Metabolites

20 pages, 2023 KiB

Open AccessReview

Potential of Chlorogenic Acid in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Animal Studies and Clinical Trials—A Narrative Review

by Agnieszka Ziółkiewicz, Przemysław Niziński, Jakub Soja, Tomasz Oniszczuk, Maciej Combrzyński, Adrianna Kondracka and Anna Oniszczuk

Metabolites 2024, 14(6), 346; https://doi.org/10.3390/metabo14060346 - 20 Jun 2024

Viewed by 282

Abstract

Chlorogenic acid (CGA) is a natural polyphenol found in coffee, tea, vegetables, and fruits. It exhibits strong antioxidant activity and possesses several other biological properties, including anti-inflammatory effects, antimicrobial activity, and insulin-sensitizing properties. Moreover, it may improve lipid and glucose metabolism. This review [...] Read more.

Chlorogenic acid (CGA) is a natural polyphenol found in coffee, tea, vegetables, and fruits. It exhibits strong antioxidant activity and possesses several other biological properties, including anti-inflammatory effects, antimicrobial activity, and insulin-sensitizing properties. Moreover, it may improve lipid and glucose metabolism. This review summarizes the available information on the therapeutic effect of CGA in metabolic dysfunction-associated steatotic liver disease (MASLD). As the literature search engine, the browsers in the PubMed, Scopus, Web of Science databases, and ClinicalTrials.gov register were used. Animal trials and clinical studies suggest that CGA has promising therapeutic potential in treating MASLD and hepatic steatosis. Its mechanisms of action include antioxidant, anti-inflammatory, and anti-apoptotic effects via the activation of the Nrf2 signaling pathway and the inhibition of the TLR4/NF-κB signaling cascade. Furthermore, the alleviation of liver disease by CGA also involves other important molecules such as AMPK and important physiological processes such as the intestinal barrier and gut microbiota. Nevertheless, the specific target cell and key molecule to which CGA is directed remain unidentified and require further study. Full article

(This article belongs to the Special Issue Effects of Bioactive Compounds on Metabolic Syndrome)

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16 pages, 9806 KiB

Open AccessArticle

Insight into Fructose-to-Sucrose Ratio as the Potential Target of Urinalysis in Bladder Cancer

by Dewang Zhou, Jianxu Huang, Haoxiang Zheng, Yujun Liu, Shimao Zhu and Yang Du

Metabolites 2024, 14(6), 345; https://doi.org/10.3390/metabo14060345 - 20 Jun 2024

Viewed by 281

Abstract

Bladder cancer usually has been diagnosed in elderly patients as it stays asymptomatic until it presents. Current detection methods for bladder cancer cannot be considered as an adequate screening strategy due to their high invasiveness and low sensitivity. However, there remains uncertainty about [...] Read more.

Bladder cancer usually has been diagnosed in elderly patients as it stays asymptomatic until it presents. Current detection methods for bladder cancer cannot be considered as an adequate screening strategy due to their high invasiveness and low sensitivity. However, there remains uncertainty about targets with high sensitivity and specificity for non-invasive bladder cancer examination. Our study aims to investigate the actionable non-invasive screening biomarkers in bladder cancer. Here, we employed scRNA-seq to explore the crucial biological processes for bladder cancer development. We then utilized bidirectional Mendelian randomization (MR) analysis to explore the bidirectional causal relationship between ATP-associated metabolites in urine and bladder cancer. Lastly, we used a BBN-induced mouse model of bladder cancer to validate the crucial gene identified by scRNA-seq and MR analysis. We found that (1) the ATP metabolism process plays a critical role in bladder cancer development; (2) there is a bidirectional and negative causal relationship between fructose-to-sucrose ratio in urine and the risk of bladder cancer; and (3) the higher expression of TPI1, a critical gene in the fructose metabolism pathway, was validated in BBN-induced bladder tumors. Our results reveal that fructose-to-sucrose ratio can serve as a potential target of urinalysis in bladder cancer. Full article

(This article belongs to the Special Issue New Biomarkers for Diagnostics in Metabolic Diseases)

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15 pages, 1097 KiB

Open AccessReview

The Impact of Weight Cycling on Health and Obesity

by Huan Wang, Wenbi He, Gaoyuan Yang, Lin Zhu and Xiaoguang Liu

Metabolites 2024, 14(6), 344; https://doi.org/10.3390/metabo14060344 - 19 Jun 2024

Viewed by 443

Abstract

Obesity is a systemic and chronic inflammation, which seriously endangers people’s health. People tend to diet to control weight, and the short-term effect of dieting in losing weight is significant, but the prognosis is limited. With weight loss and recovery occurring frequently, people [...] Read more.

Obesity is a systemic and chronic inflammation, which seriously endangers people’s health. People tend to diet to control weight, and the short-term effect of dieting in losing weight is significant, but the prognosis is limited. With weight loss and recovery occurring frequently, people focus on weight cycling. The effect of weight cycling on a certain tissue of the body also has different conclusions. Therefore, this article systematically reviews the effects of body weight cycling on the body and finds that multiple weight cycling (1) increased fat deposition in central areas, lean mass decreased in weight loss period, and fat mass increased in weight recovery period, which harms body composition and skeletal muscle mass; (2) enhanced the inflammatory response of adipose tissue, macrophages infiltrated into adipose tissue, and increased the production of pro-inflammatory mediators in adipocytes; (3) blood glucose concentration mutation and hyperinsulinemia caused the increase or decrease in pancreatic β-cell population, which makes β-cell fatigue and leads to β-cell failure; (4) resulted in additional burden on the cardiovascular system because of cardiovascular rick escalation. Physical activity combined with calorie restriction can effectively reduce metabolic disease and chronic inflammation, alleviating the adverse effects of weight cycling on the body. Full article

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27 pages, 688 KiB

Open AccessReview

Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions

by Jing-Jing Li, Wei-Dong Sun, Xiao-Juan Zhu, Ya-Zhong Mei, Wen-Song Li and Jiang-Hua Li

Metabolites 2024, 14(6), 343; https://doi.org/10.3390/metabo14060343 - 19 Jun 2024

Viewed by 693

Abstract

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its [...] Read more.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Cancer, Cardiovascular and Metabolic Diseases: Potential Therapies and Treatments)

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12 pages, 1323 KiB

Open AccessArticle

Characterization and Metabolism of Drug Products Containing the Cocaine-Like New Psychoactive Substances Indatraline and Troparil

by Sascha K. Manier, Paula Mumber, Josef Zapp, Niels Eckstein and Markus R. Meyer

Metabolites 2024, 14(6), 342; https://doi.org/10.3390/metabo14060342 - 18 Jun 2024

Viewed by 275

Abstract

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) and troparil (Methyl (1R,2S,3S,5 [...] Read more.

