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Discovery of Delirium Biomarkers through Minimally Invasive Serum Molecular Fingerprinting
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Utilising a Clinical Metabolomics LC-MS Study to Determine the Integrity of Biological Samples for Statistical Modelling after Long Term −80 °C Storage: A TOFI_Asia Sub-Study
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Machine Learning Metabolomics Profiling of Dietary Interventions from a Six-Week Randomised Trial
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Metabolites Associated with Polygenic Risk of Breast Cancer
Journal Description
Metabolites
Metabolites
is an international, peer-reviewed, open access journal of metabolism and metabolomics, published monthly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q2 (Biochemistry and Molecular Biology) / CiteScore - Q2 (Endocrinology, Diabetes and Metabolism)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 13.9 days after submission; acceptance to publication is undertaken in 3.5 days (median values for papers published in this journal in the first half of 2024).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Impact Factor:
3.4 (2023);
5-Year Impact Factor:
4.0 (2023)
Latest Articles
Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment
Metabolites 2024, 14(8), 413; https://doi.org/10.3390/metabo14080413 (registering DOI) - 27 Jul 2024
Abstract
Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood.
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Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches.
Full article
(This article belongs to the Section Lipid Metabolism)
Open AccessReview
Metabolic Pathways in Hydrocephalus: Profiling with Proteomics and Advanced Imaging
by
Laura May Davis and Misun Hwang
Metabolites 2024, 14(8), 412; https://doi.org/10.3390/metabo14080412 (registering DOI) - 27 Jul 2024
Abstract
Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways
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Hemorrhagic hydrocephalus is a common pathology in neonates with high mortality and morbidity. Current imaging approaches fail to capture the mechanisms behind its pathogenesis. Here, we discuss the processes underlying this pathology, the metabolic dysfunction that occurs as a result, and the ways in which these metabolic changes inform novel methods of clinical imaging. The imaging advances described allow earlier detection of the cellular and metabolic changes, leading to better outcomes for affected neonates.
Full article
(This article belongs to the Special Issue Neurometabolic Monitoring and Imaging in Pediatric Critical Care)
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Open AccessArticle
Metabolomic Profiling of Adipose Tissue in Type 2 Diabetes: Associations with Obesity and Insulin Resistance
by
Argyri Mathioudaki, Giovanni Fanni, Jan W. Eriksson and Maria J. Pereira
Metabolites 2024, 14(8), 411; https://doi.org/10.3390/metabo14080411 - 26 Jul 2024
Abstract
The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT)
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The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions.
Full article
(This article belongs to the Special Issue Metabolism in Diabetes Progression and Diabetic Complications)
Open AccessArticle
Oligomalt, a New Slowly Digestible Carbohydrate, Reduces Post-Prandial Glucose and Insulin Trajectories Compared to Maltodextrin across Different Population Characteristics: Double-Blind Randomized Controlled Trials in Healthy Individuals, People with Obesity, and People with Type 2 Diabetes
by
Odd Erik Johansen, Joel Neutel, Sanjay Gupta, Barbara Mariani, Gerhard Ufheil, Emilie Perrin, Andreas Rytz, Anirban Lahiry, Frederik Delodder, Jaclyn Lerea-Antes, Naomi Ocampo and Maximilian von Eynatten
Metabolites 2024, 14(8), 410; https://doi.org/10.3390/metabo14080410 (registering DOI) - 26 Jul 2024
Abstract
We assessed the glucometabolic effects of oligomalt, a novel fully slowly digestible carbohydrate, compared with maltodextrin, in cross-over randomized controlled trials (NCT05058144; NCT05963594) involving healthy volunteers (HV), people with overweight or obesity (PwO), and people with type 2 diabetes (T2D). We tested 33
[...] Read more.
