Metabolites

12 pages, 3161 KiB

Open AccessArticle

Profiling and Discrimination of Euryale Ferox Seeds from Different Processing Methods Using Liquid Chromatography High-Resolution Mass Spectrometry Combined with Molecular Networking and Statistical Analysis

by Xiaoyu Xie, Chuntao Zeng, Ruonan Zhang, Wenting Zhu, Huijie Li and Zhi Huang

Metabolites 2025, 15(4), 225; https://doi.org/10.3390/metabo15040225 (registering DOI) - 25 Mar 2025

Abstract

Background: Euryale ferox seeds (EFSs) serve both medicinal and culinary purposes. They possess high nutritional value and are rich in polysaccharides, polyphenols, glycolipids, cyclic peptides, and other beneficial components. EFSs are known for their effects in tonifying the kidneys and strengthening essence, invigorating [...] Read more.

Background: Euryale ferox seeds (EFSs) serve both medicinal and culinary purposes. They possess high nutritional value and are rich in polysaccharides, polyphenols, glycolipids, cyclic peptides, and other beneficial components. EFSs are known for their effects in tonifying the kidneys and strengthening essence, invigorating the spleen and alleviating diarrhea, as well as removing dampness and leucorrhea. Processing can alter the chemical composition of EFSs, with different methods yielding varying effects on their chemical makeup and, consequently, their efficacy. However, to date, no studies have systematically investigated the overall chemical composition of EFSs using different processing methods. Methods: In this study, we employed liquid chromatography high-resolution mass spectrometry (LC-HRMS) to identify the compounds in EFSs by searching databases and Global Natural Products Social Molecular Networking (GNPS), and we comprehensively explored the changes in the chemical composition of EFSs resulting from various processing methods via statistical analysis. Results: A total of 438 compounds were identified from EFSs, of which 283 were identified through database searches and 155 were identified via GNPS propagation. Statistical analysis revealed 32 and 38 differential compounds in dry-fried Euryale ferox seeds (DFEFSs) and bran-fried Euryale ferox seeds (BFEFSs), respectively. Additionally, we found a significant increase in the lipid content of the fried EFSs. Conclusions: This study provides valuable data to support the quality evaluation of processed EFSs and contributes to the research on the material basis of their medicinal efficacy. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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39 pages, 1588 KiB

Open AccessSystematic Review

Current Prognostic Biomarkers for Peripheral Arterial Disease: A Comprehensive Systematic Review of the Literature

by Hamzah Khan, Natasha R. Girdharry, Sophia Z. Massin, Mohamed Abu-Raisi, Gustavo Saposnik, Muhammad Mamdani and Mohammad Qadura

Metabolites 2025, 15(4), 224; https://doi.org/10.3390/metabo15040224 - 25 Mar 2025

Abstract

Background: Peripheral arterial disease (PAD) is a chronic atherosclerotic disease characterized by atheromatous plaque buildup within arteries of the lower limbs. It can lead to claudication, skin ulcerations, and, in severe cases, chronic limb-threatening ischemia, requiring amputation. There are several plasma protein biomarkers [...] Read more.

Background: Peripheral arterial disease (PAD) is a chronic atherosclerotic disease characterized by atheromatous plaque buildup within arteries of the lower limbs. It can lead to claudication, skin ulcerations, and, in severe cases, chronic limb-threatening ischemia, requiring amputation. There are several plasma protein biomarkers that have been suggested as prognostic markers for adverse events, including major adverse cardiovascular and limb events. However, the clinical benefit and ability to clinically adapt these biomarkers remains uncertain due to inconsistent findings possibly related to heterogenous study designs and differences in methodology. Objectives: This review aims to evaluate the current literature on the prognostic value of plasma protein biomarkers for PAD, their predictive ability for PAD-related adverse outcomes, and their potential roles in guiding PAD management. Methods: To address these challenges, we conducted a systematic review of MEDLINE, Embase, and Cochrane CENTRAL libraries of the current literature (2010–2024). Results: We found 55 studies that evaluated the prognostic value of 44 distinct plasma proteins across various pathophysiological processes. These included markers of immunity and inflammation, markers of metabolism, cardiac biomarkers, markers of kidney function, growth factors and hormones, markers of coagulation and platelet function, extracellular matrix and tissue remodeling proteins, and transport proteins. This review summarizes the existing evidence for prognostic protein plasma biomarkers for PAD and their association with adverse events related to PAD. Conclusions: With this review, we hope to provide a comprehensive list of the prognostic markers and their value as prognostic biomarkers to guide clinical decision making in these patients. Full article

(This article belongs to the Special Issue Cardiovascular Biomarkers and Metabolism in Cardiovascular Diseases)

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15 pages, 1075 KiB

Open AccessArticle

Green Extraction Method: Microwave-Assisted Water Extraction Followed by HILIC-HRMS Analysis to Quantify Hydrophilic Compounds in Plants

by Alexandra Louis, Jean François Chich, Hadrien Chepca, Isabelle Schmitz, Philippe Hugueney and Alessandra Maia-Grondard

Metabolites 2025, 15(4), 223; https://doi.org/10.3390/metabo15040223 - 25 Mar 2025

Abstract

Background: Hydrophilic compounds, such as amino acids, organic acids and sugars, among others, are present in large amounts in plant cells. The analysis and quantification of these major hydrophilic compounds are particularly relevant in plant science because they have a considerable impact on [...] Read more.