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) and troparil (Methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate) become popular as well. Both substances share a similar pharmacological profile as cocaine, while their potency is higher, and their duration of action is longer. This study investigated their metabolic fate in rat urine and incubations using pooled human liver S9 fraction (pHLS9). Indatraline formed two phase I and four phase II metabolites, with aromatic hydroxylation and glucuronidation being the main metabolic steps. All metabolites were detected in rat urine, while the parent compound was not detectable. Although low in abundance, indatraline metabolites were well identifiable due to their specific isotopic patterns caused by chlorine. Troparil formed four phase I and three phase II metabolites, with demethylation being the main metabolic step. Hydroxylation of the tropane ring, the phenyl ring, and combinations of these steps, as well as glucuronidation, were found. Phase I metabolites were detectable in rat urine and pHLS9, while phase II metabolites were only detectable in rat urine. Full article

(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)

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25 pages, 1276 KiB

Open AccessReview

Nicotinamide Mononucleotide Supplementation: Understanding Metabolic Variability and Clinical Implications

by Candace Benjamin and Rebecca Crews

Metabolites 2024, 14(6), 341; https://doi.org/10.3390/metabo14060341 - 18 Jun 2024

Viewed by 560

Abstract

Recent years have seen a surge in research focused on NAD+ decline and potential interventions, and despite significant progress, new discoveries continue to highlight the complexity of NAD+ biology. Nicotinamide mononucleotide (NMN), a well-established NAD+ precursor, has garnered considerable interest due to its [...] Read more.

Recent years have seen a surge in research focused on NAD+ decline and potential interventions, and despite significant progress, new discoveries continue to highlight the complexity of NAD+ biology. Nicotinamide mononucleotide (NMN), a well-established NAD+ precursor, has garnered considerable interest due to its capacity to elevate NAD+ levels and induce promising health benefits in preclinical models. Clinical trials investigating NMN supplementation have yielded variable outcomes while shedding light on the intricacies of NMN metabolism and revealing the critical roles played by gut microbiota and specific cellular uptake pathways. Individual variability in factors such as lifestyle, health conditions, genetics, and gut microbiome composition likely contributes to the observed discrepancies in clinical trial results. Preliminary evidence suggests that NMN’s effects may be context-dependent, varying based on a person’s physiological state. Understanding these nuances is critical for definitively assessing the impact of manipulating NAD+ levels through NMN supplementation. Here, we review NMN metabolism, focusing on current knowledge, pinpointing key areas where further research is needed, and outlining future directions to advance our understanding of its potential clinical significance. Full article

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19 pages, 2681 KiB

Open AccessArticle

Daily Eicosapentaenoic Acid Infusion in IUGR Fetal Lambs Reduced Systemic Inflammation, Increased Muscle ADRβ2 Content, and Improved Myoblast Function and Muscle Growth

by Haley N. Beer, Taylor A. Lacey, Rachel L. Gibbs, Micah S. Most, Zena M. Hicks, Pablo C. Grijalva, Eileen S. Marks-Nelson, Ty B. Schmidt, Jessica L. Petersen and Dustin T. Yates

Metabolites 2024, 14(6), 340; https://doi.org/10.3390/metabo14060340 - 18 Jun 2024

Viewed by 444

Abstract

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n [...] Read more.

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O₂ but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24–39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) β2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished β2 adrenergic sensitivity. Although IL6R remained elevated, β2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention. Full article

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

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2 pages, 561 KiB

Open AccessCorrection

Correction: Zatkova et al. Analysis of the Phenotype Differences in Siblings with Alkaptonuria. Metabolites 2022, 12, 990

by Andrea Zatkova, Birgitta Olsson, Lakshminarayan R. Ranganath and Richard Imrich

Metabolites 2024, 14(6), 339; https://doi.org/10.3390/metabo14060339 - 18 Jun 2024

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Abstract

In the original publication [...] Full article

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18 pages, 7242 KiB

Open AccessArticle

Serum Metabolomic and Lipidomic Profiling Reveals the Signature for Postoperative Obesity among Adult-Onset Craniopharyngioma

by Qiongyue Zhang, Yonghao Feng, Dou Wu, Yinyin Xie, Guoming Wu, Wei Wu, Hui Wang, Xiaoyu Liu, Linling Fan, Boni Xiang, Quanya Sun, Yiming Li, Yongfei Wang and Hongying Ye

Metabolites 2024, 14(6), 338; https://doi.org/10.3390/metabo14060338 - 17 Jun 2024

Viewed by 352

Abstract

Craniopharyngioma patients often suffer from a diminished quality of life after surgery, which is usually associated with metabolic disorders and hypothalamic obesity. However, the precise etiology of these conditions remains elusive. To identify the metabolic changes after surgery, we conducted a cross-sectional study [...] Read more.

