two different rates of gain (GAIN; low gain (LG), 0.28 kg/d, or moderate gain (MG), 0.79 kg/d). [...] Read more.

Herein, we evaluated the hepatic lipid metabolic profiles of bovine fetuses in response to maternal vitamin and mineral supplementation (VMSUP; supplemented (VTM) or not (NoVTM)) and two different rates of gain (GAIN; low gain (LG), 0.28 kg/d, or moderate gain (MG), 0.79 kg/d). Crossbred Angus heifers (n = 35; initial BW = 359.5 ± 7.1 kg) were randomly assigned to a 2 × 2 factorial arrangement, resulting in the following treatment combinations: NoVTM-LG (n = 9), NoVTM-MG (n = 9), VTM-LG (n = 9), and VTM-MG (n = 8). Heifers received their treatments until d 83 of gestation, when they were ovariohysterectomized. Fetuses were harvested and liver samples were analyzed via ultrahigh-performance liquid chromatography–tandem mass spectroscopy to characterize lipid profiles and abundances. We identified 374 biochemicals/metabolites belonging to 57 sub-pathways of the lipid metabolism super-pathway. The majority of the biochemicals/metabolites (n = 152) were significantly affected by the main effect of GAIN. Maternal moderate rates of gain resulted in greater abundances (p ≤ 0.0001) of ω-3 fatty acids (eicosapentaenoate, docosapentaenoate, and docosahexaenoate) and lower abundances (p ≤ 0.0001) of ω-6 fatty acids. Further, MG resulted in the accumulation of several diacylglycerols and depletion of the majority of the monoacylglycerols. Concentrations of nearly all acylcarnitines (p ≤ 0.03) were decreased in VTM-LG fetal livers compared to all other treatment combinations, indicating a greater rate of complete oxidation of fatty acids. Levels of secondary bile acids were impacted by VMSUP, being greater (p ≤ 0.0048) in NoVTM than in VTM fetal livers. Moreover, NoVTM combined with lower rate of gain resulted in greater concentrations of most secondary bile acid biochemicals/metabolites. These data indicate that maternal diet influenced and altered fetal hepatic lipid composition in the first trimester of gestation. Maternal body weight gain exerted a greater influence on fetal lipid profiles than vitamin and mineral supplementation. Specifically, lower rate of gain (0.28 kg/d) resulted in an increased abundance of the majority of the biochemicals/metabolites identified in this study. Full article

(This article belongs to the Special Issue Mineral and Energy Metabolism of Mammals during Pregnancy)

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