Metabolites

31 pages, 401 KiB

Open AccessArticle

Replacement of Dietary Carbohydrate with Protein versus Fat Differentially Alters Postprandial Circulating Hormones and Macronutrient Metabolism in Dogs

by Matthew Irick Jackson

Metabolites 2024, 14(7), 373; https://doi.org/10.3390/metabo14070373 (registering DOI) - 30 Jun 2024

Abstract

The effect of dietary macronutrients on fasting and postprandial responses was examined. Thirty-six healthy dogs were fed a high-carbohydrate (HiCHO) food once daily for 5 weeks, followed by randomization to either a high-protein, low-carbohydrate (PROT_LoCHO) or high-fat, low-carbohydrate (FAT_LoCHO) food for 5 weeks, [...] Read more.

The effect of dietary macronutrients on fasting and postprandial responses was examined. Thirty-six healthy dogs were fed a high-carbohydrate (HiCHO) food once daily for 5 weeks, followed by randomization to either a high-protein, low-carbohydrate (PROT_LoCHO) or high-fat, low-carbohydrate (FAT_LoCHO) food for 5 weeks, then crossed over to the other LoCHO food for 5 weeks. Plasma samples were obtained at the end of each feeding period at timepoints before (0 h) and 2 h post-feeding. Apparent total circulating energy availability was assessed as a summation of the energetic contributions of measured glucose, β-hydroxybutyrate, triglycerides (TGs), non-esterified fatty acids (NEFAs), and fatty acids not from TGs or NEFAs. In both the fed and fasted states, there were increases in circulating apparent total energy availability after feeding the FAT_LoCHO food compared with the HiCHO or PROT_LoCHO foods. Changes from the postabsorptive to postprandial points in catabolic, anabolic, and signaling lipids all exhibited food effects. Consumption of either LoCHO food led to lower leptin/ghrelin ratios in the fasted state relative to the HiCHO food. The FAT_LoCHO food led to the highest postprandial levels of the incretins gastric inhibitory peptide and glucagon-like peptide-1, yet the lowest increases in insulin relative to the other foods. These findings provide information on how macronutrients can influence dietary energy processing and metabolic health. Full article

(This article belongs to the Section Nutrition and Metabolism)

30 pages, 5103 KiB

Open AccessArticle

Exploring Salivary Metabolic Alterations in Type 2 Diabetes: Implications for Dental Caries and Potential Influences of HbA1c and Vitamin D Levels

by Ashwaq Alkahtani, Martin Grootveld, Mohammed Bhogadia and Aylin Baysan

Metabolites 2024, 14(7), 372; https://doi.org/10.3390/metabo14070372 (registering DOI) - 30 Jun 2024

Abstract

Diabetes mellitus is considered to be the most common health issue affecting almost 1 in 11 adults globally. Oral health complications including xerostomia, periodontal disease, dental caries, and soft tissue lesions are prevalent among individuals with diabetes, and therefore an understanding of the [...] Read more.

Diabetes mellitus is considered to be the most common health issue affecting almost 1 in 11 adults globally. Oral health complications including xerostomia, periodontal disease, dental caries, and soft tissue lesions are prevalent among individuals with diabetes, and therefore an understanding of the potential association between salivary metabolites and dental caries progression would enable the early detection and prevention of this non-communicable disease. Therefore, the aim of this study was to compare salivary biomarkers between individuals with type 2 diabetes (T2DM) with those without this disorder (ND) using ¹H NMR-based metabolomics strategies. The objectives were to identify T2DM-associated biomarker signatures and their potential impact on dental caries. In addition, HbA1c and vitamin D levels were also analysed for this purpose. Methods: Stimulated whole-mouth saliva (SWS) samples were collected from T2DM and ND (n = 30 in each case) participants randomly selected from a group of 128 participants recruited for this case–control study. All participants were advised to refrain from eating, drinking, and smoking for at least 1–2 h prior to sample collection. Following preparation, SWS supernatants underwent ¹H NMR analysis at an operating frequency of 800 MHz, and the dataset acquired was analysed using a range of multivariate metabolomics techniques. Results: Metabolomics analysis of data acquired demonstrated that, together with up- and downregulated blood HbA1c and vitamin D levels, key salivary discriminators between these two classifications included lactate, taurine, creatinine, α-glucose, and formate to a lesser extent. The bacterial catabolites lactate and formate were both significantly upregulated in the T2DM group, and these have previously been implicated in the pathogenesis of dental caries. Significance analysis of metabolites (SAM)-facilitated AUROC analysis yielded an 83% accuracy for this distinction. Conclusion: In conclusion, this study highlights the significant differences in salivary metabolites between individuals with T2DM and healthy controls. Such differences appear to be related to the development and progression of dental caries in T2DM patients. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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12 pages, 583 KiB

Open AccessArticle

Associations of Insulin Resistance and High-Sensitivity C-Reactive Protein with Metabolic Abnormalities in Korean Patients with Type 2 Diabetes Mellitus: A Preliminary Study

by Yuchul Jeong, Beom Jun Lee, Wonjai Hur, Minjoon Lee and Se-Hyeon Han

Metabolites 2024, 14(7), 371; https://doi.org/10.3390/metabo14070371 (registering DOI) - 30 Jun 2024

Abstract

We conducted this single-center, retrospective, cohort study to examine whether insulin resistance (IR) and high-sensitivity C-reactive protein (hsCRP) have a relationship with metabolic abnormalities in patients with type 2 diabetes mellitus (T2DM). In a total of 3758 patients (n = 3758) with [...] Read more.