We assessed the glucometabolic effects of oligomalt, a novel fully slowly digestible carbohydrate, compared with maltodextrin, in cross-over randomized controlled trials (NCT05058144; NCT05963594) involving healthy volunteers (HV), people with overweight or obesity (PwO), and people with type 2 diabetes (T2D). We tested 33 g and/or 50 g of oligomalt/maltodextrin, which were dissolved in 300 mL of water and consumed after fasting in the morning. The primary exploratory endpoint was the incremental area under the curve (iAUC) for postprandial glucose, assessed by frequent blood sampling over 3 h. Insulin levels were also assessed. In the HV cohort, a 4 h hydrogen breath test was performed with 15 g of inulin as a positive control. Analysis was performed by a mixed model. Oligomalt elicited a lower post-prandial glucose response compared to maltodextrin in HV (50 g, n = 15 [7 women], mean age/BMI 31 years/22.6 kg/m2), in PwO (33 g and 50 g, n = 26 [10 women], age/BMI 44 years/29.9 kg/m2, mean HbA1c 5.3%), and in people with T2D (50 g, n = 22 [13 women], age/BMI 61 years/31.8 kg/m2, HbA1c 7.4%), with significant reductions observed in PwO and T2D for the 0–1 h window (HV: −19% [p = 0.149]/PwO33g-38% [p = 0.0002]/PwO50g-28% [p = 0.0027]/T2D-38% [p < 0.0001]; the 0–2 h window (HV: −17% [p = 0.311]/PwO33g-34% [p = 0.0057]/PwO50g-21% [p = 0.0415]/T2D-37% [p < 0.0001]), and the 0–3 h window (HV: −15% [p = 0.386]/PwO33g-30% [p = 0.0213]/PwO50g0−19% [p = 0.0686]/T2D−37% [p = 0.0001]). The post-prandial insulin response was significantly lower, by 38–60%, across all populations, dose, and time points, with oligomalt. In HV, the breath-hydrogen pattern was comparable between oligomalt and maltodextrin, but increased significantly with inulin. These data support the glucometabolic advantages of oligomalt over maltodextrin, hence confirming it as a healthier carbohydrate, and underscoring its full digestibility. This therefore opens up the possibility for the incorporation of oligomalt in relevant food products/matrices.
Full article
(This article belongs to the Special Issue Impact of Macronutrients on Metabolism)
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Open AccessArticle
Epiphytic Patterns Impacting Metabolite Diversity of Drynaria roosii Rhizomes Based on Widely Targeted Metabolomics
by
Nana Chang, Xianping Yang, Xiaoqing Wang, Chao Chen, Chu Wang, Yang Xu, Hengyu Huang and Ye Wang
Metabolites 2024, 14(8), 409; https://doi.org/10.3390/metabo14080409 - 26 Jul 2024
Abstract
Drynaria roosii Nakaike, a fern widely distributed in China and some countries in Southeast Asia, is a commonly used herbal medicine in tonic diets and Chinese patented medicine. The metabolites of its dried rhizomes are easily affected by the epiphytic pattern, whether on
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Drynaria roosii Nakaike, a fern widely distributed in China and some countries in Southeast Asia, is a commonly used herbal medicine in tonic diets and Chinese patented medicine. The metabolites of its dried rhizomes are easily affected by the epiphytic pattern, whether on rock tunnels (RTs) or tree trunks (TTs). The current research focused on rhizomes from these two patterns, RTs and TTs (further divided into subclasses TA, TB, TC, and TD, based on trunk differences) and conducted a widely targeted metabolomics analysis. A total of 1435 components were identified across 13 categories, with flavonoids, amino acids, and their derivative, lipids, identified as the main components. They accounted for 19.96%, 12.07%, and 12.14% of all metabolites, respectively. The top five flavonoids in TB were eriodicty-ol-7-O-(6″-acetyl)glucoside, quercetin-3-O-sophoroside (baimaside), dihydrochar-cone-4′-O-glucoside, morin, and hesperetin-7-O-glucoside, with relative contents 76.10, 24.20, 17.02, 15.84, and 14.64 times higher than in RTs. Principal component analysis revealed that samples with different epiphytic patterns clustered into five groups. The RT patterns revealed unique metabolites that were not detected in the other four epiphytic species (TA, TB, TC, and TD), including 16 authenticated metabolites: 1 alkaloid, 1 amino acid derivative, 7 flavonoids, 2 lignans, 1 lipid, 1 alcohol, 1 aldehyde, and 2 phenolic acids. These differences in epiphytic patterns considerably affected the accumulation of both primary and secondary metabolites. The comparison of diversity between RTs and TTs can guide the selection of a cultivation substance and the grading of collective rhizomes in the wild. This comprehensive analysis of D. roosii rhizome metabolites also offers fundamental insights for identifying active components and understanding the mechanisms underlying their potential pharmacological activities.
Full article
(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics Identification of Plant Components)
Open AccessPerspective
From Hypothalamic Obesity to Metabolic Dysfunction-Associated Steatotic Liver Disease: Physiology Meets the Clinics via Metabolomics
by
Amedeo Lonardo and Ralf Weiskirchen
Metabolites 2024, 14(8), 408; https://doi.org/10.3390/metabo14080408 - 26 Jul 2024
Abstract
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Metabolic health is tightly regulated by neuro-hormonal control, and systemic metabolic dysfunction may arise from altered function of the hypothalamic–anterior pituitary axis (HAPA). Ancient experimental observations of hypothalamic obesity (HO) and liver cirrhosis occurring among animals subjected to hypothalamic injury can now be
[...] Read more.