Craniopharyngioma patients often suffer from a diminished quality of life after surgery, which is usually associated with metabolic disorders and hypothalamic obesity. However, the precise etiology of these conditions remains elusive. To identify the metabolic changes after surgery, we conducted a cross-sectional study using metabolomic and lipidomic analysis to profile metabolic alterations in adult-onset craniopharyngioma patients with postoperative obesity. A cohort of 120 craniopharyngioma patients who had undergone surgery were examined. Differential analyses, including clinical characteristics, serum metabolome, and lipidome, were conducted across distinct body mass index (BMI) groups. Our findings indicated no statistically significant differences in age, sex, and fasting blood glucose among postoperative craniopharyngioma patients when stratified by BMI. However, a noteworthy difference was observed in uric acid and blood lipid levels. Further investigation revealed that alterations in metabolites and lipids were evidently correlated with increased BMI, indicating that postoperative obesity of craniopharyngioma patients affected their whole-body metabolism. Additionally, the multi-omics analysis identified specific metabolites and lipids, including uric acid and DG(18:2/20:4), as contributors to the metabolic disorders associated with postoperative obesity of craniopharyngioma patients. This work provides valuable insight into the involvement of metabolites and lipids in metabolic disorders subsequent to craniopharyngioma surgery. Full article

(This article belongs to the Special Issue Metabolomics in the Interventions of Metabolic Diseases and Physical Activity)

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18 pages, 3846 KiB

Open AccessArticle

Metabolic Insight into Glioma Heterogeneity: Mapping Whole Exome Sequencing to In Vivo Imaging with Stereotactic Localization and Deep Learning

by Mahsa Servati, Courtney N. Vaccaro, Emily E. Diller, Renata Pellegrino Da Silva, Fernanda Mafra, Sha Cao, Katherine B. Stanley, Aaron A. Cohen-Gadol and Jason G. Parker

Metabolites 2024, 14(6), 337; https://doi.org/10.3390/metabo14060337 - 16 Jun 2024

Viewed by 542

Abstract

Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic alterations. While multiparametric imaging enhances the characterization of ITH by capturing both spatial and functional variations, it falls short in directly assessing [...] Read more.

Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic alterations. While multiparametric imaging enhances the characterization of ITH by capturing both spatial and functional variations, it falls short in directly assessing the metabolic activities that underpin these phenotypic differences. This gap stems from the challenge of integrating easily accessible, colocated pathology and detailed genomic data with metabolic insights. This study presents a multifaceted approach combining stereotactic biopsy with standard clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based GAM, and whole-exome sequencing. This work aims to demonstrate the potential of machine learning algorithms to predict variations in cellular and molecular tumor characteristics. This retrospective study enrolled ten treatment-naïve patients with radiologically confirmed glioma. Each patient underwent a multiparametric MR scan (T1_W, T1_W-CE, T2_W, T2_W-FLAIR, DWI) prior to surgery. During standard craniotomy, at least 1 stereotactic biopsy was collected from each patient, with screenshots of the sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing the signatures of five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, and NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard receiver operating characteristic (ROC) analyses were used to evaluate detection, with AUC (area under curve) calculated for each gene target and MR contrast combination. Mean AUC for five gene targets and 31 MR contrast combinations was 0.75 ± 0.11; individual AUCs were as high as 0.96 for both IDH1 and TP53 with T2_W-FLAIR and ADC, and 0.99 for EGFR with T2_W and ADC. These results suggest the possibility of predicting exome-wide mutation events from noninvasive, in vivo imaging by combining stereotactic localization of glioma samples and a semi-parametric deep learning method. The genomic alterations identified, particularly in IDH1, TP53, EGFR, PIK3CA, and NF1, are known to play pivotal roles in metabolic pathways driving glioma heterogeneity. Our methodology, therefore, indirectly sheds light on the metabolic landscape of glioma through the lens of these critical genomic markers, suggesting a complex interplay between tumor genomics and metabolism. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors. Full article

(This article belongs to the Special Issue Metabolomics and Machine Learning for Improved Diagnostics and as a Tool to Accelerate Drug Development)

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30 pages, 933 KiB

Open AccessReview

Adaptive Effects of Endocrine Hormones on Metabolism of Macronutrients during Fasting and Starvation: A Scoping Review

by Reza Karimi, Alina Yanovich, Fawzy Elbarbry and Anita Cleven

Metabolites 2024, 14(6), 336; https://doi.org/10.3390/metabo14060336 - 16 Jun 2024

Viewed by 440

Abstract

Food deprivation can occur for different reasons. Fasting (<24 h duration) occurs to meet religious or well-being goals. Starvation (>1-day duration) occurs when there is intentional (hunger strike or treatment of a medical condition) or unintentional (anorexia nervosa, drought, epidemic famine, war, or [...] Read more.

Food deprivation can occur for different reasons. Fasting (<24 h duration) occurs to meet religious or well-being goals. Starvation (>1-day duration) occurs when there is intentional (hunger strike or treatment of a medical condition) or unintentional (anorexia nervosa, drought, epidemic famine, war, or natural disaster) food deprivation. A scoping review was undertaken using the PubMed database to explore 1805 abstracts and review 88 eligible full-text articles to explore the adaptive relationships that emerge between cortisol, insulin, glucagon, and thyroid hormones on the metabolic pathways of macronutrients in humans during fasting and starvation. The collected data indicate that fasting and starvation prime the human body to increase cortisol levels and decrease the insulin/glucagon ratio and triiodothyronine (T₃) levels. During fasting, increased levels of cortisol and a decreased insulin/glucagon ratio enhance glycogenolysis and reduce the peripheral uptake of glucose and glycogenesis, whereas decreased T₃ levels potentially reduce glycogenolysis. During starvation, increased levels of cortisol and a decreased insulin/glucagon ratio enhance lipolysis, proteolysis, fatty acid and amino acid oxidation, ketogenesis, and ureagenesis, and decreased T₃ levels reduce thermogenesis. We present a potential crosstalk between T₃ and the above hormones, including between T₃ and leptin, to extend their adaptive roles in the metabolism of endogenous macronutrients during food deprivation. Full article

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

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17 pages, 2836 KiB

Open AccessArticle

Intra-Individual Variations in How Insulin Sensitivity Responds to Long-Term Exercise: Predictions by Machine Learning Based on Large-Scale Serum Proteomics

by Jonas Krag Viken, Thomas Olsen, Christian André Drevon, Marit Hjorth, Kåre Inge Birkeland, Frode Norheim and Sindre Lee-Ødegård

Metabolites 2024, 14(6), 335; https://doi.org/10.3390/metabo14060335 - 15 Jun 2024

Viewed by 583

Abstract

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a [...] Read more.