We conducted this single-center, retrospective, cohort study to examine whether insulin resistance (IR) and high-sensitivity C-reactive protein (hsCRP) have a relationship with metabolic abnormalities in patients with type 2 diabetes mellitus (T2DM). In a total of 3758 patients (n = 3758) with T2DM, we analyzed medical records and thereby evaluated their baseline characteristics such as age, sex, duration of T2DM, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, body mass index (BMI), visceral fat thickness (VFT), fasting plasma insulin levels, C-peptide levels, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), homeostatic model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of β-cell function (HOMA-β), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), albuminuria, intima-media thickness (IMT) and hsCRP. The patients were stratified according to the tertile of the K index of the insulin tolerance test (KITT) or hsCRP. Thus, they were divided into the lowest (≥2.37), middle (1.54–2.36) and highest tertile (0–1.53) of KITT and the lowest (0.00–0.49), middle (0.50–1.21) and highest tertile (≥1.22) of hsCRP. Moreover, associations of KITT and hsCRP with metabolic abnormalities, such as steatotic liver disease (SLD), metabolic syndrome (MetS), albuminuria, diabetic retinopathy and carotid atherosclerosis, were also analyzed. There was a significant positive correlation between the prevalence of SLD, MetS, albuminuria and diabetic retinopathy and KITT (p < 0.001). Moreover, there was a significant positive association between the prevalence of SLD, MetS and albuminuria and hsCRP (p < 0.001). In conclusion, our results indicate that clinicians should consider the relationships of IR and hsCRP with metabolic abnormalities in the management of patients with T2DM. However, further large-scale, prospective, multi-center studies are warranted to confirm our results. Full article

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

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19 pages, 1928 KiB

Open AccessArticle

Automated Liquid Handling Extraction and Rapid Quantification of Underivatized Amino Acids and Tryptophan Metabolites from Human Serum and Plasma Using Dual-Column U(H)PLC-MRM-MS and Its Application to Prostate Cancer Study

by Tobias Kipura, Madlen Hotze, Alexa Hofer, Anna-Sophia Egger, Lea E. Timpen, Christiane A. Opitz, Paul A. Townsend, Lee A. Gethings, Kathrin Thedieck and Marcel Kwiatkowski

Metabolites 2024, 14(7), 370; https://doi.org/10.3390/metabo14070370 (registering DOI) - 30 Jun 2024

Abstract

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample [...] Read more.

Amino acids (AAs) and their metabolites are important building blocks, energy sources, and signaling molecules associated with various pathological phenotypes. The quantification of AA and tryptophan (TRP) metabolites in human serum and plasma is therefore of great diagnostic interest. Therefore, robust, reproducible sample extraction and processing workflows as well as rapid, sensitive absolute quantification are required to identify candidate biomarkers and to improve screening methods. We developed a validated semi-automated robotic liquid extraction and processing workflow and a rapid method for absolute quantification of 20 free, underivatized AAs and six TRP metabolites using dual-column U(H)PLC-MRM-MS. The extraction and sample preparation workflow in a 96-well plate was optimized for robust, reproducible high sample throughput allowing for transfer of samples to the U(H)PLC autosampler directly without additional cleanup steps. The U(H)PLC-MRM-MS method, using a mixed-mode reversed-phase anion exchange column with formic acid and a high-strength silica reversed-phase column with difluoro-acetic acid as mobile phase additive, provided absolute quantification with nanomolar lower limits of quantification within 7.9 min. The semi-automated extraction workflow and dual-column U(H)PLC-MRM-MS method was applied to a human prostate cancer study and was shown to discriminate between treatment regimens and to identify metabolites responsible for discriminating between healthy controls and patients on active surveillance. Full article

(This article belongs to the Special Issue Metabolomics in Human Diseases and Health)

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16 pages, 4088 KiB

Open AccessArticle

Impaired Mitochondrial Energy Metabolism Regulated by p70S6K: A Putative Pathological Feature in Alzheimer’s Disease

by Wenyu Gu, **nli Cong, Yechun Pei, Nuela Manka’a Che Ajuyo, Yi Min and Dayong Wang

Metabolites 2024, 14(7), 369; https://doi.org/10.3390/metabo14070369 (registering DOI) - 29 Jun 2024