Metabolic health is tightly regulated by neuro-hormonal control, and systemic metabolic dysfunction may arise from altered function of the hypothalamic–anterior pituitary axis (HAPA). Ancient experimental observations of hypothalamic obesity (HO) and liver cirrhosis occurring among animals subjected to hypothalamic injury can now be explained using the more recent concepts of lipotoxicity and metabolic dysfunction-associated steatotic liver disease (MASLD). Lipotoxicity, the range of abnormalities resulting from the harmful effects of fatty acids accumulated in organs outside of adipose tissue, is the common pathogenic factor underlying closely related conditions like hypothalamic syndrome, HO, and MASLD. The hormonal deficits and the array of metabolic and metabolomic disturbances that occur in cases of HO are discussed, along with the cellular and molecular mechanisms that lead, within the MASLD spectrum, from uncomplicated steatotic liver disease to steatohepatitis and cirrhosis. Emphasis is placed on knowledge gaps and how they can be addressed through novel studies. Future investigations should adopt precision medicine approaches by precisely defining the hormonal imbalances and metabolic dysfunctions involved in each individual patient with HO, thus paving the way for tailored management of MASLD that develops in the context of altered HAPA.
Full article
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Open AccessArticle
Serum Metabolomics and NF-κB Pathway Analysis Revealed the Antipyretic Mechanism of Ellagic Acid on LPS-Induced Fever in Rabbits
by
Feng-Feng Xie, Li-Ba Xu, Hua Zhu, Xiu-Qi Yu, Lin-Yu Deng, Hui-Zhen Qin and Si Lin
Metabolites 2024, 14(8), 407; https://doi.org/10.3390/metabo14080407 - 25 Jul 2024
Abstract
Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway,
[...] Read more.
Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism.
Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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Open AccessArticle
Combination of Transcriptomics and Metabolomics Analyses Provides Insights into the Mechanisms of Growth Differences in Spotted Seabass (Lateolabrax maculatus) Fed a Low-Phosphorus Diet
by
Nan Jin, Ling Wang, Kai Song, Kangle Lu, Xueshan Li and Chunxiao Zhang
Metabolites 2024, 14(8), 406; https://doi.org/10.3390/metabo14080406 - 25 Jul 2024
Abstract
To analyze the potential mechanisms of growth differences in spotted seabass (Lateolabrax maculatus) fed a low-phosphorus diet, a total of 150 spotted seabass with an initial body weight of 4.49 ± 0.01 g were used (50 fish per tank) and fed
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To analyze the potential mechanisms of growth differences in spotted seabass (Lateolabrax maculatus) fed a low-phosphorus diet, a total of 150 spotted seabass with an initial body weight of 4.49 ± 0.01 g were used (50 fish per tank) and fed a low-phosphorus diet for eight weeks. At the end of the experiment, five of the heaviest and five of the lightest fish were selected from each tank as fast-growing spotted seabass (FG) and slow-growing spotted seabass (SG), respectively, and their livers were analyzed by metabolomics and transcriptomics. The hepatic antioxidant capacity of the FG fed a low-phosphorus diet was significantly higher than that of the SG. A total of 431 differentially expressed genes (DEGs) were determined in the two groups, and most of the DEGs were involved in metabolism-related pathways such as steroid biosynthesis, glycolysis/gluconeogenesis, and protein digestion and absorption. Substance transport-related regulators and transporters were predominantly up-regulated. Furthermore, a large number of metabolites in the liver of FG were significantly up-regulated, especially amino acids, decanoyl-L-carnitine and dehydroepiandrosterone. The integration analysis of differential metabolites and genes further revealed that the interaction between protein digestion and absorption, as well as phenylalanine metabolism pathways were significantly increased in the liver of FG compared to those of the SG. In general, FG fed a low-phosphorus diet induced an enhancement in hepatic immune response, substance transport, and amino acid metabolism. This study provides new information on genetic mechanisms and regulatory pathways underlying differential growth rate and provides a basis for the foundation of efficient utilization of low-phosphorus diets and selective breeding programs for spotted seabass.
