Metabolites

13 pages, 2634 KB

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 4 | Viewed by 2571

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)

► Show Figures

Graphical abstract

34 pages, 1476 KB

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 15 | Viewed by 5522

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)

► Show Figures

Figure 1

14 pages, 279 KB

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 13 | Viewed by 4795

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 KB

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 8 | Viewed by 5508

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)

► Show Figures

Figure 1

15 pages, 2322 KB

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 5 | Viewed by 3475

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)

► Show Figures

Graphical abstract

15 pages, 3081 KB

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 7 | Viewed by 2325

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)

► Show Figures

Figure 1

16 pages, 2234 KB

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 2587

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)

► Show Figures

Figure 1

15 pages, 2094 KB

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 2362

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)

► Show Figures

Graphical abstract

15 pages, 2673 KB

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 4 | Viewed by 2609

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)

► Show Figures

Graphical abstract

18 pages, 3022 KB

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 2 | Viewed by 2765

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)

► Show Figures

Figure 1

12 pages, 1308 KB

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 4 | Viewed by 2868

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)

► Show Figures

Figure 1

10 pages, 266 KB

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 16 | Viewed by 4608

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 KB

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 17 | Viewed by 4147

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)

► Show Figures

Graphical abstract

14 pages, 1834 KB

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 11 | Viewed by 4756

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)

► Show Figures

Graphical abstract

12 pages, 3064 KB

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 6 | Viewed by 2679

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)

► Show Figures

Figure 1

18 pages, 38737 KB

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 13 | Viewed by 3812

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)

► Show Figures

Figure 1

21 pages, 887 KB

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 19 | Viewed by 3747

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)

► Show Figures

Graphical abstract

10 pages, 2338 KB

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 4 | Viewed by 2346

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)

► Show Figures

Graphical abstract

13 pages, 3423 KB

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 14 | Viewed by 4096

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)

► Show Figures

Figure 1

18 pages, 1852 KB

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 11 | Viewed by 4522

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)

► Show Figures

Figure 1

29 pages, 370 KB

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 22 | Viewed by 2876

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)

22 pages, 2684 KB

Open AccessEditor’s ChoiceArticle

Integration of LC-MS-Based and GC-MS-Based Metabolic Profiling to Reveal the Effects of Domestication and Boiling on the Composition of Duck Egg Yolks

by Yong Tian, Guoqin Li, Xizhong Du, Tao Zeng, Li Chen, Wenwu Xu, Tiantian Gu, Zhengrong Tao and Lizhi Lu

Metabolites 2023, 13(1), 135; https://doi.org/10.3390/metabo13010135 - 16 Jan 2023

Cited by 6 | Viewed by 3267

Abstract

Egg yolks contain abundant lipids, proteins, and minerals that provide not only essential nutrients for embryonic development but also cheap sources of nutrients for consumers worldwide. Previous composition analyses of egg yolks primarily focused on nutrients such as lipids and minerals. However, few [...] Read more.

Egg yolks contain abundant lipids, proteins, and minerals that provide not only essential nutrients for embryonic development but also cheap sources of nutrients for consumers worldwide. Previous composition analyses of egg yolks primarily focused on nutrients such as lipids and minerals. However, few studies have reported the effects of domestication and heating on yolk composition and characteristics. The objective of this study was to investigate the impact of domestication and boiling on the metabolite contents of egg yolks via untargeted metabolomics using GC-MS and LC-MS. In this study, eggs were collected from Fenghua teals, captive mallards, and Shaoxing ducks. Twelve duck eggs (half raw and half cooked) were randomly selected from each variety, and the egg yolks were separated for metabolic profiling. The analysis identified 1205 compounds in the egg yolks. Domestication generated more differential metabolites than boiling, which indicated that the changes in the metabolome of duck egg yolk caused by domestication were greater than those caused by boiling. In a comparative analysis of domestic and mallard ducks, 48 overlapping differential metabolites were discovered. Among them, nine metabolites were upregulated in domesticated ducks, including monoolein, emodin, daidzein, genistein, and glycitein, which may be involved in lipid metabolism; some of them may also act as phytoestrogens (flavonoids). Another 39 metabolites, including imethylethanolamine, harmalan, mannitol, nornicotine, linoleic acid, diphenylamine, proline betaine, alloxanthin, and resolvin d1, were downregulated by domestication and were linked to immunity, anti-inflammatory, antibacterial, and antioxidant properties. Furthermore, four overlapping differential metabolites that included amino acids and dipeptides were discovered in paired comparisons of the raw and boiled samples. Our findings provided new insights into the molecular response of duck domestication and supported the use of metabolomics to examine the impact of boiling on the composition of egg yolks. Full article

(This article belongs to the Section Nutrition and Metabolism)

► Show Figures

Figure 1

20 pages, 3190 KB

Open AccessEditor’s ChoiceArticle

Activity of Microbial-Derived Phenolic Acids and Their Conjugates against LPS-Induced Damage in Neuroblastoma Cells and Macrophages

by Dolores González de Llano, Mikel Roldán, Laura Parro, Begoña Bartolomé and M. Victoria Moreno-Arribas

Metabolites 2023, 13(1), 108; https://doi.org/10.3390/metabo13010108 - 9 Jan 2023

Cited by 10 | Viewed by 3351

Abstract

The aim of this study was to investigate whether microbial-derived phenolic acids, 3,4-dihydroxyphenylacetic (DHPA), protocatechuic acid (PCA), and dihydrocaffeic acid (DHCFA) and their conjugated forms (DHCFA 3-O-sulfate and DHCFA 3-O-β-D-glucuronide), exhibit protective effects against neuroinflammation and oxidative stress. Experiments were performed on human [...] Read more.

The aim of this study was to investigate whether microbial-derived phenolic acids, 3,4-dihydroxyphenylacetic (DHPA), protocatechuic acid (PCA), and dihydrocaffeic acid (DHCFA) and their conjugated forms (DHCFA 3-O-sulfate and DHCFA 3-O-β-D-glucuronide), exhibit protective effects against neuroinflammation and oxidative stress. Experiments were performed on human neuronal SH-SY5Y cells stimulated with bacterial lipopolysaccharide (LPS) and tert-butyl hydroperoxide (tBHP). Anti-inflammatory activity in terms of pro-inflammatory cytokine production was also evaluated in LPS-stimulated RAW 264.7 macrophages as a reactive microglial model. Treatment of the SH-SY5Y cells with the free phenolic acids, as well as with the conjugated metabolites, at physiologically concentrations (1, 10 and 50 μM), resulted in increased cell viability of LPS- and tBHP-stimulated cells. Phenolic metabolites and, especially, the conjugated derivatives also protected neuronal cells through significant attenuation of inflammation by decreasing ROS levels. Furthermore, the conjugated and microbial-derived phenolic metabolites significantly inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-8) in LPS-stimulated macrophages. Among the phenolic metabolites tested, different efficacies were observed, with the glucuronide form standing out. Overall, these results suggest, for the first time, that conjugated derivatives of phenolic acids seem to be more effective at protecting neurons from inflammation damage and oxidative stress. Further in vivo studies are warranted. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