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease. Mitochondrial energy metabolism and p70 ribosomal protein S6 kinase (p70S6K) play significant roles in AD pathology. However, the potential relationship between them is unclear. In this study, bioinformatics methods were initially applied to analyze the transcriptomic [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease. Mitochondrial energy metabolism and p70 ribosomal protein S6 kinase (p70S6K) play significant roles in AD pathology. However, the potential relationship between them is unclear. In this study, bioinformatics methods were initially applied to analyze the transcriptomic data in the CA1 and the primary visual cortex of patients with AD and Aβ42-treated SH-SY5Y cells. By applying secreted Aβ42 and p70S6K gene silencing in cells, we explored disorders in mitochondrial function and the regulatory roles of p70S6K by flow cytometry, laser scanning confocal microscopy, high-performance liquid chromatography, Western blotting, and quantitative reverse transcription PCR. The study reveals that impaired mitochondrial energy metabolism is a potential pathological feature of AD and that p70S6K gene silencing reversed most of the changes induced by Aβ42, such as the activities of the electron transport chain complexes I and III, as well as ATP synthase, ATP production, generation of reactive oxygen species, mitochondrial membrane potential, and phosphorylation of AMPK, PINK1, and Parkin, all of which are required for mitochondria to function properly in the cell. Full article

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

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22 pages, 1500 KiB

Open AccessArticle

Identification of Anastatica hierochuntica L. Methanolic-Leaf-Extract-Derived Metabolites Exhibiting Xanthine Oxidase Inhibitory Activities: In Vitro and In Silico Approaches

by Saranya Rameshbabu, Zeyad Alehaideb, Sahar S. Alghamdi, Rasha S. Suliman, Feras Almourfi, Syed Ali Mohamed Yacoob, Anuradha Venkataraman, Safia Messaoudi and Sabine Matou-Nasri

Metabolites 2024, 14(7), 368; https://doi.org/10.3390/metabo14070368 (registering DOI) - 28 Jun 2024

Abstract

There is a growing interest in the discovery of novel xanthine oxidase inhibitors for gout prevention and treatment with fewer side effects. This study aimed to identify the xanthine oxidase (XO) inhibitory potential and drug-likeness of the metabolites present in the methanolic leaf [...] Read more.

There is a growing interest in the discovery of novel xanthine oxidase inhibitors for gout prevention and treatment with fewer side effects. This study aimed to identify the xanthine oxidase (XO) inhibitory potential and drug-likeness of the metabolites present in the methanolic leaf extract of Anastatica (A.) hierochuntica L. using in vitro and in silico models. The extract-derived metabolites were identified by liquid-chromatography–quadrupole-time-of-flight-mass-spectrometry (LC-QTOF-MS). Molecular docking predicted the XO inhibitory activity of the identified metabolites and validated the best scored in vitro XO inhibitory activities for experimental verification, as well as predictions of their anticancer, pharmacokinetic, and toxic properties; oral bioavailability; and endocrine disruption using SwissADMET, PASS, ProTox-II, and Endocrine Disruptome web servers. A total of 12 metabolites, with a majority of flavonoids, were identified. Rutin, quercetin, and luteolin flavonoids demonstrated the highest ranked docking scores of −12.39, −11.15, and −10.43, respectively, while the half-maximal inhibitory concentration (IC₅₀) values of these metabolites against XO activity were 11.35 µM, 11.1 µM, and 21.58 µM, respectively. In addition, SwissADMET generated data related to the physicochemical properties and drug-likeness of the metabolites. Similarly, the PASS, ProTox-II, and Endocrine Disruptome prediction models stated the safe and potential use of these natural compounds. However, in vivo studies are necessary to support the development of the prominent and promising therapeutic use of A. hierochuntica methanolic-leaf-extract-derived metabolites as XO inhibitors for the prevention and treatment of hyperuricemic and gout patients. Furthermore, the predicted findings of the present study open a new paradigm for these extract-derived metabolites by revealing novel oncogenic targets for the potential treatment of human malignancies. Full article

13 pages, 769 KiB

Open AccessStudy Protocol

Optimising Extracellular Vesicle Metabolomic Methodology for Prostate Cancer Biomarker Discovery

by Mahmoud Assem Hamed, Valerie Wasinger, Qi Wang, Joanna Biazik, Peter Graham, David Malouf, Joseph Bucci and Yong Li

Metabolites 2024, 14(7), 367; https://doi.org/10.3390/metabo14070367 (registering DOI) - 28 Jun 2024

Abstract

Conventional diagnostic tools for prostate cancer (PCa), such as prostate-specific antigen (PSA), transrectal ultrasound (TRUS), digital rectal examination (DRE), and tissue biopsy face, limitations in individual risk stratification due to invasiveness or reliability issues. Liquid biopsy is a less invasive and more accurate [...] Read more.