Background: Hydrophilic compounds, such as amino acids, organic acids and sugars, among others, are present in large amounts in plant cells. The analysis and quantification of these major hydrophilic compounds are particularly relevant in plant science because they have a considerable impact on the quality of plant-derived products and on plant–pathogen relationships. Our objective was to develop and validate a complete analysis workflow combining a water-based extraction procedure with a fast separation using hydrophilic interaction liquid chromatography coupled to high-resolution mass spectrometry (HILIC-HRMS) for quantitative analysis of hydrophilic compounds in plant tissues. Results: Water-based microwave-assisted extraction (MAE) methods for hydrophilic compounds were compared using HILIC-HRMS. The newly developed method involved 20 s MAE time followed by a 10 min HILIC-HRMS analysis. This bioanalytical method was validated for 24 polar metabolites, including amino acids, organic acids, and sugars, to ensure the reliability of analytical results: selectivity, limits of detection and quantification, calibration range and precision. Depending on the compounds, quantification limit was as low as 0.10 µM up to 4.50 µM. Between-run RSDs evaluated on Vitis vinifera and Arabidopsis samples were all below 20% except for three compounds. Conclusions: A water-based MAE method, coupled with HILIC-HRMS, was developed for the absolute quantification of free amino acids, organic acids, and sugars in plant tissues. Its effectiveness was demonstrated in both lignified plants, such as Vitis vinifera, and non-lignified plants, such as Arabidopsis. This method is suitable for medium- to high-throughput analysis of key polar metabolites from small amounts of plant material. Full article

(This article belongs to the Section Plant Metabolism)

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18 pages, 11082 KiB

Open AccessArticle

Metabolic Reprogramming of Gastric Cancer Revealed by a Liquid Chromatography–Mass Spectrometry-Based Metabolomics Study

by Lina Zhou, Benzhe Su, Zexing Shan, Zhenbo Gao, Xingyu Guo, Weiwei Wang, Xiaolin Wang, Wenli Sun, Shuai Yuan, Shulan Sun, Jianjun Zhang, Guowang Xu and Xiaohui Lin

Metabolites 2025, 15(4), 222; https://doi.org/10.3390/metabo15040222 - 25 Mar 2025

Abstract

Background/Objectives: Gastric cancer (GC) is a prevalent malignant tumor worldwide, with its pathological mechanisms largely unknown. Understanding the metabolic reprogramming associated with GC is crucial for the prevention and treatment of this disease. This study aims to identify significant alterations in metabolites and [...] Read more.

Background/Objectives: Gastric cancer (GC) is a prevalent malignant tumor worldwide, with its pathological mechanisms largely unknown. Understanding the metabolic reprogramming associated with GC is crucial for the prevention and treatment of this disease. This study aims to identify significant alterations in metabolites and pathways related to the development of GC. Methods: A liquid chromatography–mass spectrometry-based non-targeted metabolomics data acquisition was performed on paired tissues from 80 GC patients. Differences in metabolic profiles between tumor and adjacent normal tissues were first investigated through univariate and multivariate statistical analyses. Additionally, differential correlation network analysis and a newly proposed network analysis method (NAM) were employed to explore significant metabolite pathways and subnetworks related to tumorigenesis and various TNM stages of GC. Results: Over half of the annotated metabolites exhibited significant alterations. Phosphatidylcholine (PC)_30_0 and fatty acid C20_3 demonstrated strong diagnostic performance for GC, with AUCs of 0.911 and 0.934 in the discovery and validation sets, respectively. Differential correlation network analysis revealed significant fatty acid-related metabolic reprogramming in GC with elevated levels of medium-chain acylcarnitines and increased activity of medium-chain acyl-CoA dehydrogenase, firstly observed in clinical GC tissues. Of note, using NAM, two correlation subnetworks were identified as having significant alterations across different TNM stages, centered with choline and carnitine C4_0-OH, respectively. Conclusions: The identified significant alterations in fatty acid metabolism and TNM-related metabolic subnetworks in GC tissues will facilitate future investigations into the metabolic reprogramming associated with gastric cancer. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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53 pages, 1912 KiB

Open AccessFeature PaperReview

Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer

by Salvatore Zarrella, Maria Rosaria Miranda, Verdiana Covelli, Ignazio Restivo, Sara Novi, Giacomo Pepe, Luisa Tesoriere, Manuela Rodriquez, Alessia Bertamino, Pietro Campiglia, Mario Felice Tecce and Vincenzo Vestuto

Metabolites 2025, 15(4), 221; https://doi.org/10.3390/metabo15040221 - 24 Mar 2025

Abstract

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In [...] Read more.