► Show Figures

Graphical abstract

12 pages, 794 KB

Open AccessEditor’s ChoiceReview

Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD

by Lingxuan An, Ulrich Wirth, Dominik Koch, Malte Schirren, Moritz Drefs, Dionysios Koliogiannis, Hanno Niess, Joachim Andrassy, Markus Guba, Alexandr V. Bazhin, Jens Werner and Florian Kühn

Metabolites 2023, 13(1), 101; https://doi.org/10.3390/metabo13010101 - 7 Jan 2023

Cited by 21 | Viewed by 3668

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

► Show Figures

Figure 1

10 pages, 566 KB

Open AccessEditor’s ChoiceReview

The Effect of a Gluten-Free Diet on Vitamin D Metabolism in Celiac Disease: The State of the Art

by Michele Di Stefano, Emanuela Miceli, Caterina Mengoli, Gino Roberto Corazza and Antonio Di Sabatino

Metabolites 2023, 13(1), 74; https://doi.org/10.3390/metabo13010074 - 2 Jan 2023

Cited by 10 | Viewed by 5989

Abstract

Celiac disease is a chronic autoimmune disorder involving the small intestine, characterized by villous atrophy, crypt hyperplasia and an increase in intraepithelial lymphocytes. Due to both calcium malabsorption and immune activation, a high prevalence of bone mass derangement is evident in this condition, [...] Read more.

Celiac disease is a chronic autoimmune disorder involving the small intestine, characterized by villous atrophy, crypt hyperplasia and an increase in intraepithelial lymphocytes. Due to both calcium malabsorption and immune activation, a high prevalence of bone mass derangement is evident in this condition, regardless of the presence of overt malabsorption. Alterations of mineral metabolism are also frequently described, and in this review, the modifications of serum levels of vitamin D are analyzed, according to the available literature on this topic. In untreated patients, secondary hyperparathyroidism is responsible for the hyperconversion of 25-vitamin D into 1,25-vitamin D making mandatory the determination of serum levels of both vitamin metabolites to avoid a wrong diagnosis of vitamin D deficit. A gluten-free diet allows for a normalization of bone and mineral metabolism, reverting these abnormalities and raising some doubts on the need for vitamin supplementation in all the patients. Data available do not support this wide indication, and a complete evaluation of bone and mineral metabolism should be performed to select patients who need this therapeutic approach. Full article

(This article belongs to the Special Issue Effect of Diet on Vitamin D Metabolism: Implications in Health and Disease)

► Show Figures

Figure 1

10 pages, 2174 KB

Open AccessEditor’s ChoiceArticle

ConCISE: Consensus Annotation Propagation of Ion Features in Untargeted Tandem Mass Spectrometry Combining Molecular Networking and In Silico Metabolite Structure Prediction

by Zachary A. Quinlan, Irina Koester, Allegra T. Aron, Daniel Petras, Lihini I. Aluwihare, Pieter C. Dorrestein, Craig E. Nelson and Linda Wegley Kelly

Metabolites 2022, 12(12), 1275; https://doi.org/10.3390/metabo12121275 - 16 Dec 2022

Cited by 16 | Viewed by 3647

Abstract

Recent developments in molecular networking have expanded our ability to characterize the metabolome of diverse samples that contain a significant proportion of ion features with no mass spectral match to known compounds. Manual and tool-assisted natural annotation propagation is readily used to classify [...] Read more.

Recent developments in molecular networking have expanded our ability to characterize the metabolome of diverse samples that contain a significant proportion of ion features with no mass spectral match to known compounds. Manual and tool-assisted natural annotation propagation is readily used to classify molecular networks; however, currently no annotation propagation tools leverage consensus confidence strategies enabled by hierarchical chemical ontologies or enable the use of new in silico tools without significant modification. Herein we present ConCISE (Consensus Classifications of In Silico Elucidations) which is the first tool to fuse molecular networking, spectral library matching and in silico class predictions to establish accurate putative classifications for entire subnetworks. By limiting annotation propagation to only structural classes which are identical for the majority of ion features within a subnetwork, ConCISE maintains a true positive rate greater than 95% across all levels of the ChemOnt hierarchical ontology used by the ClassyFire annotation software (superclass, class, subclass). The ConCISE framework expanded the proportion of reliable and consistent ion feature annotation up to 76%, allowing for improved assessment of the chemo-diversity of dissolved organic matter pools from three complex marine metabolomics datasets comprising dominant reef primary producers, five species of the diatom genus Pseudo-nitzchia, and stromatolite sediment samples. Full article

(This article belongs to the Special Issue Marine Microbes Related Metabolic Studies)

► Show Figures

Figure 1

15 pages, 1705 KB

Open AccessEditor’s ChoiceArticle

Metabolomics and Lipidomics Signatures of Insulin Resistance and Abdominal Fat Depots in People Living with Obesity

by Yen Chin Koay, Adelle C. F. Coster, Daniel L. Chen, Brad Milner, Amani Batarseh, John F. O’Sullivan, Jerry R. Greenfield and Dorit Samocha-Bonet

Metabolites 2022, 12(12), 1272; https://doi.org/10.3390/metabo12121272 - 15 Dec 2022

Cited by 12 | Viewed by 3564

Abstract

The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the [...] Read more.

The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m², n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic clamp with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman’s rank correlation analyses that passed the Benjamini–Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p < 7.2 × 10⁻⁴). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify diverse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity. Full article

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

► Show Figures

Figure 1

11 pages, 597 KB

Open AccessEditor’s ChoiceArticle

Metabolomic Analysis of Renal Cell Carcinoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

by Kathleen M. McClain, Joshua N. Sampson, Jessica L. Petrick, Kaitlyn M. Mazzilli, Robert E. Gerszten, Clary B. Clish, Mark P. Purdue, Loren Lipworth and Steven C. Moore

Metabolites 2022, 12(12), 1189; https://doi.org/10.3390/metabo12121189 - 29 Nov 2022

Cited by 6 | Viewed by 2243

Abstract

Background: In the US in 2021, 76,080 kidney cancers are expected and >80% are renal cell carcinomas (RCCs). Along with excess fat, metabolic dysfunction is implicated in RCC etiology. To identify RCC-associated metabolites, we conducted a 1:1 matched case–control study nested within the [...] Read more.