Conventional diagnostic tools for prostate cancer (PCa), such as prostate-specific antigen (PSA), transrectal ultrasound (TRUS), digital rectal examination (DRE), and tissue biopsy face, limitations in individual risk stratification due to invasiveness or reliability issues. Liquid biopsy is a less invasive and more accurate alternative. Metabolomic analysis of extracellular vesicles (EVs) holds a promise for detecting non-genetic alterations and biomarkers in PCa diagnosis and risk assessment. The current research gap in PCa lies in the lack of accurate biomarkers for early diagnosis and real-time monitoring of cancer progression or metastasis. Establishing a suitable approach for observing dynamic EV metabolic alterations that often occur earlier than being detectable by other omics technologies makes metabolomics valuable for early diagnosis and monitoring of PCa. Using four distinct metabolite extraction approaches, the metabolite cargo of PC3-derived large extracellular vesicles (lEVs) was evaluated using a combination of methanol, cell shearing using microbeads, and size exclusion filtration, as well as two fractionation chemistries (pHILIC and C18 chromatography) that are also examined. The unfiltered methanol–microbeads approach (MB-UF), followed by pHILIC LC-MS/MS for EV metabolite extraction and analysis, is effective. Identified metabolites such as L-glutamic acid, pyruvic acid, lactic acid, and methylmalonic acid have important links to PCa and are discussed. Our study, for the first time, has comprehensively evaluated the extraction and separation methods with a view to downstream sample integrity across omics platforms, and it presents an optimised protocol for EV metabolomics in PCa biomarker discovery. Full article

(This article belongs to the Section Advances in Metabolomics)

21 pages, 2117 KiB

Open AccessReview

NAFLD/MASLD and the Gut–Liver Axis: From Pathogenesis to Treatment Options

by Natalia G. Vallianou, Dimitris Kounatidis, Sotiria Psallida, Nikolaos Vythoulkas-Biotis, Andreas Adamou, Tatiana Zachariadou, Sofia Kargioti, Irene Karampela and Maria Dalamaga

Metabolites 2024, 14(7), 366; https://doi.org/10.3390/metabo14070366 - 28 Jun 2024

Abstract

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). The introduction of this new terminology has sparked a debate about the interchangeability of these terms. The pathogenesis of NAFLD/MASLD is thought to be multifactorial, involving both genetic and environmental factors. Among these factors, alterations in gut microbiota and gut dysbiosis have recently garnered significant attention. In this context, this review will further discuss the gut–liver axis, which refers to the bidirectional interaction between the human gut microbiota and the liver. Additionally, the therapeutic potential of probiotics, particularly next-generation probiotics and genetically engineered bacteria, will be explored. Moreover, the role of prebiotics, synbiotics, postbiotics, and phages as well as fecal microbiota transplantation will be analyzed. Particularly for lean patients with NAFLD/MASLD, who have limited treatment options, approaches that modify the diversity and composition of the gut microbiota may hold promise. However, due to ongoing safety concerns with approaches that modulate gut microbiota, further large-scale studies are necessary to better assess their efficacy and safety in treating NAFLD/MASLD. Full article

(This article belongs to the Special Issue New Insights into Gut Microbiota and Obesity)

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23 pages, 1784 KiB

Open AccessReview

Current State, Challenges, and Opportunities in Genome-Scale Resource Allocation Models: A Mathematical Perspective

by Wheaton L. Schroeder, Patrick F. Suthers, Thomas C. Willis, Eric J. Mooney and Costas D. Maranas

Metabolites 2024, 14(7), 365; https://doi.org/10.3390/metabo14070365 - 28 Jun 2024

Abstract

Stoichiometric genome-scale metabolic models (generally abbreviated GSM, GSMM, or GEM) have had many applications in exploring phenotypes and guiding metabolic engineering interventions. Nevertheless, these models and predictions thereof can become limited as they do not directly account for protein cost, enzyme kinetics, and [...] Read more.

Stoichiometric genome-scale metabolic models (generally abbreviated GSM, GSMM, or GEM) have had many applications in exploring phenotypes and guiding metabolic engineering interventions. Nevertheless, these models and predictions thereof can become limited as they do not directly account for protein cost, enzyme kinetics, and cell surface or volume proteome limitations. Lack of such mechanistic detail could lead to overly optimistic predictions and engineered strains. Initial efforts to correct these deficiencies were by the application of precursor tools for GSMs, such as flux balance analysis with molecular crowding. In the past decade, several frameworks have been introduced to incorporate proteome-related limitations using a genome-scale stoichiometric model as the reconstruction basis, which herein are called resource allocation models (RAMs). This review provides a broad overview of representative or commonly used existing RAM frameworks. This review discusses increasingly complex models, beginning with stoichiometric models to precursor to RAM frameworks to existing RAM frameworks. RAM frameworks are broadly divided into two categories: coarse-grained and fine-grained, with different strengths and challenges. Discussion includes pinpointing their utility, data needs, highlighting framework strengths and limitations, and appropriateness to various research endeavors, largely through contrasting their mathematical frameworks. Finally, promising future applications of RAMs are discussed. Full article

(This article belongs to the Special Issue Recent Developments and Emerging Trends in Metabolic Modelling and Metabolomics)