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO₂max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO₂max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes. Full article

(This article belongs to the Special Issue Machine Learning in Metabolic Diseases)

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14 pages, 897 KiB

Open AccessArticle

Association of Indoleamine 2,3-Dioxygenase (IDO) Activity with Outcome after Cardiac Surgery in Adult Patients

by Andrea Stieger, Markus Huber, Zhanru Yu, Benedikt M. Kessler, Roman Fischer, Lukas Andereggen, Beatrice Kobel, Frank Stueber, Markus M. Luedi and Mark G. Filipovic

Metabolites 2024, 14(6), 334; https://doi.org/10.3390/metabo14060334 - 14 Jun 2024

Viewed by 495

Abstract

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding [...] Read more.

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0–73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (−2.298, 95% CI −4.028 to −596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients. Full article

(This article belongs to the Special Issue Metabolomics: An Emerging Potential Approach to Study Critical Illnesses, 2nd Edition)

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21 pages, 1326 KiB

Open AccessArticle

Metabolite Profiling Analysis of the Tongmai Sini Decoction in Rats after Oral Administration through UHPLC-Q-Exactive-MS/MS

by Xianhui Zheng, Yingying Zhan, Mengling Peng, Wen Xu and Guanghai Deng

Metabolites 2024, 14(6), 333; https://doi.org/10.3390/metabo14060333 - 14 Jun 2024

Viewed by 396

Abstract

Tongmai Sini decoction (TSD), the classical prescriptions of traditional Chinese medicine, consisting of three commonly used herbal medicines, has been widely applied for the treatment of myocardial infarction and heart failure. However, the absorbed components and their metabolism in vivo of TSD still [...] Read more.

Tongmai Sini decoction (TSD), the classical prescriptions of traditional Chinese medicine, consisting of three commonly used herbal medicines, has been widely applied for the treatment of myocardial infarction and heart failure. However, the absorbed components and their metabolism in vivo of TSD still remain unknown. In this study, a reliable and effective method using ultra-performance liquid chromatography coupled with hybrid quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Exactive-MS/MS) was employed to identify prototype components and metabolites in vivo (rat plasma and urine). Combined with mass defect filtering (MDF), dynamic background subtraction (DBS), and neutral loss filtering (NLF) data-mining tools, a total of thirty-two major compounds were selected and investigated for their metabolism in vivo. As a result, a total of 82 prototype compounds were identified or tentatively characterized in vivo, including 41 alkaloids, 35 phenolic compounds, 6 saponins. Meanwhile, A total of 65 metabolites (40 alkaloids and 25 phenolic compounds) were tentatively identified. The metabolic reactions were mainly hydrogenation, demethylation, hydroxylation, hydration, methylation, deoxylation, and sulfation. These findings will be beneficial for an in-depth understanding of the pharmacological mechanism and pharmacodynamic substance basis of TSD. Full article

(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites)

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15 pages, 3898 KiB

Open AccessArticle

Explainable AI to Facilitate Understanding of Neural Network-Based Metabolite Profiling Using NMR Spectroscopy

by Hayden Johnson and Aaryani Tipirneni-Sajja

Metabolites 2024, 14(6), 332; https://doi.org/10.3390/metabo14060332 - 14 Jun 2024

Viewed by 368

Abstract

Neural networks (NNs) are emerging as a rapid and scalable method for quantifying metabolites directly from nuclear magnetic resonance (NMR) spectra, but the nonlinear nature of NNs precludes understanding of how a model makes predictions. This study implements an explainable artificial intelligence algorithm [...] Read more.

Neural networks (NNs) are emerging as a rapid and scalable method for quantifying metabolites directly from nuclear magnetic resonance (NMR) spectra, but the nonlinear nature of NNs precludes understanding of how a model makes predictions. This study implements an explainable artificial intelligence algorithm called integrated gradients (IG) to elucidate which regions of input spectra are the most important for the quantification of specific analytes. The approach is first validated in simulated mixture spectra of eight aqueous metabolites and then investigated in experimentally acquired lipid spectra of a reference standard mixture and a murine hepatic extract. The IG method revealed that, like a human spectroscopist, NNs recognize and quantify analytes based on an analyte’s respective resonance line-shapes, amplitudes, and frequencies. NNs can compensate for peak overlap and prioritize specific resonances most important for concentration determination. Further, we show how modifying a NN training dataset can affect how a model makes decisions, and we provide examples of how this approach can be used to de-bug issues with model performance. Overall, results show that the IG technique facilitates a visual and quantitative understanding of how model inputs relate to model outputs, potentially making NNs a more attractive option for targeted and automated NMR-based metabolomics. Full article

(This article belongs to the Special Issue Machine Learning Applications in Metabolomics Analysis)

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11 pages, 650 KiB

Open AccessArticle

Additive Effect of Metabolic Syndrome on Brain Atrophy in People Living with HIV–Magnetic Resonance Volumetry Study

by Vanja Andric, Jasmina Boban, Daniela Maric, Dusko Kozic, Snezana Brkic and Aleksandra Bulovic

Metabolites 2024, 14(6), 331; https://doi.org/10.3390/metabo14060331 - 13 Jun 2024

Viewed by 360

Abstract

With people living with HIV (PLWH) reaching the senium, the importance of aging-related comorbidities such as metabolic syndrome (MS) becomes increasingly important. This study aimed to determine the additive effect of MS on brain atrophy in PLWH. This prospective study included 43 PLWH, [...] Read more.