Background: In the US in 2021, 76,080 kidney cancers are expected and >80% are renal cell carcinomas (RCCs). Along with excess fat, metabolic dysfunction is implicated in RCC etiology. To identify RCC-associated metabolites, we conducted a 1:1 matched case–control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We measured 522 serum metabolites in 267 cases/control pairs. Cases were followed for a median 7.1 years from blood draw to diagnosis. Using conditional logistic regression, we computed adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing risk between 90th and 10th percentiles of log metabolite intensity, with the significance threshold at a false discovery rate <0.20. Results: Four metabolites were inversely associated with risk of RCC during follow-up—C38:4 PI, C34:0 PC, C14:0 SM, and C16:1 SM (ORs ranging from 0.33–0.44). Two were positively associated with RCC risk—C3-DC-CH3 carnitine and C5 carnitine (ORs = 2.84 and 2.83, respectively). These results were robust when further adjusted for metabolic risk factors (body mass index (BMI), physical activity, diabetes/hypertension history). Metabolites associated with RCC had weak correlations (|r| < 0.2) with risk factors of BMI, physical activity, smoking, alcohol, and diabetes/hypertension history. In mutually adjusted models, three metabolites (C38:4 PI, C14:0 SM, and C3-DC-CH3 carnitine) were independently associated with RCC risk. Conclusions: Serum concentrations of six metabolites were associated with RCC risk, and three of these had independent associations from the mutually adjusted model. These metabolites may point toward new biological pathways of relevance to this malignancy. Full article

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

► Show Figures

Figure 1

14 pages, 1150 KB

Open AccessEditor’s ChoiceArticle

Integration of Liver Glycogen and Triglyceride NMR Isotopomer Analyses Provides a Comprehensive Coverage of Hepatic Glucose and Fructose Metabolism

by Ivan Viegas, Giada Di Nunzio, Getachew D. Belew, Alejandra N. Torres, João G. Silva, Luis Perpétuo, Cristina Barosa, Ludgero C. Tavares and John G. Jones

Metabolites 2022, 12(11), 1142; https://doi.org/10.3390/metabo12111142 - 19 Nov 2022

Cited by 7 | Viewed by 6479

Abstract

Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice [...] Read more.

Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice were fed a chow diet supplemented with 35 g/100 mL drinking water of a 55/45 fructose/glucose mixture for 18 weeks. On the final night, the sugar mixture was enriched with either [U-¹³C]glucose or [U-¹³C]fructose, and deuterated water (²H₂O) was also administered. ¹³C-isotopomers representing newly synthesized hepatic glucose-6-phosphate (glucose-6-P), glycerol-3-phosphate, and lipogenic acetyl-CoA were quantified by ²H and ¹³C NMR analysis of post-mortem liver glycogen and triglyceride. These data were applied to a metabolic model covering glucose-6-P, PPP, triose-P, and de novo lipogenesis (DNL) fluxes. The glucose supplement was converted to glucose-6-P via the direct pathway, while the fructose supplement was metabolized by the liver to gluconeogenic triose-P via fructokinase–aldolase–triokinase. Glucose-6-P from all carbohydrate sources accounted for 40–60% of lipogenic acetyl-CoA and 10–12% was oxidized by the pentose phosphate pathway (PPP). The yield of NADPH from PPP flux accounted for a minority (~30%) of the total DNL requirement. In conclusion, this approach integrates measurements of glucose-6-P, PPP, and DNL fluxes to provide a holistic and informative assessment of hepatic glucose and fructose metabolism. Full article

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

► Show Figures

Figure 1

19 pages, 3328 KB

Open AccessEditor’s ChoiceArticle

Exposure to Environmentally Relevant Levels of PFAS Causes Metabolic Changes in the Freshwater Amphipod Austrochiltonia subtenuis

by Georgia M. Sinclair, Sara M. Long, Navneet Singh, Timothy L. Coggan, Matthew P. J. Askeland and Oliver A. H. Jones

Metabolites 2022, 12(11), 1135; https://doi.org/10.3390/metabo12111135 - 18 Nov 2022

Cited by 9 | Viewed by 3479

Abstract

Per and polyfluoroalkyl substances (PFAS) are of concern to environmental regulators due to their widespread occurrence, persistence and reported toxicity. However, little data exist on the effects of PFAS at environmentally relevant concentrations. The development of molecular markers for PFAS exposure would therefore [...] Read more.

Per and polyfluoroalkyl substances (PFAS) are of concern to environmental regulators due to their widespread occurrence, persistence and reported toxicity. However, little data exist on the effects of PFAS at environmentally relevant concentrations. The development of molecular markers for PFAS exposure would therefore be useful to better understand the environmental risks of these compounds. In this study, we assessed if such markers could be developed using Gas Chromatography–Mass Spectrometry-based metabolomics. We exposed the freshwater amphipod Austrochiltonia subtenuis to a range of environmentally relevant concentrations of perfluoro-octane sulfonic acid (PFOS), hexafluoropropylene oxide dimer acid (GenX) and perfluorohexanesulphonic acid (PFHxS) for 7 days at five concentrations. A metabolic response was detected in all concentrations and treatments even though the survival rates only differed significantly at the highest exposure levels. The metabolic response differed between compounds but all three PFAS induced changes in the levels of amino acids, fatty acids, and cholesterol, in line with the literature. PFOS was found to bioaccumulate. Both GenX and PFHxS were eliminated from the amphipods, but PFHxS was eliminated at a slower rate than GenX. This information improves our understanding of the sublethal effects of PFAS as well as their environmental fate and behaviour. Full article

(This article belongs to the Special Issue Integrated Systems Biology: Challenges and Future Perspectives)

► Show Figures

Graphical abstract

19 pages, 4054 KB

Open AccessEditor’s ChoiceArticle

Multiparametric Magnetic Resonance Imaging and Metabolic Characterization of Patient-Derived Xenograft Models of Clear Cell Renal Cell Carcinoma

by Joao Piraquive Agudelo, Deepti Upadhyay, Dalin Zhang, Hongjuan Zhao, Rosalie Nolley, Jinny Sun, Shubhangi Agarwal, Robert A. Bok, Daniel B. Vigneron, James D. Brooks, John Kurhanewicz, Donna M. Peehl and Renuka Sriram

Metabolites 2022, 12(11), 1117; https://doi.org/10.3390/metabo12111117 - 15 Nov 2022

Cited by 7 | Viewed by 2433

Abstract

Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are [...] Read more.

Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are needed to evaluate novel imaging and therapeutic approaches targeting metabolism. We characterized 5 PDX from high-grade or metastatic ccRCC by multiparametric magnetic resonance imaging (MRI) and steady state metabolic profiling and flux analysis. Similar to MRI of clinical ccRCC, T₂-weighted images of orthotopic tumors of most PDX were homogeneous. The increased hyperintense (cystic) areas observed in one PDX mimicked the cystic phenotype typical of some RCC. The negligible hypointense (necrotic) areas of PDX grown under the highly vascularized renal capsule are beneficial for preclinical studies. Mean apparent diffusion coefficient (ADC) values were equivalent to those of ccRCC in human patients. Hyperpolarized (HP) [1-¹³C]pyruvate MRI of PDX showed high glycolytic activity typical of high-grade primary and metastatic ccRCC with considerable intra- and inter-tumoral variability, as has been observed in clinical HP MRI of ccRCC. Comparison of steady state metabolite concentrations and metabolic flux in [U-¹³C]glucose-labeled tumors highlighted the distinctive phenotypes of two PDX with elevated levels of numerous metabolites and increased fractional enrichment of lactate and/or glutamate, capturing the metabolic heterogeneity of glycolysis and the TCA cycle in clinical ccRCC. Culturing PDX cells and reimplanting to generate xenografts (XEN), or passaging PDX in vivo, altered some imaging and metabolic characteristics while transcription remained like that of the original PDX. These findings show that PDX are realistic models of ccRCC for imaging and metabolic studies but that the plasticity of metabolism must be considered when manipulating PDX for preclinical studies. Full article

(This article belongs to the Special Issue Imaging and Spectroscopic Based Methods to Understand Cancer Metabolism and Biology)

► Show Figures

Figure 1

15 pages, 2939 KB

Open AccessEditor’s ChoiceArticle

Effects of Proteases from Pineapple and Papaya on Protein Digestive Capacity and Gut Microbiota in Healthy C57BL/6 Mice and Dose-Manner Response on Mucosal Permeability in Human Reconstructed Intestinal 3D Tissue Model

by Olha Kostiuchenko, Nadiia Kravchenko, Jan Markus, Stephen Burleigh, Olexandr Fedkiv, Ling Cao, Silvia Letasiova, Galyna Skibo, Frida Fåk Hållenius and Olena Prykhodko

Metabolites 2022, 12(11), 1027; https://doi.org/10.3390/metabo12111027 - 26 Oct 2022

Cited by 17 | Viewed by 7065

Abstract

Cysteine proteases obtained from the stem of pineapple or papaya latex, bromelain and papain, respectively, exhibit a broad spectrum of beneficial effects on human health. However, their effects on gut microbiota composition or dose-manner effects on the intestinal integrity of healthy tissue have [...] Read more.

Cysteine proteases obtained from the stem of pineapple or papaya latex, bromelain and papain, respectively, exhibit a broad spectrum of beneficial effects on human health. However, their effects on gut microbiota composition or dose-manner effects on the intestinal integrity of healthy tissue have not been evaluated. In this study, C57BL/6 young, healthy mice were fed bromelain or papain in a dose of 1 mg per animal/day for three consecutive days, followed by the assessment of digestive protein capacity, intestinal morphology and gut microbiota composition. Furthermore, a human reconstructed 3D tissue model EpiIntestinal (SMI-100) was used to study the effects of 1, 0.1 and 10 mg/mL doses of each enzyme on tissue integrity and mucosal permeability using TEER measurements and passage of Lucifer Yellow marker from the apical to the basolateral side of the mucosa. The results indicated that fruit proteases have the potential to modulate gut microbiota with decreasing abundance of Proteobacteria and increasing beneficial Akkermansia muciniphila. The enhancement of pancreatic trypsin was observed in bromelain and papain supplementation, while bromelain also increased the thickness of the ileal mucosa. Furthermore, an in vitro study showed a dose-dependent interruption in epithelial integrity, which resulted in increased paracellular permeability by the highest doses of enzymes. These findings define bromelain and papain as promising enzymatic supplementation for controlled enhancement of paracellular uptake when needed, together with beneficial effects on the gut microbiota. Full article

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

► Show Figures

Figure 1

18 pages, 1500 KB

Open AccessEditor’s ChoiceArticle

A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice

by Erin R. Saito, Cali E. Warren, Cameron M. Hanegan, John G. Larsen, Johannes D. du Randt, Mio Cannon, Jeremy Y. Saito, Rachel J. Campbell, Colin M. Kemberling, Gavin S. Miller, Jeffrey G. Edwards and Benjamin T. Bikman

Metabolites 2022, 12(11), 1019; https://doi.org/10.3390/metabo12111019 - 25 Oct 2022

Cited by 12 | Viewed by 9675

Abstract

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer’s disease and major depressive disorder. However, [...] Read more.

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer’s disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O₂ consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O₂ ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease. Full article

(This article belongs to the Special Issue The Metabolomic Landscape of Carbohydrate Restriction)

► Show Figures

Figure 1

10 pages, 1522 KB

Open AccessEditor’s ChoiceArticle

Liver Fetuin-A at Initiation of Insulin Resistance

by Nicolas Lanthier, Valérie Lebrun, Olivier Molendi-Coste, Nico van Rooijen and Isabelle A. Leclercq

Metabolites 2022, 12(11), 1023; https://doi.org/10.3390/metabo12111023 - 25 Oct 2022

Cited by 20 | Viewed by 3279

Abstract

Hepatokines (liver secreted proteins with possible distant action) are emerging potential players in insulin resistance in type 2 diabetic patients. Here, we explored the effect of a high-fat diet on the expression of fetuin-A, one of those candidate liver proteins, and its relationship [...] Read more.

Hepatokines (liver secreted proteins with possible distant action) are emerging potential players in insulin resistance in type 2 diabetic patients. Here, we explored the effect of a high-fat diet on the expression of fetuin-A, one of those candidate liver proteins, and its relationship with liver macrophage activation. Mice were fed a normal diet or a high-fat diet for 3 days, known to initiate steatosis and liver insulin resistance. A preventive liver macrophage depletion was obtained by intravenous injection of clodronate-loaded liposomes. The mRNA and protein expression of fetuin-A was evaluated by qPCR, Western blot and immunofluorescence on different insulin-sensitive tissues (liver, adipose tissue, and muscle). Short-term high-fat diet-induced steatosis, liver macrophage activation, and hepatic insulin resistance together with a significantly increased expression of liver AHSG (α2-HS glycoprotein/fetuin-A) mRNA and serum fetuin-A concentration. On immunofluorescence, fetuin-A was mostly expressed in centrilobular hepatocytes. This increase in fetuin-A under high-fat diet was not evidenced in other peripheral insulin-sensitive tissues (skeletal muscle and adipose tissue). The mRNA expression of α2-HS glycoprotein was 800 times higher within the liver compared with the adipose tissue or the muscle. Liver macrophage depletion that significantly ameliorated insulin sensitivity was associated with a significant decrease in α2-HS glycoprotein mRNA expression. In conclusion, this study demonstrated liver fetuin-A overexpression at the initiation of high-fat diet feeding, concurrent with hepatic steatosis and insulin resistance. Targeting liver macrophages in this setting reduced liver α2-HS glycoprotein expression suggesting that fetuin-A acts as an hepatokine with proinsulin resistance effects. Full article

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

► Show Figures

Figure 1

17 pages, 2720 KB

Open AccessEditor’s ChoiceArticle

Combining Feature-Based Molecular Networking and Contextual Mass Spectral Libraries to Decipher Nutrimetabolomics Profiles

by Lapo Renai, Marynka Ulaszewska, Fulvio Mattivi, Riccardo Bartoletti, Massimo Del Bubba and Justin J. J. van der Hooft

Metabolites 2022, 12(10), 1005; https://doi.org/10.3390/metabo12101005 - 21 Oct 2022

Cited by 6 | Viewed by 3600

Abstract

Untargeted metabolomics approaches deal with complex data hindering structural information for the comprehensive analysis of unknown metabolite features. We investigated the metabolite discovery capacity and the possible extension of the annotation coverage of the Feature-Based Molecular Networking (FBMN) approach by adding two novel [...] Read more.