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies. Full article

(This article belongs to the Special Issue NMR-Metabolomics in Peptide and Antibody Drug Discovery)

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26 pages, 1447 KiB

Open AccessReview

Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health

by Eugenio Caradonna, Federico Abate, Elisabetta Schiano, Francesca Paparella, Fulvio Ferrara, Emilio Vanoli, Rossana Difruscolo, Vito Maria Goffredo, Bruno Amato, Carlo Setacci, Francesco Setacci and Ettore Novellino

Metabolites 2025, 15(4), 220; https://doi.org/10.3390/metabo15040220 - 24 Mar 2025

Abstract

The intestinal microbiota, hosting trillions of microorganisms that inhabit the gastrointestinal tract, functions as a symbiotic organism that plays a crucial role in regulating health by producing biologically active molecules that can enter systemic circulation. Among them, trimethylamine-N-oxide (TMAO), an organic compound derived [...] Read more.

The intestinal microbiota, hosting trillions of microorganisms that inhabit the gastrointestinal tract, functions as a symbiotic organism that plays a crucial role in regulating health by producing biologically active molecules that can enter systemic circulation. Among them, trimethylamine-N-oxide (TMAO), an organic compound derived from dietary sources and microbial metabolism, has emerged as a critical biomarker linking diet, the gut microbiota, and the host metabolism to various pathological conditions. This comprehensive review highlights TMAO’s biosynthesis, physiological functions, and clinical significance, focusing on its mechanistic contributions to cardiovascular and neurodegenerative diseases. Notably, TMAO-mediated pathways include endothelial dysfunction, inflammation via NLRP3 inflammasome activation, and cholesterol metabolism disruption, which collectively accelerate atherosclerosis and disease progression. Nonetheless, this work underscores the innovative potential of targeting TMAO through dietary, nutraceutical, and microbiota-modulating strategies to mitigate its pathological effects, marking a transformative approach in the prevention and management of TMAO-related disorders. Full article

(This article belongs to the Special Issue Metabolism of Bioactives and Natural Products)

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18 pages, 321 KiB

Open AccessReview

Mycotoxins in Feed: Hazards, Toxicology, and Plant Extract-Based Remedies

by Xiangnan Zhang, Jiashun Chen, Xiaokang Ma, Xiongzhuo Tang, Bie Tan, Peng Liao, Kang Yao and Qian Jiang

Metabolites 2025, 15(4), 219; https://doi.org/10.3390/metabo15040219 - 24 Mar 2025

Abstract

Background: Mycotoxins, which are secondary metabolites produced by fungi, are prevalent in animal feed and pose a serious risk to the healthy growth of livestock and poultry. Methods: This review aims to conclude current knowledge on the detrimental effects of mycotoxins on animal [...] Read more.

Background: Mycotoxins, which are secondary metabolites produced by fungi, are prevalent in animal feed and pose a serious risk to the healthy growth of livestock and poultry. Methods: This review aims to conclude current knowledge on the detrimental effects of mycotoxins on animal health and to demonstrate the potential of plant extracts as a means to counteract mycotoxin toxicity in feed. A systematic review of the literature was conducted to identify studies on the impact of mycotoxins on livestock and poultry health, as well as research into the use of plant extracts as feed additives to mitigate mycotoxin effects. Studies were selected based on their relevance to the topic, and data were extracted regarding the mechanisms of action and the efficacy of plant extracts. Results: Excessive mycotoxins in feed can lead to reduced appetite, impaired digestion, and general health issues in animals, resulting in decreased food intake, slowed weight gain, and instances of acute poisoning. Plant extracts with antioxidant, anti-inflammatory, and anti-mutagenic properties have shown the potential to improve production efficiency and reduce the toxic effects of mycotoxins. Conclusion: This comprehensive review not only consolidates the well-documented adverse effects of mycotoxins on animal health but also introduces a novel perspective by highlighting the potential of plant extracts as a promising and natural solution to counteract mycotoxin toxicity. Full article

(This article belongs to the Special Issue Intestinal Health and Metabolites in Farm Animals)

17 pages, 1314 KiB

Open AccessArticle

Short-Term Supplementation with 100% Bilberry Products and Its Effects on Body Composition and Lipid Profile in Overweight/Obese Women

by Marta Habanova, Maros Bihari, Radek Latal, Martina Gažarova, Petra Lenártová, Jana Pastrnakova and Jadwiga Hamulka

Metabolites 2025, 15(4), 218; https://doi.org/10.3390/metabo15040218 - 24 Mar 2025

Abstract

Introduction: Overweight and obesity are major public health concerns, often leading to increased cardiovascular risk. Methods: This eight-week interventional study examined whether regular consumption of two natural bilberry products could improve body composition and lipid profiles in overweight/obese women. A total [...] Read more.