With people living with HIV (PLWH) reaching the senium, the importance of aging-related comorbidities such as metabolic syndrome (MS) becomes increasingly important. This study aimed to determine the additive effect of MS on brain atrophy in PLWH. This prospective study included 43 PLWH, average age of 43.02 ± 10.93 years, and 24 healthy controls, average age of 36.87 ± 8.89 years. PLWH were divided into two subgroups: without MS and with MS, according to NCEP ATP III criteria. All patients underwent brain magnetic resonance imaging (MRI) on a 3T clinical scanner with MR volumetry, used for defining volumes of cerebrospinal fluid (CSF) spaces and white and grey matter structures, including basal ganglia. A Student’s t-test was used to determine differences in brain volumes between subject subgroups. The binary classification was performed to determine the sensitivity and specificity of volumetry findings and cut-off values. Statistical significance was set at p < 0.05. PLWH presented with significantly lower volumes of gray matter, putamen, thalamus, globus pallidus, and nc. accumbens compared to healthy controls; cut-off values were: for gray matter 738.130 cm³, putamen 8.535 cm³, thalamus 11.895 cm³, globus pallidus 2.252 cm³, and nc. accumbens 0.715 cm³. The volumes of CSF and left lateral ventricles were found to be higher in PLWH with MS compared to those without MS, where, with a specificity of 0.310 and sensitivity of 0.714, it can be assumed that PLWH with a CSF volume exceeding 212.83 cm³ are likely to also have MS. This suggests that PLWH with metabolic syndrome may exhibit increased CSF volume above 212.83 cm³ as a consequence of brain atrophy. There seems to be an important connection between MS and brain volume reduction in PLWH with MS, which may add to the accurate identification of persons at risk of developing HIV-associated cognitive impairment. Full article

(This article belongs to the Special Issue Harnessing the Power of NMR Metabolomics in Unraveling Metabolic Diseases)

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15 pages, 2778 KiB

Open AccessArticle

Melatonin Combined with Wax Treatment Enhances Tolerance to Chilling Injury in Red Bell Pepper

by Magalí Darré, María José Zaro, Michelle Guijarro-Fuertes, Ludmila Careri and Analia Concellón

Metabolites 2024, 14(6), 330; https://doi.org/10.3390/metabo14060330 - 13 Jun 2024

Viewed by 443

Abstract

Bell peppers (Capsicum annuum L.) are prone to chilling injury (CI) when stored at temperatures below 7 °C. Melatonin, a natural plant regulator, plays a critical role in defending against different pre- and post-harvest abiotic stresses, including those associated with cold storage. [...] Read more.

Bell peppers (Capsicum annuum L.) are prone to chilling injury (CI) when stored at temperatures below 7 °C. Melatonin, a natural plant regulator, plays a critical role in defending against different pre- and post-harvest abiotic stresses, including those associated with cold storage. This study aimed to assess the effects of applying exogenous melatonin alone and in combination with a commercial wax on the CI tolerance, postharvest life, and potential biomarker search of red bell peppers. In the initial experiment, the effective melatonin concentration to reduce CI effects was determined. Peppers were sprayed with either distilled water (control) or a melatonin aqueous solution (M100 = 100 μM or M500 = 500 μM) and then stored for 33 d at 4 °C, followed by 2 d at 20 °C. The M500 treatment proved to be more effective in reducing fruit CI incidence (superficial scalds) and metabolic rate, while weight loss, softening, and color were comparable to the control. A second experiment assessed the potential synergistic effects of a combined melatonin and commercial wax treatment on pepper CI and quality. Fruits were sprayed with distilled water (control), melatonin (M500), commercial wax (Wax), or the combined treatment (Wax + M500) and stored for 28 d at 4 °C, followed by 2 d at 20 °C. The Wax + M500 was the most effective in significantly reducing the incidence of fruit CI symptoms and calyx fungal infection. Furthermore, this combined treatment enhanced fruit weight loss prevention compared with individual melatonin or wax treatment. Also, Wax + M500-treated peppers exhibited notable proline accumulation, indicative of a metabolic response counteracting the cold effects, resulting in better fruit stress acclimation. This treatment also preserved the peppers’ color and antioxidant capacity. In summary, these findings highlight the suitability of applying a combined Wax + M500 treatment as a highly effective strategy to enhance the CI tolerance of peppers and extend their postharvest life. Full article

(This article belongs to the Special Issue Metabolic Changes during Pre- and Post-harvest Fruit and Vegetable Decay, Ripening and Senescence)

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21 pages, 3549 KiB

Open AccessArticle

Identification and Characterization of Cannabichromene’s Major Metabolite Following Incubation with Human Liver Microsomes

by Alexandra M. Ward, Touraj Shokati, Jost Klawitter, Jelena Klawitter, Vu Nguyen, Laura Kozell, Atheir I. Abbas, David Jones and Uwe Christians

Metabolites 2024, 14(6), 329; https://doi.org/10.3390/metabo14060329 - 13 Jun 2024

Viewed by 355

Abstract

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated [...] Read more.

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2′-hydroxycannabicitran to fit in the orthosteric site of both the CB₁ and CB₂ receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB₁ or CB₂ receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors. Full article

(This article belongs to the Special Issue Drug Metabolism: Latest Advances and Prospects)

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16 pages, 1044 KiB

Open AccessArticle

Development of an LC-HRMS/MS Method for Quantifying Steroids and Thyroid Hormones in Capillary Blood: A Potential Tool for Assessing Relative Energy Deficiency in Sport (RED-S)

by Chiara Tuma, Andreas Thomas, Hans Braun and Mario Thevis

Metabolites 2024, 14(6), 328; https://doi.org/10.3390/metabo14060328 - 12 Jun 2024

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Abstract

Relative energy deficiency in sport (RED-S) is a condition that arises from persistent low energy availability (LEA), which affects the hypothalamic–pituitary axis and results in alterations of several hormones in both male and female athletes. As frequent blood hormone status determinations using venipuncture [...] Read more.