Untargeted metabolomics approaches deal with complex data hindering structural information for the comprehensive analysis of unknown metabolite features. We investigated the metabolite discovery capacity and the possible extension of the annotation coverage of the Feature-Based Molecular Networking (FBMN) approach by adding two novel nutritionally-relevant (contextual) mass spectral libraries to the existing public ones, as compared to widely-used open-source annotation protocols. Two contextual mass spectral libraries in positive and negative ionization mode of ~300 reference molecules relevant for plant-based nutrikinetic studies were created and made publicly available through the GNPS platform. The postprandial urinary metabolome analysis within the intervention of Vaccinium supplements was selected as a case study. Following the FBMN approach in combination with the added contextual mass spectral libraries, 67 berry-related and human endogenous metabolites were annotated, achieving a structural annotation coverage comparable to or higher than existing non-commercial annotation workflows. To further exploit the quantitative data obtained within the FBMN environment, the postprandial behavior of the annotated metabolites was analyzed with Pearson product-moment correlation. This simple chemometric tool linked several molecular families with phase II and phase I metabolism. The proposed approach is a powerful strategy to employ in longitudinal studies since it reduces the unknown chemical space by boosting the annotation power to characterize biochemically relevant metabolites in human biofluids. Full article

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

► Show Figures

Graphical abstract

14 pages, 2145 KB

Open AccessEditor’s ChoiceArticle

Identification of Metabolic Signature Associated with Idiopathic Inflammatory Myopathy Reveals Polyamine Pathway Alteration in Muscle Tissue

by Jihyun Kang, Jeong Yeon Kim, Youjin Jung, Seon Uk Kim, Eun Young Lee and Joo-Youn Cho

Metabolites 2022, 12(10), 1004; https://doi.org/10.3390/metabo12101004 - 21 Oct 2022

Cited by 3 | Viewed by 2472

Abstract

Idiopathic inflammatory myopathy (IIM) is hard to diagnose without a muscle biopsy. We aimed to identify a metabolite panel for IIM detection by metabolomics approach in serum samples and to explore the metabolomic signature in tissue samples from a mouse model. We obtained [...] Read more.

Idiopathic inflammatory myopathy (IIM) is hard to diagnose without a muscle biopsy. We aimed to identify a metabolite panel for IIM detection by metabolomics approach in serum samples and to explore the metabolomic signature in tissue samples from a mouse model. We obtained serum samples from IIM patients, ankylosing spondylitis (AS) patients, healthy volunteers and muscle tissue samples from IIM murine model. All samples were subjected to a targeted metabolomic approach with various statistical analyses on serum and tissue samples to identify metabolic alterations. Three machine learning methods, such as logistic regression (LR), support vector machine (SVM), and random forest (RF), were applied to build prediction models. A set of 7 predictive metabolites was calculated using backward stepwise selection, and the model was evaluated within 5-fold cross-validation by using three machine algorithms. The model produced an area under the receiver operating characteristic curve values of 0.955 (LR), 0.908 (RF) and 0.918 (SVM). A total of 68 metabolites were significantly changed in mouse tissue. Notably, the most influential pathways contributing to the inflammation of muscle were the polyamine pathway and the beta-alanine pathway. Our metabolomic approach offers the potential biomarkers of IIM and reveals pathologically relevant metabolic pathways that are associated with IIM. Full article

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

► Show Figures

Figure 1

20 pages, 1294 KB

Open AccessEditor’s ChoiceArticle

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study

by Madis Parksepp, Liina Haring, Kalle Kilk, Egon Taalberg, Raul Kangro, Mihkel Zilmer and Eero Vasar

Metabolites 2022, 12(10), 983; https://doi.org/10.3390/metabo12100983 - 17 Oct 2022

Cited by 14 | Viewed by 2727

Abstract

The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the [...] Read more.

The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the early course of the disorder. A total of 112 adults participated in the study (54 patients with first-episode psychosis (FEP) and 58 control subjects). Biomolecule profiles were measured at the onset of first-episode psychosis and 0.6 years and 5.1 years after the initiation of APs. The results of the present study confirmed that specific metabolic–inflammatory imbalance characterizes AP-naïve patients. Short-term (0.6-years) AP treatment has a favourable effect on psychotic symptoms, as well as the recovery of metabolic flexibility and resolution of low-level inflammation. However, 5.1 years of AP treatment resulted in weight gain and increased serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-γ, hexoses, acetylcarnitine, short-chain ACs (C3, C4) and long-chain ACs (C16:2, C18:1, C18:2). In conclusion, despite the improvement in psychotic symptoms, 5.1 years of AP treatment was accompanied by a pronounced metabolic–inflammatory imbalance, which was confirmed by the presence of enhanced pro-inflammatory activity and increased obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites. Full article

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

► Show Figures

Graphical abstract

17 pages, 678 KB

Open AccessEditor’s ChoiceReview

Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment

by Spyridon Giannopoulos, Cansu Cimen Bozkus, Eleni Zografos, Aikaterini Athanasiou, Ann Marie Bongiovanni, Georgios Doulaveris, Chris N. Bakoyiannis, Georgios E. Theodoropoulos, Georgios C. Zografos, Steven S. Witkin and Theofano Orfanelli

Metabolites 2022, 12(10), 966; https://doi.org/10.3390/metabo12100966 - 12 Oct 2022

Cited by 6 | Viewed by 3209

Abstract

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied [...] Read more.

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

► Show Figures

Figure 1

19 pages, 3397 KB

Open AccessEditor’s ChoiceArticle

Multi-Omics, an Integrated Approach to Identify Novel Blood Biomarkers of Alzheimer’s Disease

by Maxime François, Avinash V. Karpe, Jian-Wei Liu, David J. Beale, Maryam Hor, Jane Hecker, Jeff Faunt, John Maddison, Sally Johns, James D. Doecke, Stephen Rose and Wayne R. Leifert

Metabolites 2022, 12(10), 949; https://doi.org/10.3390/metabo12100949 - 6 Oct 2022

Cited by 20 | Viewed by 4271

Abstract

The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD/MCI pathogenesis is unclear. This study compared the metabolomic and proteomic signature of plasma from cognitively normal [...] Read more.