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23 pages, 2920 KiB

Open AccessArticle

Physicochemical Characterization of Moroccan Honey Varieties from the Fez-Meknes Region and Their Antioxidant and Antibacterial Properties

by Atika Ailli, Khalid Zibouh, Brahim Eddamsyry, Aziz Drioiche, Dounia Fetjah, Fatima Zahra Ayyad, Ramzi A. Mothana, Mohammed F. Hawwal, Mohamed Radi, Redouane Tarik, Abdelhakim Elomri, Aicha Mouradi and Touriya Zair

Metabolites 2024, 14(7), 364; https://doi.org/10.3390/metabo14070364 - 27 Jun 2024

Abstract

Honey, with its varied and extensive characteristics, is a complex and diverse biological substance that has been used since ancient times. The aim of this study is to thoroughly characterize the physicochemical, phytochemical, and biological properties of four floral honey varieties from the [...] Read more.

Honey, with its varied and extensive characteristics, is a complex and diverse biological substance that has been used since ancient times. The aim of this study is to thoroughly characterize the physicochemical, phytochemical, and biological properties of four floral honey varieties from the Fez-Meknes region in Morocco, with the goal of promoting the valorization of Moroccan honey in skincare and cosmetic products. The analyses of their physicochemical characteristics encompass various parameters such as pH, acidity, density, water content, Brix index, conductivity, ash content, hydroxymethylfurfural (HMF) content, and color. The levels of polyphenols range from 22.1 ± 0.4 to 69.3 ± 0.17 mg GAE/100 g of honey, measured using the Folin–Ciocalteu method for polyphenol quantification. Additionally, the estimation of flavonoid quantities in 100 g of honey, conducted using the aluminum trichloride method, reveals values ranging from 3.6 ± 0.2 to 7.2 ± 0.6 mg QE. Furthermore, it is noteworthy that honey exhibits high levels of glucose and relatively low concentrations of proteins. The quantitative evaluation of antioxidant effects, carried out through the 2,2-diphenyl-1-picrylhydrazyl free-radical-scavenging method and the ferric-reducing antioxidant power (FRAP) method, highlights the strong antioxidant capacity of multifloral honey, characterized by low inhibitory concentration values (IC₅₀ = 30.43 mg/mL and EC₅₀ = 16.06 mg/mL). Moreover, all honey varieties demonstrate antibacterial and antifungal properties, with multifloral honey standing out for its particularly pronounced antimicrobial activity. The correlation analyses between phytochemical composition and antioxidant and antibacterial activities reveal an inverse relationship between polyphenols and IC₅₀ (DPPH) and EC₅₀ (FRAP) concentrations of honey. The correlation coefficients are established at R² = −0.97 and R² = −0.99, respectively. Additionally, a significant negative correlation is observed between polyphenols, flavonoids, and antifungal power (R² = −0.95 and R² = −0.96). In parallel, a marked positive correlation is highlighted between antifungal efficacy, DPPH antioxidant activity (R² = 0.95), and FRAP (R² = 0.92). These results underscore the crucial importance of phytochemical components in the beneficial properties of honey, meeting international quality standards. Consequently, honey could serve as a natural alternative to synthetic additives. Full article

(This article belongs to the Special Issue Bioactive Compounds in Animal Nutrition Resources and Animal By-Products)

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17 pages, 482 KiB

Open AccessReview

The Effect of L-Carnitine on Critical Illnesses Such as Traumatic Brain Injury (TBI), Acute Kidney Injury (AKI), and Hyperammonemia (HA)

by Bharti Sharma, Lee Schmidt, Cecilia Nguyen, Samantha Kiernan, Jacob Dexter-Meldrum, Zachary Kuschner, Scott Ellis, Navin D. Bhatia, George Agriantonis, Jennifer Whittington and Kate Twelker

Metabolites 2024, 14(7), 363; https://doi.org/10.3390/metabo14070363 - 27 Jun 2024

Abstract

L-carnitine (LC) through diet is highly beneficial for critical patients. Studies have found that acetyl-L-carnitine (ALC) can reduce cerebral edema and neurological complications in TBI patients. It significantly improves their neurobehavioral and neurocognitive functions. ALC has also been shown to have a neuroprotective [...] Read more.

L-carnitine (LC) through diet is highly beneficial for critical patients. Studies have found that acetyl-L-carnitine (ALC) can reduce cerebral edema and neurological complications in TBI patients. It significantly improves their neurobehavioral and neurocognitive functions. ALC has also been shown to have a neuroprotective effect in cases of global and focal cerebral ischemia. Moreover, it is an effective agent in reducing nephrotoxicity by suppressing downstream mitochondrial fragmentation. LC can reduce the severity of renal ischemia-reperfusion injury, renal cast formation, tubular necrosis, iron accumulation in the tubular epithelium, CK activity, urea levels, Cr levels, and MDA levels and restore the function of enzymes such as SOD, catalase, and GPx. LC can also be administered to patients with hyperammonemia (HA), as it can suppress ammonia levels. It is important to note, however, that LC levels are dysregulated in various conditions such as aging, cirrhosis, cardiomyopathy, malnutrition, sepsis, endocrine disorders, diabetes, trauma, starvation, obesity, and medication interactions. There is limited research on the effects of LC supplementation in critical illnesses such as TBI, AKI, and HA. This scarcity of studies highlights the need for further research in this area. Full article