Relative energy deficiency in sport (RED-S) is a condition that arises from persistent low energy availability (LEA), which affects the hypothalamic–pituitary axis and results in alterations of several hormones in both male and female athletes. As frequent blood hormone status determinations using venipuncture are rare in sports practice, microsampling offers promising possibilities for preventing and assessing RED-S. Therefore, this study aimed at developing a liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS) method for quantifying relevant steroids and thyroid hormones in 30 μL of capillary blood obtained using Mitra^® devices with volumetric absorptive microsampling technology (VAMS^®). The results of the study showed that all validation criteria were met, including a storage stability of more than 28 days in a frozen state (−18 °C) and 14 days at room temperature (20 °C). The validated assay provided precise (<12%) and accurate (<13%) results for all the target analytes. Furthermore, as a proof of concept, autonomously collected VAMS^® samples from 50 female and male, healthy, active adults were analyzed. The sensitivity of all analytes was adequate to quantify the decreased hormone concentrations in the RED-S state, as all authentic samples could be measured accordingly. These findings suggest that self-collected VAMS^® samples offer a practical opportunity for regular hormone measurements in athletes and can be used for early RED-S assessment and progress monitoring during RED-S recovery. Full article

(This article belongs to the Special Issue Sports: Nutrition and Metabolism in Relation to Athletes’ Health and Performance)

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47 pages, 2310 KiB

Open AccessReview

Comprehensive Strategies for Metabolic Syndrome: How Nutrition, Dietary Polyphenols, Physical Activity, and Lifestyle Modifications Address Diabesity, Cardiovascular Diseases, and Neurodegenerative Conditions

by Giovanni Martemucci, Mohamad Khalil, Alessio Di Luca, Hala Abdallah and Angela Gabriella D’Alessandro

Metabolites 2024, 14(6), 327; https://doi.org/10.3390/metabo14060327 - 11 Jun 2024

Viewed by 489

Abstract

Several hallmarks of metabolic syndrome, such as dysregulation in the glucose and lipid metabolism, endothelial dysfunction, insulin resistance, low-to-medium systemic inflammation, and intestinal microbiota dysbiosis, represent a pathological bridge between metabolic syndrome and diabesity, cardiovascular, and neurodegenerative disorders. This review aims to highlight [...] Read more.

Several hallmarks of metabolic syndrome, such as dysregulation in the glucose and lipid metabolism, endothelial dysfunction, insulin resistance, low-to-medium systemic inflammation, and intestinal microbiota dysbiosis, represent a pathological bridge between metabolic syndrome and diabesity, cardiovascular, and neurodegenerative disorders. This review aims to highlight some therapeutic strategies against metabolic syndrome involving integrative approaches to improve lifestyle and daily diet. The beneficial effects of foods containing antioxidant polyphenols, intestinal microbiota control, and physical activity were also considered. We comprehensively examined a large body of published articles involving basic, animal, and human studie, as well as recent guidelines. As a result, dietary polyphenols from natural plant-based antioxidants and adherence to the Mediterranean diet, along with physical exercise, are promising complementary therapies to delay or prevent the onset of metabolic syndrome and counteract diabesity and cardiovascular diseases, as well as to protect against neurodegenerative disorders and cognitive decline. Modulation of the intestinal microbiota reduces the risks associated with MS, improves diabetes and cardiovascular diseases (CVD), and exerts neuroprotective action. Despite several studies, the estimation of dietary polyphenol intake is inconclusive and requires further evidence. Lifestyle interventions involving physical activity and reduced calorie intake can improve metabolic outcomes. Full article

(This article belongs to the Special Issue Effects of Bioactive Compounds on Metabolic Syndrome)

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24 pages, 4116 KiB

Open AccessArticle

Metabolic Changes in Pseudomonas oleovorans Isolated from Contaminated Construction Material Exposed to Varied Biocide Treatments

by Muatasem Latif Ali, Lionel Ferrieres, Jana Jass and Tuulia Hyötyläinen

Metabolites 2024, 14(6), 326; https://doi.org/10.3390/metabo14060326 - 10 Jun 2024

Viewed by 400

Abstract

Biocide resistance poses a significant challenge in industrial processes, with bacteria like Pseudomonas oleovorans exhibiting intrinsic resistance to traditional antimicrobial agents. In this study, the impact of biocide exposure on the metabolome of two P. oleovorans strains, namely, P. oleovorans P4A, isolated from [...] Read more.

Biocide resistance poses a significant challenge in industrial processes, with bacteria like Pseudomonas oleovorans exhibiting intrinsic resistance to traditional antimicrobial agents. In this study, the impact of biocide exposure on the metabolome of two P. oleovorans strains, namely, P. oleovorans P4A, isolated from contaminated coating material, and P. oleovorans 1045 reference strain, were investigated. The strains were exposed to 2-Methylisothiazol-3(2H)-one (MI) MIT, 1,2-Benzisothiazol-3(2H)-one (BIT), and 5-chloro-2-methyl-isothiazol-3-one (CMIT) at two different sub-inhibitory concentrations and the lipids and polar and semipolar metabolites were analyzed by ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry UPLC–Q–TOF/MS. Exposure to the BIT biocide induced significant metabolic modifications in P. oleovorans. Notable changes were observed in lipid and metabolite profiles, particularly in phospholipids, amino acid metabolism, and pathways related to stress response and adaptation. The 1045 strain showed more pronounced metabolic alterations than the P4A strain, suggesting potential implications for lipid, amino acid metabolism, energy metabolism, and stress adaptation. Improving our understanding of how different substances interact with bacteria is crucial for making antimicrobial chemicals more effective and addressing the challenges of resistance. We observed that different biocides trigged significantly different metabolic responses in these strains. Our study shows that metabolomics can be used as a tool for the investigation of metabolic mechanisms underlying biocide resistance, and thus in the development of targeted biocides. This in turn can have implications in combating biocide resistance in bacteria such as P. oleovorans. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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38 pages, 3041 KiB

Open AccessReview

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

by Anqi Li, Rui Wang, Yuqiang Zhao, Peiran Zhao and Jing Yang

Metabolites 2024, 14(6), 325; https://doi.org/10.3390/metabo14060325 - 8 Jun 2024