The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD/MCI pathogenesis is unclear. This study compared the metabolomic and proteomic signature of plasma from cognitively normal (CN) and dementia patients diagnosed with MCI or AD, to identify specific cellular pathways and new biomarkers altered with the progression of the disease. We analysed 80 plasma samples from individuals with MCI or AD, as well as age- and gender-matched CN individuals, by utilising mass spectrometry methods and data analyses that included combined pathway analysis and model predictions. Several proteins clearly identified AD from the MCI and CN groups and included plasma actins, mannan-binding lectin serine protease 1, serum amyloid A2, fibronectin and extracellular matrix protein 1 and Keratin 9. The integrated pathway analysis showed various metabolic pathways were affected in AD, such as the arginine, alanine, aspartate, glutamate and pyruvate metabolism pathways. Therefore, our multi-omics approach identified novel plasma biomarkers for the MCI and AD groups, identified changes in metabolic processes, and may form the basis of a biomarker panel for stratifying dementia participants in future clinical trials. Full article

(This article belongs to the Special Issue Integrated Systems Biology: Challenges and Future Perspectives)

► Show Figures

Figure 1

16 pages, 1635 KB

Open AccessEditor’s ChoiceArticle

Serum Bile Acid Profiling and Mixed Model Analysis Reveal Biomarkers Associated with Pruritus Reduction in Maralixibat-Treated Patients with BSEP Deficiency

by Xueheng Zhao, Wujuan Zhang, Pamela Vig, Cory Kostrub and Kenneth D. R. Setchell

Metabolites 2022, 12(10), 952; https://doi.org/10.3390/metabo12100952 - 6 Oct 2022

Cited by 8 | Viewed by 3030

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The [...] Read more.

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The aim of this study was to determine whether specific changes in the composition of the serum bile acid metabolome could predict pruritus response to treatment. Serum BAs (sBA) and 7α-hydroxy-4-cholesten-3-one (7α-C4), a surrogate marker of BA synthesis, were monitored by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry over 72 weeks in PFIC patients with mild to moderate non-truncating bile salt export pump (BSEP) mutations (n = 19) treated with MRX. The weekly itch reported outcome observer (ItchRO[Obs]) score measured pruritus severity. Linear mixed models (LMM) were applied to explore the effects of individual sBA profiles and their relationship to pruritus response. Changes in the composition of sBA correlated with pruritus improvement. Notably, the trajectory of serum total and individual BA species and 7α-C4 were significantly associated with ItchRO[Obs] score (p < 0.05). These results reveal that beyond simple total sBA concentrations, specific changes to the BA metabolome are associated with pruritus reduction in patients with BSEP deficiency, thus providing further insight into causal relationship of bile acids and pruritus. Full article

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

► Show Figures

Graphical abstract

23 pages, 1746 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

by Heikki V. Sarin, Juha J. Hulmi, Youwen Qin, Michael Inouye, Scott C. Ritchie, Susan Cheng, Jeramie D. Watrous, Thien-Tu C. Nguyen, Joseph H. Lee, Zhezhen Jin, Joseph D. Terwilliger, Teemu Niiranen, Aki Havulinna, Veikko Salomaa, Kirsi H. Pietiläinen, Ville Isola, Juha P. Ahtiainen, Keijo Häkkinen, Mohit Jain and Markus Perola

Metabolites 2022, 12(10), 928; https://doi.org/10.3390/metabo12100928 - 30 Sep 2022

Cited by 4 | Viewed by 4576

Abstract

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial [...] Read more.

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low body fat (12.7 ± 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 ± 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects. Full article

(This article belongs to the Special Issue Effects of Exercise and Nutritional Interventions on Metabolic Health)

► Show Figures

Graphical abstract

16 pages, 2237 KB

Open AccessEditor’s ChoiceArticle

Association of Metabolic Signatures with Nonalcoholic Fatty Liver Disease in Pediatric Population

by Woori Chae, Kyung Jae Lee, Ki Young Huh, Jin Soo Moon, Jae Sung Ko and Joo-Youn Cho

Metabolites 2022, 12(9), 881; https://doi.org/10.3390/metabo12090881 - 19 Sep 2022

Cited by 7 | Viewed by 3372

Abstract

Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this [...] Read more.

Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this study, we aimed to evaluate the metabolome profile and metabolic pathway changes associated with pediatric NAFLD to elucidate its pathophysiology and to develop machine learning-based NAFLD diagnostic models. We analyzed the metabolic profiles of healthy control, lean NAFLD, overweight control, and overweight NAFLD groups of children and adolescent participants (N = 165) by assessing plasma samples. Additionally, we constructed diagnostic models by applying three machine learning methods (ElasticNet, random forest, and XGBoost) and multiple logistic regression by using NAFLD-specific metabolic features, genetic variants, and clinical data. We identified 18 NAFLD-specific metabolic features and metabolic changes in lipid, glutathione-related amino acid, and branched-chain amino acid metabolism by comparing the control and NAFLD groups in the overweight pediatric population. Additionally, we successfully developed and cross-validated diagnostic models that showed excellent diagnostic performance (ElasticNet and random forest model: area under the receiver operating characteristic curve, 0.95). Metabolome changes in the plasma of pediatric patients with NAFLD are associated with the pathophysiology of the disease and can be utilized as a less-invasive approach to diagnosing the disease. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

► Show Figures

Figure 1

13 pages, 596 KB

Open AccessEditor’s ChoiceArticle

Fecal Bile Acids and Neutral Sterols Are Associated with Latent Microbial Subgroups in the Human Gut

by Taylor A. Breuninger, Nina Wawro, Dennis Freuer, Sandra Reitmeier, Anna Artati, Harald Grallert, Jerzy Adamski, Christa Meisinger, Annette Peters, Dirk Haller and Jakob Linseisen

Metabolites 2022, 12(9), 846; https://doi.org/10.3390/metabo12090846 - 8 Sep 2022

Cited by 5 | Viewed by 2376

Abstract

Bile acids, neutral sterols, and the gut microbiome are intricately intertwined and each affects human health and metabolism. However, much is still unknown about this relationship. This analysis included 1280 participants of the KORA FF4 study. Fecal metabolites (primary and secondary bile acids, [...] Read more.