Full article
(This article belongs to the Special Issue Nutrition, Metabolism and Physiology in Aquatic Animals)
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Open AccessArticle
Serum Metabolites as Potential Markers and Predictors of Depression-like Behavior and Effective Fluoxetine Treatment in Chronically Socially Isolated Rats
by
Dragana Filipović, Julica Inderhees, Alexandra Korda, Predrag Tadić, Markus Schwaninger, Dragoš Inta and Stefan Borgwardt
Metabolites 2024, 14(8), 405; https://doi.org/10.3390/metabo14080405 - 25 Jul 2024
Abstract
Metabolic perturbation has been associated with depression. An untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry was employed to detect and measure the rat serum metabolic changes following chronic social isolation (CSIS), an animal model of depression, and effective antidepressant fluoxetine (Flx)
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Metabolic perturbation has been associated with depression. An untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry was employed to detect and measure the rat serum metabolic changes following chronic social isolation (CSIS), an animal model of depression, and effective antidepressant fluoxetine (Flx) treatment. Univariate and multivariate statistics were used for metabolic data analysis and differentially expressed metabolites (DEMs) determination. Potential markers and predictive metabolites of CSIS-induced depressive-like behavior and Flx efficacy in CSIS were evaluated by the receiver operating characteristic (ROC) curve, and machine learning (ML) algorithms, such as support vector machine with linear kernel (SVM–LK) and random forest (RF). Upregulated choline following CSIS may represent a potential marker of depressive-like behavior. Succinate, stachydrine, guanidinoacetate, kynurenic acid, and 7-methylguanine were revealed as potential markers of effective Flx treatment in CSIS rats. RF yielded better accuracy than SVM–LK (98.50% vs. 85.70%, respectively) in predicting Flx efficacy in CSIS vs. CSIS, however, it performed almost identically in classifying CSIS vs. control (75.83% and 75%, respectively). Obtained DEMs combined with ROC curve and ML algorithms provide a research strategy for assessing potential markers or predictive metabolites for the designation or classification of stress-induced depressive phenotype and mode of drug action.
Full article
Open AccessSystematic Review
Dietary Intake of Polyphenols and All-Cause Mortality: A Systematic Review with Meta-Analysis
by
Roberta Zupo, Fabio Castellana, Giuseppe Lisco, Filomena Corbo, Pasquale Crupi, Rodolfo Sardone, Francesco Panza, Madia Lozupone, Mariangela Rondanelli and Maria Lisa Clodoveo
Metabolites 2024, 14(8), 404; https://doi.org/10.3390/metabo14080404 - 25 Jul 2024
Abstract
Polyphenols are secondary metabolites found in plants, foods, and drinks, occurring in small quantities and showcasing antioxidant and anti-inflammatory qualities. The primary polyphenols consist of flavonoids, phenolic acids, stilbenes, and lignans. However, there is currently no comprehensive quantitative analysis of epidemiological data on
[...] Read more.
Polyphenols are secondary metabolites found in plants, foods, and drinks, occurring in small quantities and showcasing antioxidant and anti-inflammatory qualities. The primary polyphenols consist of flavonoids, phenolic acids, stilbenes, and lignans. However, there is currently no comprehensive quantitative analysis of epidemiological data on overall death rates. This systematic review with meta-analysis aims to identify the exposure–response relationship between dietary polyphenol intake and all-cause mortality. The literature was reviewed from its earliest study to May 2024, utilizing six distinct electronic databases. No specific criteria were used to choose participants based on the recruiting environment, their general health condition, country, or ethnicity. The inclusion criteria for studies were as follows: a longitudinal design, exposure to dietary polyphenols, all-cause mortality as the outcome, and hazard risk (HR) as the impact measure. The Newcastle–Ottawa Scale was used to evaluate the methodological rigor of the study. The hazard risks (HRs) and 95% confidence intervals (CIs) were estimated by pooling data using common effects models. A protocol has been registered on PROSPERO with the identification number CRD42024545524. The meta-analysis comprised seven cohort studies that involved 178,657 adult people aged 18 years and older. These studies examined the relationship between total dietary polyphenol consumption and the risk of all-cause death. The recruitment settings exclusively used community-based approaches, with a preference for Europe (71%) in terms of geographic distribution. The study’s quality was assessed to be moderate to high. The meta-analysis showed consistent evidence that increased dietary exposure to polyphenols reduces the risk of all-cause mortality by 7% (HR 0.93, 95% CI 0.91–0.95, I2: 48%). Pooled data from the available evidence consistently show that individuals exposed to an antioxidant diet rich in polyphenol sources may be at lower risk of all-cause mortality.