Viewed by 373

Abstract

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. [...] Read more.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC. Full article

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

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15 pages, 1020 KiB

Open AccessReview

Gut Microbiota and Sinusoidal Vasoregulation in MASLD: A Portal Perspective

by Gyorgy Baffy and Piero Portincasa

Metabolites 2024, 14(6), 324; https://doi.org/10.3390/metabo14060324 - 7 Jun 2024

Viewed by 339

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique sinusoidal capillary network of the liver. Early sinusoidal vasoregulatory changes in MASLD lead to increased intrahepatic vascular resistance and represent the beginning of portal hypertension. In addition, the composition and function of gut microbiota in MASLD are distinctly different from the healthy state, and multiple lines of evidence demonstrate the association of dysbiosis with these vasoregulatory changes. The gut microbiota is involved in the biotransformation of nutrients, production of de novo metabolites, release of microbial structural components, and impairment of the intestinal barrier with impact on innate immune responses, metabolism, inflammation, fibrosis, and vasoregulation in the liver and beyond. The gut–liver axis is a conceptual framework in which portal circulation is the primary connection between gut microbiota and the liver. Accordingly, biochemical and hemodynamic attributes of portal circulation may hold the key to better understanding and predicting disease progression in MASLD. However, many specific details remain hidden due to limited access to the portal circulation, indicating a major unmet need for the development of innovative diagnostic tools to analyze portal metabolites and explore their effect on health and disease. We also need to safely and reliably monitor portal hemodynamics with the goal of providing preventive and curative interventions in all stages of MASLD. Here, we review recent advances that link portal metabolomics to altered sinusoidal vasoregulation and may allow for new insights into the development of portal hypertension in MASLD. Full article

(This article belongs to the Special Issue Honorary Special Issue Dedicated to Prof. Giovanni Targher–the Metabolic Fatty Liver Syndromes: MASLD/MAFLD/NAFLD)

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12 pages, 270 KiB

Open AccessArticle

Serum Uric Acid, Hypertriglyceridemia, and Carotid Plaques: A Sub-Analysis of the URic Acid Right for Heart Health (URRAH) Study

by Claudia Agabiti Rosei, Anna Paini, Giacomo Buso, Alessandro Maloberti, Cristina Giannattasio, Massimo Salvetti, Edoardo Casiglia, Valerie Tikhonoff, Fabio Angeli, Carlo Maria Barbagallo, Michele Bombelli, Federica Cappelli, Rosario Cianci, Michele Ciccarelli, Arrigo Francesco Giuseppe Cicero, Massimo Cirillo, Pietro Cirillo, Raffaella Dell’Oro, Lanfranco D’Elia, Giovambattista Desideri, Claudio Ferri, Ferruccio Galletti, Loreto Gesualdo, Guido Grassi, Guido Iaccarino, Luciano Lippa, Francesca Mallamaci, Stefano Masi, Maria Masulli, Alberto Mazza, Alessandro Mengozzi, Pietro Nazzaro, Paolo Palatini, Gianfranco Parati, Roberto Pontremoli, Fosca Quarti-Trevano, Marcello Rattazzi, Gianpaolo Reboldi, Giulia Rivasi, Elisa Russo, Giuliano Tocci, Andrea Ungar, Paolo Verdecchia, Francesca Viazzi, Massimo Volpe, Agostino Virdis, Maria Lorenza Muiesan and Claudio Borghi Show full author list Hide full author list

Metabolites 2024, 14(6), 323; https://doi.org/10.3390/metabo14060323 - 7 Jun 2024

Viewed by 685

Abstract

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study [...] Read more.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04–1.27], p < 0.001 and HR 1.25 [1.09–1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques. Full article

(This article belongs to the Special Issue Exploring Uric Acid and Beyond)

12 pages, 2260 KiB

Open AccessArticle

Characterization of Urinary N-Acetyltaurine as a Biomarker of Hyperacetatemia in Mice

by Qingqing Mao, Xiaolei Shi, Yiwei Ma, Yuwei Lu and Chi Chen

Metabolites 2024, 14(6), 322; https://doi.org/10.3390/metabo14060322 - 7 Jun 2024

Viewed by 455

Abstract

Acetate is an important metabolite in metabolic fluxes. Its presence in biological entities originates from both exogenous inputs and endogenous metabolism. Because the change in blood acetate level has been associated with both beneficial and adverse health outcomes, blood acetate analysis has been [...] Read more.

Acetate is an important metabolite in metabolic fluxes. Its presence in biological entities originates from both exogenous inputs and endogenous metabolism. Because the change in blood acetate level has been associated with both beneficial and adverse health outcomes, blood acetate analysis has been used to monitor the systemic status of acetate turnover. The present study examined the use of urinary N-acetyltaurine (NAT) as a marker to reflect the hyperacetatemic status of mice from exogenous inputs and endogenous metabolism, including triacetin dosing, ethanol dosing, and streptozotocin-induced diabetes. The results showed that triacetin dosing increased serum acetate and urinary NAT but not other N-acetylated amino acids in urine. The co-occurrences of increased serum acetate and elevated urinary NAT were also observed in both ethanol dosing and streptozotocin-induced diabetes. Furthermore, the renal cortex was determined as an active site for NAT synthesis. Overall, urinary NAT behaved as an effective marker of hyperacetatemia in three experimental mouse models, warranting further investigation into its application in humans. Full article

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14 pages, 979 KiB

Open AccessArticle

Dietary Cholest-4-en-3-one, a Cholesterol Metabolite of Gut Microbiota, Alleviates Hyperlipidemia, Hepatic Cholesterol Accumulation, and Hyperinsulinemia in Obese, Diabetic db/db Mice

by Mina Higuchi, Mai Okumura, Sarasa Mitsuta and Bungo Shirouchi

Metabolites 2024, 14(6), 321; https://doi.org/10.3390/metabo14060321 - 3 Jun 2024

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Abstract

Previous studies have shown that dietary cholest-4-en-3-one (4-cholestenone, 4-STN) exerts anti-obesity and lipid-lowering effects in mice. However, its underlying mechanisms are not fully understood. In the present study, we evaluated whether 4-STN supplementation would protect obese diabetic db/db mice from obesity-related metabolic disorders. [...] Read more.