Bile acids, neutral sterols, and the gut microbiome are intricately intertwined and each affects human health and metabolism. However, much is still unknown about this relationship. This analysis included 1280 participants of the KORA FF4 study. Fecal metabolites (primary and secondary bile acids, plant and animal sterols) were analyzed using a metabolomics approach. Dirichlet regression models were used to evaluate associations between the metabolites and twenty microbial subgroups that were previously identified using latent Dirichlet allocation. Significant associations were identified between 12 of 17 primary and secondary bile acids and several of the microbial subgroups. Three subgroups showed largely positive significant associations with bile acids, and six subgroups showed mostly inverse associations with fecal bile acids. We identified a trend where microbial subgroups that were previously associated with “healthy” factors were here inversely associated with fecal bile acid levels. Conversely, subgroups that were previously associated with “unhealthy” factors were positively associated with fecal bile acid levels. These results indicate that further research is necessary regarding bile acids and microbiota composition, particularly in relation to metabolic health. Full article

(This article belongs to the Special Issue Diet, Drugs and the Gut Microbiome on the Metabolic Phenotype)

► Show Figures

Figure 1

21 pages, 803 KB

Open AccessEditor’s ChoiceArticle

Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort

by Mariana Parenti, Rebecca J. Schmidt, Sally Ozonoff, Hyeong-Moo Shin, Daniel J. Tancredi, Paula Krakowiak, Irva Hertz-Picciotto, Cheryl K. Walker and Carolyn M. Slupsky

Metabolites 2022, 12(9), 829; https://doi.org/10.3390/metabo12090829 - 2 Sep 2022

Cited by 20 | Viewed by 3798

Abstract

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and [...] Read more.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using ¹H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk. Full article

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

► Show Figures

Figure 1

14 pages, 2635 KB

Open AccessEditor’s ChoiceArticle

Site-Differentiated Iron–Sulfur Cluster Ligation Affects Flavin-Based Electron Bifurcation Activity

by Courtney E. Wise, Anastasia E. Ledinina and Carolyn E. Lubner

Metabolites 2022, 12(9), 823; https://doi.org/10.3390/metabo12090823 - 1 Sep 2022

Cited by 6 | Viewed by 2825

Abstract

Electron bifurcation is an elegant mechanism of biological energy conversion that effectively couples three different physiologically relevant substrates. As such, enzymes that perform this function often play critical roles in modulating cellular redox metabolism. One such enzyme is NADH-dependent reduced-ferredoxin: NADP⁺ oxidoreductase [...] Read more.

Electron bifurcation is an elegant mechanism of biological energy conversion that effectively couples three different physiologically relevant substrates. As such, enzymes that perform this function often play critical roles in modulating cellular redox metabolism. One such enzyme is NADH-dependent reduced-ferredoxin: NADP⁺ oxidoreductase (NfnSL), which couples the thermodynamically favorable reduction of NAD⁺ to drive the unfavorable reduction of ferredoxin from NADPH. The interaction of NfnSL with its substrates is constrained to strict stoichiometric conditions, which ensures minimal energy losses from non-productive intramolecular electron transfer reactions. However, the determinants for this are not well understood. One curious feature of NfnSL is that both initial acceptors of bifurcated electrons are unique iron–sulfur (FeS) clusters containing one non-cysteinyl ligand each. The biochemical impact and mechanistic roles of site-differentiated FeS ligands are enigmatic, despite their incidence in many redox active enzymes. Herein, we describe the biochemical study of wild-type NfnSL and a variant in which one of the site-differentiated ligands has been replaced with a cysteine. Results of dye-based steady-state kinetics experiments, substrate-binding measurements, biochemical activity assays, and assessments of electron distribution across the enzyme indicate that this site-differentiated ligand in NfnSL plays a role in maintaining fidelity of the coordinated reactions performed by the two electron transfer pathways. Given the commonality of these cofactors, our findings have broad implications beyond electron bifurcation and mechanistic biochemistry and may inform on means of modulating the redox balance of the cell for targeted metabolic engineering approaches. Full article

(This article belongs to the Special Issue The Thermodynamic Regulation of Microbial Metabolisms by Environmental Factors)

► Show Figures

Figure 1

28 pages, 3005 KB

Open AccessEditor’s ChoiceArticle

A Multi-Matrix Metabolomic Approach in Ringed Seals and Beluga Whales to Evaluate Contaminant and Climate-Related Stressors

by Antoine É. Simond, Marie Noël, Lisa Loseto, Magali Houde, Jane Kirk, Ashley Elliott and Tanya M. Brown

Metabolites 2022, 12(9), 813; https://doi.org/10.3390/metabo12090813 - 30 Aug 2022

Cited by 5 | Viewed by 3754

Abstract

As a high trophic-level species, ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) are particularly vulnerable to elevated concentrations of biomagnifying contaminants, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and mercury (Hg). These species also face [...] Read more.

As a high trophic-level species, ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) are particularly vulnerable to elevated concentrations of biomagnifying contaminants, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and mercury (Hg). These species also face climate-change-related impacts which are leading to alterations in their diet and associated contaminant exposure. The metabolomic profile of marine mammal tissues and how it changes to environmental stressors is poorly understood. This study characterizes the profiles of 235 metabolites across plasma, liver, and inner and outer blubber in adult ringed seals and beluga whales and assesses how these profiles change as a consequence of contaminants and dietary changes. In both species, inner and outer blubber were characterized by a greater proportion of lipid classes, whereas the dominant metabolites in liver and plasma were amino acids, carbohydrates, biogenic amines and lysophosphatidylcholines. Several metabolite profiles in ringed seal plasma correlated with δ¹³C, while metabolite profiles in blubber were affected by hexabromobenzene in ringed seals and PBDEs and Hg in belugas. This study provides insight into inter-matrix similarities and differences across tissues and suggests that plasma and liver are more suitable for studying changes in diet, whereas liver and blubber are more suitable for studying the impacts of contaminants. Full article

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

► Show Figures

Figure 1

15 pages, 1280 KB

Open AccessEditor’s ChoiceArticle

Bucket Fuser: Statistical Signal Extraction for 1D ¹H NMR Metabolomic Data

by Michael Altenbuchinger, Henry Berndt, Robin Kosch, Iris Lang, Jürgen Dönitz, Peter J. Oefner, Wolfram Gronwald, Helena U. Zacharias and Investigators GCKD Study

Metabolites 2022, 12(9), 812; https://doi.org/10.3390/metabo12090812 - 29 Aug 2022

Viewed by 2849

Abstract

Untargeted metabolomics is a promising tool for identifying novel disease biomarkers and unraveling underlying pathomechanisms. Nuclear magnetic resonance (NMR) spectroscopy is particularly suited for large-scale untargeted metabolomics studies due to its high reproducibility and cost effectiveness. Here, one-dimensional (1D) ¹H NMR experiments [...] Read more.