Full article
(This article belongs to the Special Issue Epidemiology, Nutrition and Metabolism, 2nd Edition)
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Open AccessArticle
Combination of Evidence from Bibliometrics and Bioinformatics Analysis Identifies miR-21 as a Potential Therapeutical Target for Diabetes
by
Yiqing Chen, Xuan Ye, Xiao Zhang, Zilin Guo, Wei Chen, Zihan Pan, Zengjie Zhang, Bing Li, Hongyun Wang and Jianhua Yao
Metabolites 2024, 14(8), 403; https://doi.org/10.3390/metabo14080403 - 25 Jul 2024
Abstract
Many microRNAs (miRNAs) have been identified as being involved in diabetes; however, the question of which ones may be the most promising therapeutical targets still needs more investigation. This study aims to understand the overall development tendency and identify a specific miRNA molecule
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Many microRNAs (miRNAs) have been identified as being involved in diabetes; however, the question of which ones may be the most promising therapeutical targets still needs more investigation. This study aims to understand the overall development tendency and identify a specific miRNA molecule to attenuate diabetes. We developed a combined analysis method based on bibliometrics and bioinformatics to visualize research institutions, authors, cited references, and keywords to identify a promising target for diabetes. Our data showed that diabetes-related miRNA is receiving continuously increasing attention, with a large number of publications, indicating that this is still a hot topic in diabetes research. Scientists from different institutions are collaborating closely in this field. miR-21, miR-146a, miR-155, and miR-34a are frequently mentioned as high-frequency keywords in the related references. Moreover, among all the above miRNAs, bioinformatics analysis further strengthens the argument that miR-21 is the top significantly upregulated molecule in diabetes patients and plays an important role in the pathogenesis of diabetes. Our study may provide a way to identify targets and promote the clinical translation of miRNA-related therapeutical strategies for diabetes, which could also indicate present and future directions for research in this area.
Full article
(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome)
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Open AccessArticle
Cultivation of Fungal Endophytes with Tissue Culture Grapevine Seedlings Reprograms Metabolism by Triggering Defence Responses
by
Xiaoxia Pan, Huizhi Liu, Yiqian Li, Lirong Guo, Yunuo Zhang, Youyong Zhu and Mingzhi Yang
Metabolites 2024, 14(8), 402; https://doi.org/10.3390/metabo14080402 - 24 Jul 2024
Abstract
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In this study, the transcriptome profiles of tissue–cultured grapevine (Vitis vinifera L. × Vitis labrusca L.: Rose Honey) seedlings inoculated with fungal endophytes Epicoccum layuense R2-21 (Epi R2-21) and Alternaria alternata XHYN2 (Alt XHYN2), were analyzed at three different time points (6
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In this study, the transcriptome profiles of tissue–cultured grapevine (Vitis vinifera L. × Vitis labrusca L.: Rose Honey) seedlings inoculated with fungal endophytes Epicoccum layuense R2-21 (Epi R2-21) and Alternaria alternata XHYN2 (Alt XHYN2), were analyzed at three different time points (6 h, 6 d, and 15 d). A total of 4783 differentially expressed genes (DEGs) was found, of which 1853 (6 h), 3878 (6 d), and 4732 (15 d) were differentially expressed relative to those of the control in endophyte Epi R2-21 treatments, while a total of 5898 DEGs, of which 2726 (6 h), 4610 (6 d), and 3938 (15 d) were differentially expressed in endophyte Alt XHYN2 treatments. DEGs enriched in secondary metabolic pathways, plant–pathogen interaction, and hormone signalling were further analysed. The upregulated DEGs in the Epi R2-21 and Alt XHYN2 treatments, both enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG), were mainly involved in flavonoid biosynthesis, phenylpropanoid biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, phenylalanine metabolism, and circadian rhythms–plant and plant–pathogen interactions, similar to the trend observed in our previous study conducted on the cultivar ‘Cabernet Sauvignon’ (Vitis vinifera L.). Taken together with the results obtained from the cultivar ‘Cabernet Sauvignon’, it was found that tissue-cultured seedlings of the cultivar ‘Rose Honey’ induced a stronger defence response to fungal endophyte infection than that of the cultivar ‘Cabernet Sauvignon’, and inoculation with the endophyte Alt XHYN2 triggered a stronger response than inoculation with the endophyte Epi R2-21. In addition, the protein–protein interaction (PPI) network revealed that the genes VIT_16s0100g00910, encoding CHS, and VIT_11s0065g00350, encoding CYP73A, were involved in secondary metabolism and thus mediated in the resistance mechanism of grapevine on both the cultivars. The results showed that inoculation with the endophytes Epi R2-21 and Alt XHYN2 had a great ability to induce defence responses and reprogram the gene expression profiles in different grapevine cultivars, which deepens our knowledge of the interaction between fungal endophytes and grapevine and gives hints for grape quality management in viticulture using candidate fungal endophytes.