(This article belongs to the Special Issue Impact of Food and Bioactive Compounds on Metabolic Diseases)

18 pages, 2035 KiB

Open AccessArticle

miR-21/SMAD2 Is Involved in the Decrease in Progesterone Synthesis Caused by Lipopolysaccharide Exposure in Follicular Granulosa Cells of Laying Goose

by ** **ao, Hao An, Rihong Guo, Zichun Dai and Wenda Wu

Metabolites 2024, 14(7), 362; https://doi.org/10.3390/metabo14070362 - 27 Jun 2024

Abstract

Lipopolysaccharide (LPS) is one of the important pathogenic substances of E. coli and Salmonella, which causes injury to the reproductive system. Ovarian dysfunction due to Gram-negative bacterial infections is a major cause of reduced reproductive performance in geese. However, the specific molecular [...] Read more.

Lipopolysaccharide (LPS) is one of the important pathogenic substances of E. coli and Salmonella, which causes injury to the reproductive system. Ovarian dysfunction due to Gram-negative bacterial infections is a major cause of reduced reproductive performance in geese. However, the specific molecular mechanisms of LPS-induced impairment of sex steroid hormone synthesis have not been determined. The regulatory mechanism of miRNA has been proposed in many physiological and pathogenic mechanisms. Therefore, the role of miRNA in breeding geese exposed to LPS during the peak laying period was investigated. In this study, twenty Yangzhou geese at peak laying period were injected with LPS for 0 h, 24 h, and 36 h. The follicular granulosa layer was taken for RNA-seq and analyzed for differentially expressed miRNAs. It was observed that LPS changed the appearance of hierarchical follicles. miRNA sequencing analysis was applied, and miR-21 and SMAD2 (SMAD family member 2) were selected from 51 differentially expressed miRNAs through bioinformatics prediction. The results showed that miR-21 down-regulated SMAD2 expression and progesterone (P4) production in LPS-treated goose granulosa cells (GCs). It also determined that overexpression of miR-21 or silence of SMAD2 suppressed the sex steroid biosynthesis pathway by decreasing STAR and CYP11A1 expression. Down-regulation of miR-21 exacerbates the LPS-induced decline in P4 synthesis and vice versa. The findings indicated that miR-21 was involved in LPS regulation of P4 synthesis in goose granulosa cells by down-regulating SMAD2. This study provides theoretical support for the prevention of LPS-induced ovarian dysfunction in geese. Full article

(This article belongs to the Special Issue Animal Nutritional Metabolism and Toxicosis Disease)

18 pages, 337 KiB

Open AccessReview

Association of DNA Methylation with Infant Birth Weight in Women with Gestational Diabetes

by Renata Saucedo, Aldo Ferreira-Hermosillo, Magalhi Robledo-Clemente, Mary Flor Díaz-Velázquez and Jorge Valencia-Ortega

Metabolites 2024, 14(7), 361; https://doi.org/10.3390/metabo14070361 - 27 Jun 2024

Abstract

Offspring exposed to gestational diabetes mellitus (GDM) exhibit greater adiposity at birth. This early-life phenotype may increase offspring risk of develo** obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease later in life. Infants born to women with GDM have a dysregulation of [...] Read more.

Offspring exposed to gestational diabetes mellitus (GDM) exhibit greater adiposity at birth. This early-life phenotype may increase offspring risk of develo** obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease later in life. Infants born to women with GDM have a dysregulation of several hormones, cytokines, and growth factors related to fetal fat mass growth. One of the molecular mechanisms of GDM influencing these factors is epigenetic alterations, such as DNA methylation (DNAm). This review will examine the role of DNAm as a potential biomarker for monitoring fetal growth during pregnancy in women with GDM. This information is relevant since it may provide useful new biomarkers for the diagnosis, prognosis, and treatment of fetal growth and its later-life health consequences. Full article

(This article belongs to the Special Issue Adipose Tissue, Reproduction and Metabolic Health in Women)

12 pages, 989 KiB

Open AccessArticle

A Novel UHPLC-MS/MS Based Method for Isomeric Separation and Quantitative Determination of Cyanogenic Glycosides in American Elderberry

by Deepak M. Kasote, Zhentian Lei, Clayton D. Kranawetter, Ashley Conway-Anderson, Barbara W. Sumner and Lloyd W. Sumner

Metabolites 2024, 14(7), 360; https://doi.org/10.3390/metabo14070360 - 26 Jun 2024

Abstract

LC-MS/MS analyses have been reported as challenging for the reliable separation and quantification of cyanogenic glycosides (CNGs), especially (R)-prunasin and sambunigrin isomers found in American elderberry (Sambucus nigra L. subsp. canadensis (L.) Bolli). Hence, a novel multiple reaction monitoring (MRM)-based [...] Read more.