Introduction: Overweight and obesity are major public health concerns, often leading to increased cardiovascular risk. Methods: This eight-week interventional study examined whether regular consumption of two natural bilberry products could improve body composition and lipid profiles in overweight/obese women. A total of 30 participants (aged 50–60 years) were assigned to consume either 125 mL/day of 100% bilberry juice or 10 g/day of 100% bilberry fibre, while maintaining their habitual diets and lifestyles. Results: Although no significant changes were found in anthropometric parameters or blood pressure in either group, both interventions reduced low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C). Surprisingly, total cholesterol (TC) levels rose in the bilberry juice group (from 6.41 ± 1.23 mmol/L to 6.94 ± 1.30 mmol/L (p < 0.001)), and in the fibre group (from 6.06 ± 1.39 mmol/L to 6.43 ± 1.05 mmol/L (p = 0.046)), likely due to elevated HDL-C (p < 0.001) overshadowing the drop in LDL-C (p < 0.05). Triglyceride (TG) levels did not change significantly and were still within the reference range. Conclusions: Notably, the bilberry juice group experienced a significant reduction in atherogenic small dense LDL (sdLDL) subfractions, suggesting a favourable shift in cardiovascular risk factors. These findings highlight the potential of bilberry-based products as a supportive strategy for improving lipid profiles in overweight/obese women. Full article

(This article belongs to the Special Issue Effects of Diet on Metabolic Health of Obese People)

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18 pages, 3237 KiB

Open AccessArticle

Metabolic Niches and Plasticity of Sand-Dune Plant Communities Along a Trans-European Gradient

by Matthew P. Davey, Rachel M. George, Mark K. J. Ooi, Mike M. Burrell and Robert P. Freckleton

Metabolites 2025, 15(4), 217; https://doi.org/10.3390/metabo15040217 - 24 Mar 2025

Abstract

Background: One of the greatest challenges to biologists is to understand the adaptive mechanisms of how plants will respond to climate at all levels from individual physiology to whole populations. For example, variation (plasticity) in the composition and concentration of metabolites will determine [...] Read more.

Background: One of the greatest challenges to biologists is to understand the adaptive mechanisms of how plants will respond to climate at all levels from individual physiology to whole populations. For example, variation (plasticity) in the composition and concentration of metabolites will determine productivity, reproduction, and ultimately survival and distribution of plants, especially those subjected to rapid climate change. Objectives: Our aim was to study how interspecific and intraspecific metabolic variation in plant species within a single community can be elucidated. Methods: We used a metabolomics approach to study metabolic acclimation (by measuring the metabolome between plants under “common garden” controlled environment conditions) and metabolic plasticity (using field based reciprocal transplant studies) in a set of Atlantic sand dune annual communities along a latitudinal gradient from Portugal to England. Results: In the common garden study, metabolically phenotyping (using a fingerprinting direct injection mass spectrometry approach) five species of annual plants showed that species living together in a community have distinct metabolic phenotypes (high inter-specific metabolic variation). There was low intra-specific metabolic variation between populations growing under standard environmental conditions. The metabolic variation in one species Veronica arvensis was measured in the reciprocal transplant study. Metabolic phenotypes obtained from all samples were similar across all sites regardless of where the plants originated from. Conclusions: This implies that the metabolome is highly plastic and the measurable metabolome in this study was influenced more by local environmental factors than inherent genetic factors. This work highlights that species are fulfilling different niches within this community. Furthermore, the measurable metabolome was highly plastic to environmental variation. Full article

(This article belongs to the Special Issue Plant Biotic and Abiotic Stress Responses and Tolerance: Phytohormonal and Metabolic Insights)

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17 pages, 3145 KiB

Open AccessReview

Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators

by Jorge Augusto Alamillo-Vásquez, Claudia-Anahí Pérez-Torres, Enrique Ibarra-Laclette, Feliza Ramón-Farías, Pilar Nicasio-Torres and Fulgencio Alatorre-Cobos

Metabolites 2025, 15(4), 216; https://doi.org/10.3390/metabo15040216 - 23 Mar 2025

Abstract

Plant-based traditional medicine integrates beliefs, knowledge, and practices to prevent and treat multiple diseases. Croton is a large and worldwide-spread genus belonging to Euphorbiaceae, a family well known for comprising many species with medicinal properties due to its high diversity of phytochemical constituents [...] Read more.

Plant-based traditional medicine integrates beliefs, knowledge, and practices to prevent and treat multiple diseases. Croton is a large and worldwide-spread genus belonging to Euphorbiaceae, a family well known for comprising many species with medicinal properties due to its high diversity of phytochemical constituents with biological activities. Among the various benefits of Croton species in traditional medicine, its use in cancer treatment has recently received significant attention from the scientific community. This review provides a general overview of different studies on the Croton genus in the research for alternative cancer treatments and the impact of its secondary metabolite catalog on cell cycle targets. Our analysis indicates that just under 30 secondary metabolites have been identified so far in latex and extracts obtained from leaves, twigs, or bark from 22 different Croton species. Based on standard assays using cell lines or human platelets, these molecules show multiple biological activities mainly compromising cell viability and cell cycle progression, supporting the ethnobotanical use of Croton species for cancer treatment. Several studies indicate that Croton metabolites target CDK–cyclin complexes and signaling routes that trigger apoptosis; however, further studies are needed to better understand the molecular mechanisms underlying Croton metabolites’ effects and their accurate future applications in cancer treatment. Full article

(This article belongs to the Special Issue Phytochemicals and Pharmacological Significance of Plant Secondary Metabolites in Medicine)

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16 pages, 250 KiB

Open AccessArticle

Impact of the Dietary Fat Concentration and Source on the Fecal Microbiota of Healthy Adult Cats

by Nadine Paßlack, Kathrin Büttner, Wilfried Vahjen and Jürgen Zentek

Metabolites 2025, 15(4), 215; https://doi.org/10.3390/metabo15040215 - 22 Mar 2025

Abstract

Background/Objectives: The dietary fat supply might interact with the intestinal microbiota via different mechanisms. Research on this topic, however, remains scarce in cats. For this reason, the present study was conducted to evaluate the impact of the fat concentration and fatty acid profile [...] Read more.

Background/Objectives: The dietary fat supply might interact with the intestinal microbiota via different mechanisms. Research on this topic, however, remains scarce in cats. For this reason, the present study was conducted to evaluate the impact of the fat concentration and fatty acid profile in the diet on the fecal microbiota of healthy cats. Methods: A low-fat basal diet was fed to ten healthy adult cats. The diet was offered without or with the daily addition of 0.5 g or 1 g of sunflower oil, fish oil or lard per kg body weight of the cats, using a randomized cross-over design. Each feeding period lasted for 21 days, and the fecal samples were collected on the last days of each period. The fecal microbiota was analyzed by 16S rDNA sequencing. Additionally, microbial metabolites (short-chain fatty acids, lactate, ammonium, biogenic amines) were measured in the fecal samples. Results: The dietary treatment had no impact on the alpha-diversity of the fecal microbiota or on the relative abundance of bacterial phyla in the samples. Only a few changes were observed in the relative abundance of bacterial genera and the concentrations of microbial metabolites in the feces, probably being of minor physiological relevance. Conclusions: The balanced intestinal microbiota of cats seems to be relatively resistant to moderate variations in the dietary fat supply over a short feeding period. Longer-term treatments and higher dietary fat levels should be evaluated in future studies to further clarify the relevance of fat intake for the feline gut microbiome. Full article

(This article belongs to the Special Issue Metabolic Research in Animal Nutrition and Production)

18 pages, 3720 KiB

Open AccessArticle

Double-Weighted Bayesian Model Combination for Metabolomics Data Description and Prediction

by Jacopo Troisi, Martina Lombardi, Alessio Trotta, Vera Abenante, Andrea Ingenito, Nicole Palmieri, Sean M. Richards, Steven J. K. Symes and Pierpaolo Cavallo

Metabolites 2025, 15(4), 214; https://doi.org/10.3390/metabo15040214 - 21 Mar 2025

Abstract

Background/Objectives: This study presents a novel double-weighted Bayesian Ensemble Machine Learning (DW-EML) model aimed at improving the classification and prediction of metabolomics data. This discipline, which involves the comprehensive analysis of metabolites in a biological system, provides valuable insights into complex biological processes [...] Read more.

Background/Objectives: This study presents a novel double-weighted Bayesian Ensemble Machine Learning (DW-EML) model aimed at improving the classification and prediction of metabolomics data. This discipline, which involves the comprehensive analysis of metabolites in a biological system, provides valuable insights into complex biological processes and disease states. As metabolomics assumes an increasingly prominent role in the diagnosis of human diseases and in precision medicine, there is a pressing need for more robust artificial intelligence tools that can offer enhanced reliability and accuracy in medical applications. The proposed DW-EML model addresses this by integrating multiple classifiers within a double-weighted voting scheme, which assigns weights based on the cross-validation accuracy and classification confidence, ensuring a more reliable prediction framework. Methods: The model was applied to publicly available datasets derived from studies on critical illness in children, chronic typhoid carriage, and early detection of ovarian cancer. Results: The results demonstrate that the DW-EML approach outperformed methods traditionally used in metabolomics, such as the Partial Least Squares Discriminant Analysis in terms of accuracy and predictive power. Conclusions: The DW-EML model is a promising tool for metabolomic data analysis, offering enhanced robustness and reliability for diagnostic and prognostic applications and potentially contributing to the advancement of personalized and precision medicine. Full article

(This article belongs to the Section Bioinformatics and Data Analysis)

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25 pages, 1151 KiB

Open AccessSystematic Review

Intestinal Metabolome for Diagnosing and Prognosing Autism Spectrum Disorder in Children: A Systematic Review

by Andrés Suárez-Jaramillo, Sara G. Cifuentes, Manuel Baldeón and Paúl Cárdenas

Metabolites 2025, 15(4), 213; https://doi.org/10.3390/metabo15040213 - 21 Mar 2025

Abstract

Background/Objectives: Currently, the diagnosis of autism spectrum disorder (ASD) relies on behavioral observations, frequently causing delays in early identification. Prognostic markers are essential for customizing therapy and monitoring progress. However, there are currently no recognized biomarkers for ASD. The current systematic review [...] Read more.

Background/Objectives: Currently, the diagnosis of autism spectrum disorder (ASD) relies on behavioral observations, frequently causing delays in early identification. Prognostic markers are essential for customizing therapy and monitoring progress. However, there are currently no recognized biomarkers for ASD. The current systematic review aims to analyze studies on the intestinal metabolome in children (both autistic and non-autistic) to identify potential metabolites for diagnostic and prognostic purposes. Methods: We searched Medline, Scopus, Embase, and Web of Science for relevant publications. Results: We identified 11 studies examining the gut metabolome that distinguished between autistic and non-autistic children. These studies also revealed connections between gut metabolites, developmental scores, and symptoms. The substances identified were associated with metabolic pathways such as amino acids, vitamins, lipids, oxidative stress, glycans, xenobiotics, and nucleotides. Conclusions: These findings suggest metabolic changes that may be linked to the causes or development of autism. Although these observations came from a few reports, only high-quality studies were included in this review. Further research is essential to confirm the identified substances as biomarkers. Full article

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19 pages, 2396 KiB

Open AccessArticle

Valorizing Agro-Industrial By-Products for Sustainable Cultivation of Chlorella sorokiniana: Enhancing Biomass, Lipid Accumulation, Metabolites, and Antimicrobial Potential

by Elia Lio, Carlo Esposito, Jacopo Paini, Stefano Gandolfi, Francesco Secundo and Gianluca Ottolina

Metabolites 2025, 15(3), 212; https://doi.org/10.3390/metabo15030212 - 20 Mar 2025

Abstract

Background/Objectives: Mixotrophic cultivation of microalgae using agro-industrial by-products as supplements offers a sustainable strategy to enhance biomass production and bioactive compound synthesis. This study aimed to evaluate the effects of different agro-industrial by-products—orange peel extract, Cladophora glomerata macroalgal hydrolysate, and solid-state fungal fermentation [...] Read more.

Background/Objectives: Mixotrophic cultivation of microalgae using agro-industrial by-products as supplements offers a sustainable strategy to enhance biomass production and bioactive compound synthesis. This study aimed to evaluate the effects of different agro-industrial by-products—orange peel extract, Cladophora glomerata macroalgal hydrolysate, and solid-state fungal fermentation hydrolysate—on the growth and bioactivity of Chlorella sorokiniana. Methods: Microalgae were cultivated under mixotrophic conditions with different agro-industrial by-products as organic carbon sources. Biomass accumulation was monitored through dry weight measurements. Lipid extraction was carried out using dimethyl carbonate. The antimicrobial activity of the extracted compounds was assessed against Escherichia coli, Bacillus megaterium, and Bacillus subtilis by determining the minimal inhibitconcentrations. Results: Orange peel extract supplementation resulted in the highest biomass production. It increased dry weight by 13.86-fold compared to autotrophic conditions. Cladophora glomerata macroalgal hydrolysate followed with a 5.79-fold increase, and solid-state fungal fermentation hydrolysate showed a 4.14-fold increase. The lipophilic fraction extracted from microalgal biomass showed high yields. Orange peel extract supplementation achieved the highest extraction yield (274.36 mg/g DW). Antimicrobial activity varied based on the supplement used: biomass cultivated with orange peel extract exhibited superior activity against E. coli, whereas Cladophora glomerata macroalgal hydrolysate biomass demonstrated potent activity against B. subtilis (MIC: 5.67 g/mL). Conclusions: These findings underscore the potential of agro-industrial by-products for enhancing microalgal biomass and metabolite production. The observed antimicrobial properties highlight the application of microalgal-derived compounds in sustainable bioprocesses, supporting their use in pharmaceutical and biotechnological applications. Full article

(This article belongs to the Special Issue Metabolism of Bioactives and Natural Products)

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19 pages, 1291 KiB

Open AccessReview

Diet-Induced Proteomic and Metabolomic Signatures in Chronic Kidney Disease: A Precision Nutrition Approach

by Sandra Cabała and Agnieszka Herosimczyk

Metabolites 2025, 15(3), 211; https://doi.org/10.3390/metabo15030211 - 20 Mar 2025

Abstract

Background: Diet is a key modifiable factor that can either support renal health or accelerate the onset and progression of chronic kidney disease (CKD). Recent advances in multiomics, particularly proteomics and metabolomics, significantly enhanced our understanding of the molecular mechanisms linking diet to [...] Read more.

Background: Diet is a key modifiable factor that can either support renal health or accelerate the onset and progression of chronic kidney disease (CKD). Recent advances in multiomics, particularly proteomics and metabolomics, significantly enhanced our understanding of the molecular mechanisms linking diet to CKD risk. Proteomics offers a comprehensive analysis of protein expression, structure, and interactions, revealing how dietary components regulate cellular processes and signaling pathways. Meanwhile, metabolomics provides a detailed profile of low-molecular-weight compounds, including endogenous metabolites and diet-derived molecules, offering insights into the metabolic states that influence kidney function. Methods: We have conducted a narrative review of key papers from databases such as PubMed, Scopus, and Web of Science to explore the potential of proteomic and metabolomic analysis in identifying molecular signatures associated with diet in human and animal biological samples, such as blood plasma, urine, and in kidney tissues. These signatures help elucidate how specific foods, food groups, and overall dietary patterns may either contribute to or mitigate CKD risk. Results: Recent studies the impact of high-fat diets on protein expression involved in energy metabolism, inflammation, and fibrosis, identifying early biomarkers of kidney injury. Metabolic, including disruptions in in fatty acid metabolism, glucose regulation, and amino acid pathways, have been recognized as key indicators of CKD risk. Additionally, several studies explore specific metabolites found in biological fluids and renal tissue in response to protein-rich foods, assessing their potential roles in a progressive loss of kidney function. Emerging evidence also suggests that dietary interventions targeting the gut microbiota may help alleviate inflammation, oxidative stress, and toxin accumulation in chronic kidney disease. Notably, recent findings highlight metabolomic signatures linked to beneficial shifts in gut microbial metabolism, particularly in the context of prebiotic supplementation. Conclusions: By integrating proteomics and metabolomics, future research can refine precision nutrition strategies, helping mitigate CKD progression. Expanding large-scale studies and clinical trials will be essential in translating these molecular insights into actionable dietary guidelines. Full article

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

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30 pages, 4051 KiB

Open AccessReview

Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease

by Yuechang Wang, Yonggang Zhang, Wei Wang, Yanmin Zhang, Xueqian Dong and Yang Liu

Metabolites 2025, 15(3), 210; https://doi.org/10.3390/metabo15030210 - 20 Mar 2025

Abstract

Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism. The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, [...] Read more.

Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism. The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine. Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions. These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities. Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases. These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease. Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation. The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health. Full article

(This article belongs to the Special Issue Metabolism of Bioactives and Natural Products)

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17 pages, 995 KiB

Open AccessArticle

A Pilot Study: Maternal Undernutrition Programs Energy Metabolism and Alters Metabolic Profile and Morphological Characteristics of Skeletal Muscle in Postnatal Beef Cattle

by Daichi Nishino, Taketo Haginouchi, Takeshi Shimogiri, Susumu Muroya, Kenji Kawabata, Saki Urasoko, Ichiro Oshima, Shinobu Yasuo and Takafumi Gotoh

Metabolites 2025, 15(3), 209; https://doi.org/10.3390/metabo15030209 - 19 Mar 2025

Abstract

Objectives: This study investigated the long-term effects of maternal undernutrition on overall muscle metabolism, growth performance, and muscle characteristics in postnatal offspring of Wagyu (Japanese Black) cattle. Methods: Wagyu cows were divided into nutrient-adequate (control, CNT; n = 4, 120% of [...] Read more.

Objectives: This study investigated the long-term effects of maternal undernutrition on overall muscle metabolism, growth performance, and muscle characteristics in postnatal offspring of Wagyu (Japanese Black) cattle. Methods: Wagyu cows were divided into nutrient-adequate (control, CNT; n = 4, 120% of requirements) and nutrient-restricted groups (NR; n = 4; 60% of requirements), and treated from day 35 of gestation until parturition. Diets were delivered on the basis of crude protein requirements, meeting 100% and 80% of dry matter requirements in CNT and NR groups, respectively. All offspring were provided with the same diet from birth to 300 days of age (d). Longissimus thoracis muscle (LM) samples were collected from the postnatal offspring. Results: The NR offspring had lower birth body weight, but their body weight caught up before weaning. These offspring showed enhanced efficiency in nutrient utilization during the post-weaning growth period. Comprehensive analyses of metabolites and transcripts revealed the accumulation of proteinogenic amino acid, asparagine, in NR offspring LM at 300 d, while the abundance of nicotinamide adenine dinucleotide (NADH) and succinate were reduced. These changes were accompanied by decreased gene expression of nicotinamide phosphoribosyltransferase (NAMPT), NADH: ubiquinone oxidoreductase subunit A12 (NDUFA12), and NADH dehydrogenase subunit 5 (ND5), which are essential for mitochondrial energy production. Additionally, NR offspring LM exhibited decreased abundance of neurotransmitter, along with a higher proportion of slow-oxidative myofibers and a lower proportion of fast-oxidative myofibers at 300 d. Conclusions: Offspring from nutrient-restricted cows might suppress muscle energy production, primarily in the mitochondria, and conserve energy expenditure for muscle protein synthesis. These findings suggest that maternal undernutrition programs a thrifty metabolism in offspring muscle, with long-term effects. Full article

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

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32 pages, 3207 KiB

Open AccessReview

Metabolomics in Parkinson’s Disease and Correlation with Disease State

by Elena A. Ostrakhovitch, Kenjiro Ono and Tritia R. Yamasaki

Metabolites 2025, 15(3), 208; https://doi.org/10.3390/metabo15030208 - 18 Mar 2025

Abstract

Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, are associated with developing diseases. Metabolite signatures in body fluids such as plasma, cerebrospinal fluid, urine, and saliva are associated with Parkinson’s disease. Here, we discuss alteration [...] Read more.

Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, are associated with developing diseases. Metabolite signatures in body fluids such as plasma, cerebrospinal fluid, urine, and saliva are associated with Parkinson’s disease. Here, we discuss alteration of metabolites in the TCA cycle, pentose phosphate pathway, kynurenic network, and redox system. We also summarize the efforts of many research groups to differentiate between metabolite profiles that characterize PD motor progression and dyskinesia, gait and balance, and non-motor symptoms such as depression and cognitive decline. Understanding how changes in metabolites lead to progression in PD may allow for the identification of individuals at the earliest stage of the disease and the development of new therapeutic strategies. Full article

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

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20 pages, 15032 KiB

Open AccessArticle

Multi-Omics Profiling Reveals Glycerolipid Metabolism-Associated Molecular Subtypes and Identifies ALDH2 as a Prognostic Biomarker in Pancreatic Cancer

by Jifeng Liu, Shurong Ma, Dawei Deng, Yao Yang, Junchen Li, Yunshu Zhang, Peiyuan Yin and Dong Shang

Metabolites 2025, 15(3), 207; https://doi.org/10.3390/metabo15030207 - 18 Mar 2025

Abstract

Background: The reprogramming of lipid metabolism, especially glycerolipid metabolism (GLM), plays a key role in cancer progression and response to therapy. However, the role and molecular characterization of GLM in pancreatic cancer (PC) remain unclear. Methods: A pan-cancer analysis of glycerolipid [...] Read more.

Background: The reprogramming of lipid metabolism, especially glycerolipid metabolism (GLM), plays a key role in cancer progression and response to therapy. However, the role and molecular characterization of GLM in pancreatic cancer (PC) remain unclear. Methods: A pan-cancer analysis of glycerolipid metabolism-related genes (GMRGs) was first conducted to assess copy-number variants, single-nucleotide variations, methylation, and mRNA expression. Subsequently, GLM in PC was characterized using lipidomics, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomic analysis. A cluster analysis based on bulk RNA sequencing data from 930 PC samples identified GLM-associated subtypes, which were then analyzed for differences in prognosis, biological function, immune microenvironment, and drug sensitivity. To prioritize prognostically relevant GMRGs in PC, we employed a random forest (RF) algorithm to rank their importance across 930 PC samples. Finally, the key biomarker of PC was validated using PCR and immunohistochemistry. Results: Pan-cancer analysis identified molecular features of GMRGs in cancers, while scRNA-seq, spatial transcriptomics, and lipidomics highlighted GLM heterogeneity in PC. Two GLM-associated subtypes with significant prognostic, biofunctional, immune microenvironmental, and drug sensitivity differences were identified in 930 PC samples. Finally, ALDH2 was identified as a novel prognostic biomarker in PC and validated in a large number of datasets and clinical samples. Conclusions: This study highlights the crucial role of GLM in PC and defines a new PC subtype and prognostic biomarker. These findings establish a novel avenue for studying prognostic prediction and precision medicine in PC patients. Full article

(This article belongs to the Special Issue New Analytical Techniques and Applications of Metabolomics and Lipidomics)

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