Full article
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Open AccessArticle
Changes in Serum Metabolome Following Low-Energy Diet-Induced Weight Loss in Women with Overweight and Prediabetes: A PREVIEW-New Zealand Sub-Study
by
Bárbara Relva, Linda M. Samuelsson, Iola F. Duarte, Ulrike Fasol, Patrick J. B. Edwards, Mikael Fogelholm, Anne Raben, Sally D. Poppitt and Marta P. Silvestre
Metabolites 2024, 14(8), 401; https://doi.org/10.3390/metabo14080401 - 24 Jul 2024
Abstract
As obesity develops, metabolic changes increase the risk of non-communicable diseases such as type 2 diabetes (T2D). Weight loss is crucial for improving health in T2D and cardiometabolic conditions. However, weight loss rates vary between individuals, even with identical diets or energy restrictions,
[...] Read more.
As obesity develops, metabolic changes increase the risk of non-communicable diseases such as type 2 diabetes (T2D). Weight loss is crucial for improving health in T2D and cardiometabolic conditions. However, weight loss rates vary between individuals, even with identical diets or energy restrictions, highlighting the need to identify markers or predictors of weight loss success to enhance intervention outcomes. Using nuclear magnetic resonance (NMR) spectroscopy-based metabolomics, we investigated the change in serum polar metabolites in 28 women with overweight or obesity and prediabetes who completed an 8-week low-energy diet (LED) as part of the PREVIEW (PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World) clinical trial. We aimed to characterize the metabolic shift in substrate oxidation under fixed energy intake (~4 MJ/day) and its relation to weight loss success. Nine of the thirty-four serum metabolites identified significantly changed during the LED phase: 3-hydroxybutyrate, O-acetylcarnitine, 2-hydroxybutyrate, mannose, dimethyl sulfone and isobutyrate increased, whilst choline, creatine and tyrosine decreased. These results confirmed a shift towards lipid oxidation, but no metabolites predicted the response to the LED-induced weight loss. Further studies in larger populations are required to validate these metabolites as biomarkers of diet exposure.
Full article
(This article belongs to the Special Issue Diet and Nutrition in Relation to Metabolic Health)
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Open AccessArticle
Photosynthetic Activities, Phytohormones, and Secondary Metabolites Induction in Plants by Prevailing Compost Residue
by
Lord Abbey, Samuel Kwaku Asiedu, Sparsha Chada, Raphael Ofoe, Peter Ofori Amoako, Stella Owusu-Nketia, Nivethika Ajeethan, Anagha Pradeep Kumar and Efoo Bawa Nutsukpo
Metabolites 2024, 14(8), 400; https://doi.org/10.3390/metabo14080400 - 24 Jul 2024
Abstract
Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites.
[...] Read more.
Compost residue enriches soil health with the potential to enhance plant metabolism and hormonal balance, but has not yet been studied. A study was performed to determine how prevailing compost residue induces tomato (Solanum lycopersicum ‘Scotia’) plant morpho-physiology, phytohormones, and secondary metabolites. Plants were grown in soils with a previous history of annual (AN) and biennial (BI) compost amendments. The controls were soil without compost (C) amendment and municipal solid waste compost (MSWC) alone. The MSWC- and AN-plants had similar and significantly (p < 0.05) highest growth and photosynthetic activities compared to the BI- or C-plants. Total phenolics and lipid peroxidase activity were significantly (p < 0.001) high in BI-plants, while hydrogen peroxide and antioxidant capacity were significantly (p < 0.001) high in AN-plants. MSWC-plants recorded the highest cis-abscisic acid, followed by AN-, and then BI- and C-plants. Cis-zeatin, trans-zeatin, and isopentenyladenine ribosides were detected in the MSWC- and AN-plants but not in the BI- or C-plants. Furthermore, gibberellins GA53, GA19, and GA8 were high in the MSWC-plants, but only GA8 was detected in the AN plants and none in the others. Besides, MSWC plants exhibited the highest content of 1-aminocyclopropane-1-carboxylic acid. Conjugated salicylic acid was highest in the BI-plants, while jasmonic acid-isoleucine was highest in MSWC-plants and C plants. In conclusion, prevailing compost chemical residues upregulate plant growth, phytohormones, and metabolic compounds that can potentially increase plant growth and abiotic stress defense. Future work should investigate the flow of these compounds in plants under abiotic stress.