LC-MS/MS analyses have been reported as challenging for the reliable separation and quantification of cyanogenic glycosides (CNGs), especially (R)-prunasin and sambunigrin isomers found in American elderberry (Sambucus nigra L. subsp. canadensis (L.) Bolli). Hence, a novel multiple reaction monitoring (MRM)-based ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated in the present study for simultaneous separation and quantification of five CNGs, including amygdalin, dhurrin, linamarin, (R)-prunasin, and (S)-prunasin (commonly referred to as sambunigrin). Initially, the role of ammonium formate was investigated as an aqueous mobile-phase additive in develo** MRM-based UHPLC-MS/MS. Later, chromatographic conditions for the resolved separation of (R)-prunasin and sambunigrin were identified. Validation studies confirmed that the developed method has good linearity and acceptable precision and accuracy. A noticeable matrix effect (mainly signal enhancement) was observed in leaf samples only. This method was used to detect and quantify CNGs, including (R)-prunasin and sambunigrin, in leaf and fruit samples of American elderberry. Among the studied CNGs, only (R)-prunasin was detected in the leaf samples. Interestingly, (S)-prunasin (sambunigrin) was not detected in the samples analyzed, even though it has been previously reported in elderberry species. Full article

(This article belongs to the Topic Advances in Separation Methods for Metabolomics and Lipidomics)

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14 pages, 3930 KiB

Open AccessArticle

Investigation of Rhizopus oligosporus Metabolites in Fermented Wheat Bran and Its Bio Function in Alleviating Colitis in Mice Model

by Afifah Zahra Agista, Yu-Shan Chien, Takuya Koseki, Hazuki Nagaoka, Takuto Ohnuma, Yusuke Ohsaki, Chiu-Li Yeh, Suh-Ching Yang, Ardiansyah, Slamet Budijanto, Michio Komai and Hitoshi Shirakawa

Metabolites 2024, 14(7), 359; https://doi.org/10.3390/metabo14070359 - 26 Jun 2024

Abstract

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control [...] Read more.

Wheat bran (WB) is a low-value by-product of the wheat milling industry. Solid-state fermentation with Rhizopus oligosporus is performed to improve WB’s nutritional quality (RH). Twenty-five mice (11-week-old C57BL/6N male mice) were divided into three groups. The first group was fed a control diet (n = 8), the second group a 10% WB-supplemented diet (n = 8), and the last group had a 10% RH-supplemented diet (n = 9). The diet treatment was administered for 4 days before dextran sodium sulfate (DSS, 3% in drinking water) was administered for 9 days. RH supplementation prevented bodyweight loss and reduced the disease activity index in mice. An increase in the level of SCFAs in mouse intestines was detected post-RH supplementation, suggesting that SCFAs might have contributed to its anti-colitis effect. Metabolome analysis was conducted to explore other bioactive compounds in RH. R. oligosporus fermentation significantly increased the amounts of ergothioneine, arginine, branched-chain amino acids, and adenosine in wheat bran. All of these compounds are known to have antioxidant and anti-inflammatory capacities. These bioactive compounds might also have contributed to the RH’s ability to ameliorate DSS-induced colitis. Full article

(This article belongs to the Special Issue Emerging Applications of Metabolomics in Fermented Food)

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26 pages, 2507 KiB

Open AccessArticle

Comparison of Ten Surrogate Insulin Resistance and Obesity Markers to Identify Metabolic Syndrome in Mexican Adults

by Iván Filiberto Contreras-Hernández, Cruz Vargas-De-León, Luis Rey García-Cortes, Adriana Flores-Miranda, Rodrigo Romero-Nava and María Esther Ocharán-Hernández

Metabolites 2024, 14(7), 358; https://doi.org/10.3390/metabo14070358 - 26 Jun 2024

Abstract

Metabolic syndrome (MetS) is a group of clinical traits directly linked to type 2 diabetes mellitus and cardiovascular diseases, whose prevalence has been rising nationally and internationally. We aimed to evaluate ten known and novel surrogate markers of insulin resistance and [...] Read more.

Metabolic syndrome (MetS) is a group of clinical traits directly linked to type 2 diabetes mellitus and cardiovascular diseases, whose prevalence has been rising nationally and internationally. We aimed to evaluate ten known and novel surrogate markers of insulin resistance and obesity to identify MetS in Mexican adults. The present cross-sectional study analyzed 10575 participants from ENSANUT-2018. The diagnosis of MetS was based on the Adult Treatment Panel III (ATP III) criteria and International Diabetes Federation (IDF) criteria, stratified by sex and age group. According to ATP III, the best biomarker was the metabolic score for insulin resistance (METS-IR) in men aged 20–39 and 40–59 years and lipid accumulation product (LAP) in those aged ≥60 years. The best biomarker was LAP in women aged 20–39 and triglyceride–glucose index (TyG) in those aged 40–59 and ≥60 years. Using the IDF criteria, the best biomarker was LAP in men of all ages. TyG gave the best results in women of all ages. The best biomarker for diagnosis of MetS in Mexican adults depends on the criteria, including sex and age group. LAP and TyG are easy to obtain, inexpensive, and especially useful at the primary care level. Full article