Previous studies have shown that dietary cholest-4-en-3-one (4-cholestenone, 4-STN) exerts anti-obesity and lipid-lowering effects in mice. However, its underlying mechanisms are not fully understood. In the present study, we evaluated whether 4-STN supplementation would protect obese diabetic db/db mice from obesity-related metabolic disorders. After four weeks of feeding of a 0.25% 4-STN-containing diet, dietary 4-STN was found to have significantly alleviated hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia; however, the effect was not sufficient to improve hepatic triglyceride accumulation or obesity. Further analysis demonstrated that dietary 4-STN significantly increased the content of free fatty acids and neutral steroids in the feces of db/db mice, indicating that the alleviation of hyperlipidemia by 4-STN was due to an increase in lipid excretion. In addition, dietary 4-STN significantly reduced the levels of desmosterol, a cholesterol precursor, in the plasma but not in the liver, suggesting that normalization of cholesterol metabolism by 4-STN is partly attributable to the suppression of cholesterol synthesis in extrahepatic tissues. In addition, dietary 4-STN increased the plasma and hepatic levels of 4-STN metabolites cholestanol (5α-cholestan-3β-ol) and coprostanol (5β-cholestan-3β-ol). Our results show that dietary 4-STN alleviates obesity-related metabolic disorders, such as hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia, in db/db mice. Full article

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

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25 pages, 751 KiB

Open AccessReview

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases

by Alisha Vohra, Patrick Keefe and Prasanth Puthanveetil

Metabolites 2024, 14(6), 320; https://doi.org/10.3390/metabo14060320 - 31 May 2024

Viewed by 319

Abstract

Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is [...] Read more.

Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases. Full article

(This article belongs to the Special Issue Cellular Metabolism in Neurological Disorders)

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21 pages, 3035 KiB

Open AccessArticle

Phenylpropanoid Metabolism in Phaseolus vulgaris during Growth under Severe Drought

by Luis Eduardo Peña Barrena, Lili Mats, Hugh J. Earl and Gale G. Bozzo

Metabolites 2024, 14(6), 319; https://doi.org/10.3390/metabo14060319 - 31 May 2024

Viewed by 324

Abstract

Drought limits the growth and development of Phaseolus vulgaris L. (known as common bean). Common bean plants contain various phenylpropanoids, but it is not known whether the levels of these metabolites are altered by drought. Here, BT6 and BT44, two white bean recombinant [...] Read more.

Drought limits the growth and development of Phaseolus vulgaris L. (known as common bean). Common bean plants contain various phenylpropanoids, but it is not known whether the levels of these metabolites are altered by drought. Here, BT6 and BT44, two white bean recombinant inbred lines (RILs), were cultivated under severe drought. Their respective growth and phenylpropanoid profiles were compared to those of well-irrigated plants. Both RILs accumulated much less biomass in their vegetative parts with severe drought, which was associated with more phaseollin and phaseollinisoflavan in their roots relative to well-irrigated plants. A sustained accumulation of coumestrol was evident in BT44 roots with drought. Transient alterations in the leaf profiles of various phenolic acids occurred in drought-stressed BT6 and BT44 plants, including the respective accumulation of two separate caftaric acid isomers and coutaric acid (isomer 1) relative to well-irrigated plants. A sustained rise in fertaric acid was observed in BT44 with drought stress, whereas the greater amount relative to well-watered plants was transient in BT6. Apart from kaempferol diglucoside (isomer 2), the concentrations of most leaf flavonol glycosides were not altered with drought. Overall, fine tuning of leaf and root phenylpropanoid profiles occurs in white bean plants subjected to severe drought. Full article

(This article belongs to the Special Issue Metabolic Responses of Plants to Abiotic Stress)

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24 pages, 1605 KiB

Open AccessReview

Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies

by Dalton Hilovsky, Joshua Hartsell, Jamey D. Young and Xiaojing Liu

Metabolites 2024, 14(6), 318; https://doi.org/10.3390/metabo14060318 - 31 May 2024

Viewed by 364

Abstract

Metabolic reprogramming is a hallmark of cancer, driving the development of therapies targeting cancer metabolism. Stable isotope tracing has emerged as a widely adopted tool for monitoring cancer metabolism both in vitro and in vivo. Advances in instrumentation and the development of new [...] Read more.

Metabolic reprogramming is a hallmark of cancer, driving the development of therapies targeting cancer metabolism. Stable isotope tracing has emerged as a widely adopted tool for monitoring cancer metabolism both in vitro and in vivo. Advances in instrumentation and the development of new tracers, metabolite databases, and data analysis tools have expanded the scope of cancer metabolism studies across these scales. In this review, we explore the latest advancements in metabolic analysis, spanning from experimental design in stable isotope-labeling metabolomics to sophisticated data analysis techniques. We highlight successful applications in cancer research, particularly focusing on ongoing clinical trials utilizing stable isotope tracing to characterize disease progression, treatment responses, and potential mechanisms of resistance to anticancer therapies. Furthermore, we outline key challenges and discuss potential strategies to address them, aiming to enhance our understanding of the biochemical basis of cancer metabolism. Full article

(This article belongs to the Special Issue Isotope-Guided Analytical Strategies for Assessing Metabolic Networks in Cancer)

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17 pages, 1309 KiB

Open AccessReview

The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease

by Qiqiang Zhou, Yahong Chen, Ying Liang and Yongchang Sun

Metabolites 2024, 14(6), 317; https://doi.org/10.3390/metabo14060317 - 31 May 2024

Viewed by 380

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or [...] Read more.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment. Full article

(This article belongs to the Special Issue Lipidomics in Health and Disease)

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