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(This article belongs to the Special Issue Plant Biotic and Abiotic Stress Responses and Tolerance: Phytohormonal and Metabolic Insights)
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Open AccessReview
Systematic Insights into the Relationship between the Microbiota–Gut–Brain Axis and Stroke with the Focus on Tryptophan Metabolism
by
Xinyu Shen and Xiaoqin Mu
Metabolites 2024, 14(8), 399; https://doi.org/10.3390/metabo14080399 - 24 Jul 2024
Abstract
Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut–brain axis as critical regulatory
[...] Read more.
Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut–brain axis as critical regulatory factors affecting stroke. Along the microbiota–gut–brain axis, tryptophan metabolism further acquires increasing attention for its intimate association with central nervous system diseases. For the purpose of exploring the potential role of tryptophan metabolism in stroke and providing systematic insights into the intricate connection of the microbiota–gut–brain axis with the pathological procedure of stroke, this review first summarized the practical relationship between microbiota and stroke by compiling the latest case-control research. Then, the microbiota–gut–brain axis, as well as its interaction with stroke, were comprehensively elucidated on the basis of the basic anatomical structure and physiological function. Based on the crosstalk of microbiota–gut–brain, we further focused on the tryptophan metabolism from the three major metabolic pathways, namely, the kynurenine pathway, serotonin pathway, and microbial pathway, within the axis. Moreover, the effects of tryptophan metabolism on stroke were appreciated and elaborated here, which is scarcely found in other reviews. Hopefully, the systematic illustration of the mechanisms and pathways along the microbiota–gut–brain axis will inspire more translational research from metabolic perspectives, along with more attention paid to tryptophan metabolism as a promising pharmaceutical target in order to reduce the risk of stroke, mitigate the stroke progression, and ameliorate the stroke prognosis.
Full article
(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)
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Open AccessArticle
Sphingolipid and Trimethylamine-N-Oxide (TMAO) Levels in Women with Obesity after Combined Physical Training
by
Camila Fernanda Cunha Brandao, Michel Krempf, Flávia Giolo de Carvalho, Audrey Aguesse, Márcia Varella Morandi Junqueira-Franco, Gabriela Batitucci, Ellen Cristini de Freitas, Natalia Yumi Noronha, Guilherme da Silva Rodrigues, Gizela Pedroso Junqueira, Diego Alcantara Borba, Stéphanie Billon-Crossouard, Mikael Croyal and Julio Sergio Marchini
Metabolites 2024, 14(8), 398; https://doi.org/10.3390/metabo14080398 - 23 Jul 2024
Abstract
Obesity causes metabolic changes, such as the development of cardiovascular diseases. Moreover, physical exercise promotes protection against these diseases. Thus, the objective of the present study was to evaluate whether combined physical training can improve the metabolic system of women with obesity, reducing
[...] Read more.
Obesity causes metabolic changes, such as the development of cardiovascular diseases. Moreover, physical exercise promotes protection against these diseases. Thus, the objective of the present study was to evaluate whether combined physical training can improve the metabolic system of women with obesity, reducing plasma concentrations of trimethylamine N-oxide (TMAO) and sphingolipids, regardless of weight loss. Fourteen obese women (BMI 30–40 kg/m2), aged 20–40 years, sedentary, were submitted to 8 weeks of combined physical training (strength and aerobic exercises). The training was performed three times/week, 55 min/session, at 75–90% maximum heart rate. All participants were evaluated pre- and post-exercise intervention, and their body composition, plasma TMAO, creatinine, lipid profile, and sphingolipid concentrations were recorded. Maximum oxygen consumption (VO2max), Speed lactate threshold 1 (SpeedLT1), and Speed lactate threshold 2 (SpeedLT2) evaluated physical performance. Results: After combined exercise, it did not change body composition, but TMAO, total cholesterol, and sphingolipid concentrations significantly decreased (p < 0.05). There was an increase in physical performance by improving VO2max, SpeedLT1, and SpeedLT2 (p < 0.05). The combined physical exercise could induce cardiovascular risk protection by decreasing TMAO in obese women, parallel to physical performance improvement, independent of weight loss.
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(This article belongs to the Special Issue Exercise Physiology and Cardiovascular Metabolism)
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Open AccessArticle
Amino Acid Profile Alterations in Phenylketonuria: Implications for Clinical Practice
by
Eliza Matuszewska, Joanna Matysiak, Łukasz Kałużny, Dariusz Walkowiak, Szymon Plewa, Monika Duś-Żuchowska, Natalia Rzetecka, Małgorzata Jamka, Agnieszka Klupczyńska-Gabryszak, Marcin Piorunek, Jan Matysiak and Jarosław Walkowiak
Metabolites 2024, 14(7), 397; https://doi.org/10.3390/metabo14070397 - 21 Jul 2024
Abstract
Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and
[...] Read more.
Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment.
Full article
(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)
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Open AccessArticle
A Multiomics, Molecular Atlas of Breast Cancer Survivors
by
Brent A. Bauer, Caleb M. Schmidt, Kathryn J. Ruddy, Janet E. Olson, Cem Meydan, Julian C. Schmidt, Sheena Y. Smith, Fergus J. Couch, John C. Earls, Nathan D. Price, Joel T. Dudley, Christopher E. Mason, Bodi Zhang, Stephen M. Phipps and Michael A. Schmidt
Metabolites 2024, 14(7), 396; https://doi.org/10.3390/metabo14070396 - 20 Jul 2024
Abstract
Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched
[...] Read more.
Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims.
Full article
(This article belongs to the Special Issue Cancer Metabolomics 2024)
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Open AccessArticle
The Severity of DSS-Induced Colitis Is Independent of the SCFA-FFAR2/3-GLP-1 Pathway Despite SCFAs Inducing GLP-1 Secretion via FFAR2/3
by
Jenna Elizabeth Hunt, Charlotte Bayer Christiansen, Mohammad Yassin, Bolette Hartmann, Stefan Offermanns, Lars Ove Dragsted, Jens Juul Holst and Hannelouise Kissow
Metabolites 2024, 14(7), 395; https://doi.org/10.3390/metabo14070395 - 20 Jul 2024
Abstract
Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and
[...] Read more.
Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content. Here, we speculated that the lowered colonic GLP-1 observed following a fiber-free diet was a consequence of decreased SCFA production and a subsequent decrease in FFAR2/3 activation. Furthermore, we explored the consequences of a fiber-free diet followed by intestinal injury, and we mechanistically explored the SCFA-FFAR2/3-GLP-1 pathway to explain the increased severity. Colonic luminal content from mice fed either a fiber-free or chow diet were analysed for SCFA content by LC–MS. FFAR2/3 receptor contributions to SCFA-mediated colonic GLP-1 secretion were assessed in isolated perfused preparations of the colon from FFAR2/3 double knockout (KO) and wild-type (WT) mice. Colitis was induced by the delivery of 3% dextran sulfate sodium (DSS) for 4 days in the drinking water of mice exposed to a fiber-free diet for 21 days. Colitis was induced by the delivery of 3% DSS for 7 days in FFAR2/3 KO mice. The removal of dietary fiber significantly decreased SCFA concentrations in the luminal contents of fiber-free fed mice compared to chow-fed mice. In the perfused colon, luminal SCFAs significantly increased colonic GLP-1 secretion in WT mice but not in FFAR2/3 KO mice. In the DSS-induced colitis model, the removal of dietary fiber increased the severity and prevented the recovery from intestinal injury. Additionally, colitis severity was similar in FFAR2/3 KO and WT mice after DSS application. In conclusion, the results confirm that the removal of dietary fiber is sufficient to decrease the colonic concentrations of SCFAs. Additionally, we show that a fiber-free diet predisposes the colon to increased intestinal injury, but this effect is independent of FFAR2 and FFAR3 signalling; therefore, it is unlikely that a fiber-free diet induces a decrease in luminal SCFAs and sensitivity to intestinal disease involves the SCFA-FFAR2/3-GLP-1 pathway.
Full article
(This article belongs to the Special Issue Role of Gut-Derived Metabolites in Health and Disease)
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Open AccessArticle
Diagnostic Potential of Alternations of Bile Acid Profiles in the Plasma of Patients with Huntington’s Disease
by
Ping-I Chiang, Kuo-Hsuan Chang, Hsiang-Yu Tang, Yih-Ru Wu, Mei-Ling Cheng and Chiung-Mei Chen
Metabolites 2024, 14(7), 394; https://doi.org/10.3390/metabo14070394 - 20 Jul 2024
Abstract
Huntington’s disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study
[...] Read more.
Huntington’s disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.
Full article
(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases)
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