19 pages, 4982 KiB

Open AccessArticle

Skeletal Muscle Metabolism Is Dynamic during Porcine Postnatal Growth

by Linnea A. Rimmer, Erika R. Geisbrecht, Michael D. Chao, Travis G. O’Quinn, Jason C. Woodworth and Morgan D. Zumbaugh

Metabolites 2024, 14(7), 357; https://doi.org/10.3390/metabo14070357 - 26 Jun 2024

Abstract

Skeletal muscle metabolism has implications for swine feed efficiency (FE); however, it remains unclear if the metabolic profile of skeletal muscle changes during postnatal growth. To assess the metabolic changes, samples were collected from the longissimus dorsi (LD, glycolytic muscle), latissimus dorsi (LAT, [...] Read more.

Skeletal muscle metabolism has implications for swine feed efficiency (FE); however, it remains unclear if the metabolic profile of skeletal muscle changes during postnatal growth. To assess the metabolic changes, samples were collected from the longissimus dorsi (LD, glycolytic muscle), latissimus dorsi (LAT, mixed muscle), and masseter (MS, oxidative muscle) at 20, 53, 87, 120, and 180 days of age from barrows. Muscles were assessed to determine the abundance of several metabolic enzymes. Lactate dehydrogenase (LDHα) decreased in all muscles from 20 to 87 d (p < 0.01), which may be attributed to the muscles being more glycolytic at weaning from a milk-based diet. Pyruvate carboxylase (PC) increased in all muscles at 53 d compared to the other time points (p < 0.01), while pyruvate dehydrogenase α 1 (PDHα1) increased at 87 and 180 d in MS compared to LD (p < 0.05), indicating that potential changes occur in pyruvate entry into the tricarboxylic acid (TCA) cycle during growth. Isolated mitochondria from each muscle were incubated with ¹³C-labeled metabolites to assess isotopomer enrichment patterns of TCA intermediates. Citrate M + 2 and M + 4 derived from [¹³C₃]-pyruvate increased at 87 d in LAT and MS mitochondria compared to LD mitochondria (p < 0.05). Regardless of the muscle, citrate M+3 increased at 87 d compared to 20, 53, and 120 d, while 180 d showed intermediate values (p < 0.01). These data support the notion that pyruvate metabolism is dynamic during growth. Our findings establish a metabolic fingerprint associated with postnatal muscle hypertrophy. Full article

(This article belongs to the Special Issue Unlocking the Mysteries of Muscle Metabolism in the Animal Sciences)

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17 pages, 3018 KiB

Open AccessArticle

Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis

by Petra Parvanovova, Petra Hnilicova, Martin Kolisek, Zuzana Tatarkova, Erika Halasova, Egon Kurca, Simona Holubcikova, Monika Turcanova Koprusakova and Eva Baranovicova

Metabolites 2024, 14(7), 356; https://doi.org/10.3390/metabo14070356 - 23 Jun 2024

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew’s correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model. Full article

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

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23 pages, 1088 KiB

Open AccessReview

The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome

by Stephanie Venn-Watson

Metabolites 2024, 14(7), 355; https://doi.org/10.3390/metabo14070355 - 23 Jun 2024

Abstract

Ferroptosis is a newly discovered form of cell death caused by the peroxidation of fragile fatty acids in cell membranes, which combines with iron to increase reactive oxygen species and disable mitochondria. Ferroptosis has been linked to aging-related conditions, including type 2 diabetes, [...] Read more.

Ferroptosis is a newly discovered form of cell death caused by the peroxidation of fragile fatty acids in cell membranes, which combines with iron to increase reactive oxygen species and disable mitochondria. Ferroptosis has been linked to aging-related conditions, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Pentadecanoic acid (C15:0), an odd-chain saturated fat, is an essential fatty acid with the primary roles of stabilizing cell membranes and repairing mitochondrial function. By doing so, C15:0 reverses the underpinnings of ferroptosis. Under the proposed “Cellular Stability Hypothesis”, evidence is provided to show that cell membranes optimally need >0.4% to 0.64% C15:0 to support long-term health and longevity. A pathophysiology of a newly identified nutritional C15:0 deficiency syndrome (“Cellular Fragility Syndrome”) is provided that demonstrates how C15:0 deficiencies (≤0.2% total circulating fatty acids) can increase susceptibilities to ferroptosis, dysmetabolic iron overload syndrome, type 2 diabetes, cardiovascular disease, and NAFLD. Further, evidence is provided that C15:0 supplementation can reverse the described C15:0 deficiency syndrome, including the key components of ferroptosis. Given the declining dietary intake of C15:0, especially among younger generations, there is a need for extensive studies to understand the potential breadth of Cellular Fragility Syndrome across populations. Full article

(This article belongs to the Special Issue Impact of Macronutrients on Metabolism)

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