Untargeted metabolomics is a promising tool for identifying novel disease biomarkers and unraveling underlying pathomechanisms. Nuclear magnetic resonance (NMR) spectroscopy is particularly suited for large-scale untargeted metabolomics studies due to its high reproducibility and cost effectiveness. Here, one-dimensional (1D) ¹H NMR experiments offer good sensitivity at reasonable measurement times. Their subsequent data analysis requires sophisticated data preprocessing steps, including the extraction of NMR features corresponding to specific metabolites. We developed a novel 1D NMR feature extraction procedure, called Bucket Fuser (BF), which is based on a regularized regression framework with fused group LASSO terms. The performance of the BF procedure was demonstrated using three independent NMR datasets and was benchmarked against existing state-of-the-art NMR feature extraction methods. BF dynamically constructs NMR metabolite features, the widths of which can be adjusted via a regularization parameter. BF consistently improved metabolite signal extraction, as demonstrated by our correlation analyses with absolutely quantified metabolites. It also yielded a higher proportion of statistically significant metabolite features in our differential metabolite analyses. The BF algorithm is computationally efficient and it can deal with small sample sizes. In summary, the Bucket Fuser algorithm, which is available as a supplementary python code, facilitates the fast and dynamic extraction of 1D NMR signals for the improved detection of metabolic biomarkers. Full article

(This article belongs to the Special Issue Development and Application of Statistical Methods for Analyzing Metabolomics Data Volume 2)

► Show Figures

Figure 1

16 pages, 2248 KB

Open AccessEditor’s ChoiceArticle

Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients

by Sultan S. Abdelhamid, Jacob Scioscia, Yoram Vodovotz, Junru Wu, Anna Rosengart, Eunseo Sung, Syed Rahman, Robert Voinchet, Jillian Bonaroti, Shimena Li, Jennifer L. Darby, Upendra K. Kar, Matthew D. Neal, Jason Sperry, Jishnu Das and Timothy R. Billiar

Metabolites 2022, 12(9), 774; https://doi.org/10.3390/metabo12090774 - 23 Aug 2022

Cited by 14 | Viewed by 4623

Abstract

Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers [...] Read more.

Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights. Full article

(This article belongs to the Special Issue Metabolomics: An Emerging Potential Approach to Study Critical Illnesses)

► Show Figures

Graphical abstract

16 pages, 1481 KB

Open AccessEditor’s ChoiceArticle

A Sample Preparation Method for the Simultaneous Profiling of Signaling Lipids and Polar Metabolites in Small Quantities of Muscle Tissues from a Mouse Model for Sarcopenia

by Yupeng He, Marlien van Mever, Wei Yang, Luojiao Huang, Rawi Ramautar, Yvonne Rijksen, Wilbert P. Vermeij, Jan H. J. Hoeijmakers, Amy C. Harms, Peter W. Lindenburg and Thomas Hankemeier

Metabolites 2022, 12(8), 742; https://doi.org/10.3390/metabo12080742 - 12 Aug 2022

Cited by 3 | Viewed by 3250

Abstract

The metabolic profiling of a wide range of chemical classes relevant to understanding sarcopenia under conditions in which sample availability is limited, e.g., from mouse models, small muscles, or muscle biopsies, is desired. Several existing metabolomics platforms that include diverse classes of signaling [...] Read more.

The metabolic profiling of a wide range of chemical classes relevant to understanding sarcopenia under conditions in which sample availability is limited, e.g., from mouse models, small muscles, or muscle biopsies, is desired. Several existing metabolomics platforms that include diverse classes of signaling lipids, energy metabolites, and amino acids and amines would be informative for suspected biochemical pathways involved in sarcopenia. The sample limitation requires an optimized sample preparation method with minimal losses during isolation and handling and maximal accuracy and reproducibility. Here, two developed sample preparation methods, BuOH-MTBE-Water (BMW) and BuOH-MTBE-More-Water (BMMW), were evaluated and compared with previously reported methods, Bligh-Dyer (BD) and BuOH-MTBE-Citrate (BMC), for their suitability for these classes. The most optimal extraction was found to be the BMMW method, with the highest extraction recovery of 63% for the signaling lipids and 81% for polar metabolites, and an acceptable matrix effect (close to 1.0) for all metabolites of interest. The BMMW method was applied on muscle tissues as small as 5 mg (dry weight) from the well-characterized, prematurely aging, DNA repair-deficient Ercc1^∆/− mouse mutant exhibiting multiple–morbidities, including sarcopenia. We successfully detected 109 lipids and 62 polar targeted metabolites. We further investigated whether fast muscle tissue isolation is necessary for mouse sarcopenia studies. A muscle isolation procedure involving 15 min at room temperature revealed a subset of metabolites to be unstable; hence, fast sample isolation is critical, especially for more oxidative muscles. Therefore, BMMW and fast muscle tissue isolation are recommended for future sarcopenia studies. This research provides a sensitive sample preparation method for the simultaneous extraction of non-polar and polar metabolites from limited amounts of muscle tissue, supplies a stable mouse muscle tissue collection method, and methodologically supports future metabolomic mechanistic studies of sarcopenia. Full article

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

► Show Figures

Graphical abstract

15 pages, 1952 KB

Open AccessEditor’s ChoiceArticle

Tissue-Wide Expression of Genes Related to Vitamin D Metabolism and FGF23 Signaling following Variable Phosphorus Intake in Pigs

by Maruf Hasan, Michael Oster, Henry Reyer, Siriluck Ponsuksili, Eduard Murani, Petra Wolf, Dagmar-Christiane Fischer and Klaus Wimmers

Metabolites 2022, 12(8), 729; https://doi.org/10.3390/metabo12080729 - 6 Aug 2022

Cited by 11 | Viewed by 4655

Abstract

Calcium (Ca) and phosphorus (P) homeostasis is maintained by several regulators, including vitamin D and fibroblast growth factor 23 (FGF23), and their tissue-specific activation and signaling cascades. In this study, the tissue-wide expression of key genes linked to vitamin D metabolism (CYP2R1 [...] Read more.

Calcium (Ca) and phosphorus (P) homeostasis is maintained by several regulators, including vitamin D and fibroblast growth factor 23 (FGF23), and their tissue-specific activation and signaling cascades. In this study, the tissue-wide expression of key genes linked to vitamin D metabolism (CYP2R1, CYP27A1, CYP27B1, CYP24A1, GC, VDR) and FGF23 signaling (FGF23, FGFR1-4, KL) were investigated in pigs fed conventional (trial 1) and divergent P diets (trial 2). The tissue set comprised kidney, liver, bone, lung, aorta, and gastrointestinal tract sections. Expression patterns revealed that non-renal tissues and cells (NRTC) express genes to form active vitamin D [1,25(OH)₂D₃] according to site-specific requirements. A low P diet resulted in higher serum calcitriol and increased CYP24A1 expression in the small intestine, indicating local suppression of vitamin D signaling. A high P diet prompted increased mRNA abundances of CYP27B1 for local vitamin D synthesis, specifically in bone. For FGF23 signaling, analyses revealed ubiquitous expression of FGFR1-4, whereas KL was expressed in a tissue-specific manner. Dietary P supply did not affect skeletal FGF23; however, FGFR4 and KL showed increased expression in bone at high P supply, suggesting regulation to balance mineralization. Specific NRTC responses influence vitamin D metabolism and P homeostasis, which should be considered for a thrifty but healthy P supply. Full article

(This article belongs to the Special Issue Effect of Diet on Vitamin D Metabolism: Implications in Health and Disease)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI