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Metabolites, Volume 15, Issue 2 (February 2025) – 44 articles

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19 pages, 5211 KiB  
Article
1H-NMR Lipidomics, Comparing Fatty Acids and Lipids in Cow, Goat, Almond, Cashew, Soy, and Coconut Milk Using NMR and Mass Spectrometry
by Brianna Williams, Shamika P. W. R. Hewage, Denzel Alexander and Harshica Fernando
Metabolites 2025, 15(2), 110; https://doi.org/10.3390/metabo15020110 (registering DOI) - 8 Feb 2025
Viewed by 84
Abstract
Background/Objectives: Lipids are an important component of human nutrition. Conventional milk is obtained from animals, and dairy milk is consumed by many people worldwide. Recently, milk consumers have been increasingly shifting towards plant-based milk options. The aim of the study was the qualitative [...] Read more.
Background/Objectives: Lipids are an important component of human nutrition. Conventional milk is obtained from animals, and dairy milk is consumed by many people worldwide. Recently, milk consumers have been increasingly shifting towards plant-based milk options. The aim of the study was the qualitative identification of lipid metabolites in animal- and plant-based milk, the identification and comparison of the fatty acids (FAs) of milk, and the qualitative identification of the lipid groups among the milk varieties. Methods: Milk samples were obtained from local grocery stores. Lipids were extracted using a modified Folch method and analyzed using nuclear magnetic resonance (NMR) metabolomics. Gas and liquid chromatography mass spectrometry methods (GC-MS and LC-MS) were used to identify the FAs and lipid groups. Lipid weights were compared and the NMR profiles of the lipids analyzed by multivariate statistical analysis. Principal component analysis was performed for the milk lipids obtained from the animal, and plant milk varieties. Results: Clustering of NMR data showed two main clusters: cow/almond/cashew and goat/soy/coconut. GC-MS analysis of the methylated fatty acids (FAs) showed the presence of 12:0, 14:0, 16:0, 16:1, 17:0, 18:0, 18:1, 18:2, 20:1, and 20:2 in all milk types, while FAs 19:0 and 20:4 were observed only in the dairy milk. LC-MS data showed common masses that may indicate the presence of mono- and diacyl glycerols and several lysophospholipids among the different types of milk. Conclusions: This study shows the advantage of using NMR, GC-MS, and LC-MS to differentiate the lipids among different milk types and compare them on one platform. Full article
(This article belongs to the Special Issue Application of NMR in Food Metabolomics)
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32 pages, 5153 KiB  
Article
Naringenin Decreases Retroperitoneal Adiposity and Improves Metabolic Parameters in a Rat Model of Western Diet-Induced Obesity
by Gabriela López-Almada, J. Abraham Domínguez-Avila, Rosario Maribel Robles-Sánchez, Jonathan Arauz-Cabrera, Gustavo Martínez-Coronilla, Gustavo A. González-Aguilar and Norma Julieta Salazar-López
Metabolites 2025, 15(2), 109; https://doi.org/10.3390/metabo15020109 (registering DOI) - 8 Feb 2025
Viewed by 95
Abstract
Background: Obesity is a multifactorial disease with detrimental effects on health and quality of life; unregulated satiety plays a crucial role in food intake and obesity development. Naringenin (NAR) has shown beneficial effects on lipid and carbohydrate metabolism, although its impact on adiposity [...] Read more.
Background: Obesity is a multifactorial disease with detrimental effects on health and quality of life; unregulated satiety plays a crucial role in food intake and obesity development. Naringenin (NAR) has shown beneficial effects on lipid and carbohydrate metabolism, although its impact on adiposity and satiety remains unclear. This study reports a Western diet (WD)-induced obesity model in rats, wherein 100 mg/kg of NAR was administered as an anti-obesity agent for 8 weeks; oxidative stress, lipid profile, and satiety biomarkers were then studied, as well as in silico interaction between NAR and cholecystokinin (CCK) and ghrelin receptors. Results: NAR supplementation resulted in a significant decrease in retroperitoneal adipose tissue and liver weight, as compared to the untreated WD group (p < 0.05), potentially associated with a decreased feed efficiency. NAR also inhibited the development of dyslipidemia, particularly by reducing serum triglycerides (p < 0.05). NAR supplementation increased CCK serum levels in the basal diet group, an effect that was abolished by the WD (p < 0.05); likewise, no changes were determined on ghrelin (p > 0.05). In silico data shows that NAR is capable of interacting with the CCK and ghrelin receptors, which suggests a potential for it to modulate hunger/satiety signaling by interacting with them. Conclusions: We conclude that NAR has anti-obesogenic effects and may regulate CCK serum levels, although further research is still needed. Full article
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6 pages, 178 KiB  
Editorial
Lipid Biomarkers and Cardiometabolic Diseases: Critical Knowledge Gaps and Future Research Directions
by Hyun Suk Yang
Metabolites 2025, 15(2), 108; https://doi.org/10.3390/metabo15020108 (registering DOI) - 7 Feb 2025
Viewed by 163
Abstract
The past decade has witnessed transformative changes in our understanding of various lipid or lipid-related biomarkers (Table 1) and their relationships with cardiometabolic diseases [...] Full article
(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases)
17 pages, 9494 KiB  
Article
Omics Analysis Revealing Flavonoid Content During Maize Grain Germination
by Xiaomin Tian, Lirong Chen, Linlin Sun, Kuijie Gong, Kaichang Liu and Yuqiu Guo
Metabolites 2025, 15(2), 107; https://doi.org/10.3390/metabo15020107 - 7 Feb 2025
Viewed by 251
Abstract
Background/Objectives: The germination process initiates an active process of secondary metabolism, which produces a series of secondary metabolites, including flavonoids. Methods: A metabolomics and transcriptomics analysis was conducted on maize grains germinated at three different stages. Results: A total of 374 metabolites were [...] Read more.
Background/Objectives: The germination process initiates an active process of secondary metabolism, which produces a series of secondary metabolites, including flavonoids. Methods: A metabolomics and transcriptomics analysis was conducted on maize grains germinated at three different stages. Results: A total of 374 metabolites were detected in maize grains. From the raw maize grain to various stages of germination, 3 anthocyanins, 61 flavones, 12 flavonols, 13 flavanones, and 6 isoflavones were identified, respectively. An integrated omics analysis discovered that a total of 16 flavonoid metabolites were mapped to 4 KEGG pathways, which were associated with 40 related genes. This indicates that germination has significant benefits in improving the nutritional function of corn kernels. Conclusions: In summary, the findings of this study provide valuable insights into flavonoid metabolites and related genes, demonstrating the profound impact of germination treatment on the nutritional and functional aspects of maize grains. Full article
(This article belongs to the Section Plant Metabolism)
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14 pages, 2993 KiB  
Article
Reference Intervals of Serum Metabolites and Lipids of a Healthy Chinese Population Determined by Liquid Chromatography-Mass Spectrometry
by Yuqing Zhang, Jinhui Zhao, Hui Zhao, Xin Lu, Xueni Jia, Xinjie Zhao and Guowang Xu
Metabolites 2025, 15(2), 106; https://doi.org/10.3390/metabo15020106 - 7 Feb 2025
Viewed by 249
Abstract
Background: Metabolomics serves as a very useful tool for elucidating disease mechanisms and identifying biomarkers. Establishing reference intervals (RIs) of metabolites in a healthy population is crucial to the application of metabolomics in life sciences and clinics. Methods: We enrolled 615 healthy Chinese [...] Read more.
Background: Metabolomics serves as a very useful tool for elucidating disease mechanisms and identifying biomarkers. Establishing reference intervals (RIs) of metabolites in a healthy population is crucial to the application of metabolomics in life sciences and clinics. Methods: We enrolled 615 healthy Chinese adults aged between 21 and 85 years. Their health status was ascertained through clinical examinations, biochemical parameters, and medical history. Targeted metabolomics and lipidomics analyses were applied to quantify 705 metabolites and lipids in the serum, establishing RIs and investigating the effect of sex and age on the metabolome and lipidome. Results: This study is the first large-scale effort in China to establish RIs for metabolites in the apparently healthy population. We found that most of the sex-related metabolites, including amino acids, acyl-carnitines and triacylglycerols, had higher concentrations in males, while the other sex-related lipids showed higher concentrations in females. Most of the age-related metabolites increased with age, including those associated with protein synthesis, nitric oxide synthesis, energy metabolism, and lipid metabolism. Conclusions: This study gives the reference intervals of the healthy Chinese metabolome and lipidome and their relationship with sex and age, which facilitates life sciences and precision medicine, especially for disease research and biomarker discovery. Full article
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14 pages, 3484 KiB  
Article
Bacillusmegaterium DSM 32963 Enhances Specialized Pro-Resolving Mediator Production from an n-3 PUFA Salt in a Dynamic Model of the Human Intestine
by Bodo Speckmann, Paul M. Jordan, Oliver Werz, Robert K. Hofstetter, Ellen Ehring, Marie-Luise Vogel and Koen Venema
Metabolites 2025, 15(2), 105; https://doi.org/10.3390/metabo15020105 - 7 Feb 2025
Viewed by 254
Abstract
Background: Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been used in the treatment of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), and their effects are potentiated upon conversion to specialized pro-resolving mediators (SPM). Recent studies indicated that the probiotic [...] Read more.
Background: Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been used in the treatment of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), and their effects are potentiated upon conversion to specialized pro-resolving mediators (SPM). Recent studies indicated that the probiotic bacterial strain Bacillus megaterium DSM 32963 can be used to enhance the production of SPM and its precursors in vivo. Methods: Here, we explored the contribution of Bacillus megaterium DSM 32963 to SPM production in a validated, dynamic model of the upper and lower intestine. The TIM-1 and TIM-2 models were applied, with the TIM-2 model inoculated with the fecal microbiota of healthy individuals and probed with an n-3 PUFA lysine salt with and without Bacillus megaterium DSM 32963 or an SPM-enriched fish oil or placebo. Kinetics of SPM production were assessed by metabololipidomics analysis, and survival and engraftment of the Bacillus megaterium strain was monitored by plate counting and by strain-specific qPCR. Results: Bacillus megaterium DSM 32963 poorly survived TIM-1 conditions but propagated in the TIM-2 model, where it enabled the metabolism of n-3 PUFA to SPM (resolvin E2 and protectin DX) and SPM precursors (e.g., 5-hydroxyeicosapentaenoic acid (5-HEPE), 15-HEPE, 18-HEPE, 4-hydroxydocosahexaenoic acid (4-HDHA), 10-HDHA, and 17-HDHA, among other EPA- and DHA-derived metabolites) with significantly higher levels of lipid mediator production compared to the n-3 PUFA lysine salt alone; esterified n-3 PUFA were hardly converted by the microbiota. Conclusions: These findings reinforce that Bacillus megaterium DSM 32963 facilitates SPM production in situ from bioavailable n-3 PUFA in the large intestine, highlighting its use to complement eukaryotic SPM biosynthesis by the host and its possible therapeutic use for, e.g., IBD and IBS. Full article
(This article belongs to the Special Issue Advances in Gut Microbiome Metabolomics)
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22 pages, 1356 KiB  
Article
A New, Validated GC-PICI-MS Method for the Quantification of 32 Lipid Fatty Acids via Base-Catalyzed Transmethylation and the Isotope-Coded Derivatization of Internal Standards
by Petr Vodrážka, Lucie Řimnáčová, Petra Berková, Jan Vojtíšek, Miroslav Verner, Martin Moos and Petr Šimek
Metabolites 2025, 15(2), 104; https://doi.org/10.3390/metabo15020104 - 7 Feb 2025
Viewed by 248
Abstract
Background: Fatty acids (FAs) represent a ubiquitous class of nonpolar alkyl carboxylate metabolites with diverse biological functions. Nutrition, metabolism, and endogenous and exogenous stress influence the overall FA metabolic status and transport via the bloodstream. FAs esterified in lipids are of particular interest, [...] Read more.
Background: Fatty acids (FAs) represent a ubiquitous class of nonpolar alkyl carboxylate metabolites with diverse biological functions. Nutrition, metabolism, and endogenous and exogenous stress influence the overall FA metabolic status and transport via the bloodstream. FAs esterified in lipids are of particular interest, as they represent promising biomarkers of pathological diseases and nutritional status. Methods: Here, we report a validated gas chromatographic-mass spectrometric (GC-MS) method for the quantitative analysis of 32 FAs exclusively bound in esterified lipids. The developed sample preparation protocol comprises three steps using only 5 µL of human serum for Folch extraction, sodium methoxide-catalyzed transesterification in tert-butyl methyl ether, and re-extraction in isooctane prior to a quantitative GC-MS analysis with positive ion chemical ionization (PICI) and selected ion monitoring (SIM). Results: The base-catalyzed transmethylation step was studied for 14 lipid classes and was found to be efficient under mild conditions for all major esterified lipids but not for free FAs, lipid amides, or sphingolipids. To minimize matrix effects and instrument bias, internal fatty acid trideuteromethyl esters (D3-FAME) standards were prepared through isotope-coded derivatization with D3-labeled methylchloroformate/methanol medium mixed with each transmethylated serum extract for the assay. The method was validated according to FDA guidelines and evaluated by analyzing NIST SRM 2378 Serum 1 and sera from three healthy donors. Conclusions: The measured quantitative FA values are consistent with the reference data of SRM 2378, and they demonstrate the application potential of the described method for general FA analysis in esterified lipids as a novel complementary tool for lipidomics, as well as for the analysis of membrane FAs in dry blood spots and red blood cells. Full article
(This article belongs to the Section Lipid Metabolism)
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31 pages, 5603 KiB  
Article
Oregano Young Plants Cultured at Low Temperature Reveal an Enhanced Healing Effect of Their Extracts: Anatomical, Physiological and Cytotoxicity Approach
by Aikaterina L. Stefi, Maria Chalkiadaki, Katerina Dimitriou, Konstantina Mitsigiorgi, Dimitrios Gkikas, Danae Papageorgiou, Georgia C. Ntroumpogianni, Dido Vassilacopoulou, Maria Halabalaki and Nikolaos S. Christodoulakis
Metabolites 2025, 15(2), 103; https://doi.org/10.3390/metabo15020103 - 7 Feb 2025
Viewed by 350
Abstract
Background: The germination and early development of Origanum vulgare L. subsp. hirtum (Link) Ietswaart (Greek oregano) were studied to assess the plant’s response to different temperatures. Methods: After germination, seedlings were cultivated in control (25 °C) and cold (15 °C) chambers with standard [...] Read more.
Background: The germination and early development of Origanum vulgare L. subsp. hirtum (Link) Ietswaart (Greek oregano) were studied to assess the plant’s response to different temperatures. Methods: After germination, seedlings were cultivated in control (25 °C) and cold (15 °C) chambers with standard growth parameters. Comparative analyses of plant morphology and leaf anatomy were conducted to identify structural modifications induced by different temperatures. Physiological evaluations, including photosynthetic pigment measurements, phenolic content, and antioxidant activity, were performed to assess differences between the plants grown under the two temperature conditions. Methanolic extracts from the leaves were tested for cytotoxicity on MCF-7 breast adenocarcinoma cells and SH-SY5Y neuroblastoma cells, as well as on nine microbial strains. Additionally, biomarkers from the leaves affected by temperature changes were determined using LC-HRMS/MS analysis. Results: Comparative analyses revealed distinct structural and physiological modifications under cold conditions. The methanolic extracts from plants grown at 15 °C exhibited notably higher cytotoxic activity in both cell lines but demonstrated no activity against microbial strains. The results highlight the influence of low temperature on enhancing the bioactive properties of Greek oregano. Conclusions: The findings provide valuable insights into the environmental adaptability of oregano, demonstrating the impact of low temperature on its bioactive properties. The therapeutic potential of methanolic extracts cultured at 15 °C is imprinted in cytotoxicity in SH-SY5Y and MCF-7 cells and the absence of any activity against microbial strains. Full article
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16 pages, 4530 KiB  
Article
Salicylic Acid Modulates Volatile Organic Compound Profiles During CEVd Infection in Tomato Plants
by Marc Balanzá, Francisco Vázquez-Prol, Ismael Rodrigo, José María Bellés, Francisco Vera-Sirera, Maria Pilar López-Gresa and Purificación Lisón
Metabolites 2025, 15(2), 102; https://doi.org/10.3390/metabo15020102 - 6 Feb 2025
Viewed by 379
Abstract
Background:Citrus Exocortis Viroid (CEVd) is a non-coding RNA pathogen capable of infecting a wide range of plant species, despite its lack of protein-coding ability. Viroid infections induce significant alterations in various physiological and biochemical processes, particularly impacting plant metabolism. This study shows [...] Read more.
Background:Citrus Exocortis Viroid (CEVd) is a non-coding RNA pathogen capable of infecting a wide range of plant species, despite its lack of protein-coding ability. Viroid infections induce significant alterations in various physiological and biochemical processes, particularly impacting plant metabolism. This study shows the metabolic changes upon viroid infection in tomato plants (Solanum lycopersicum var. ‘MoneyMaker’) exhibiting altered levels of salicylic acid (SA), a key signal molecule involved in the plant defence against this pathogen. Methods: Transgenic RNAi_S5H lines, which have the salicylic acid 5-hydroxylase gene silenced to promote SA accumulation, and NahG lines, which overexpress a salicylate hydroxylase to degrade SA into catechol and prevent its accumulation, were used to establish different SA levels in plants, resulting in varying degrees of resistance to viroid infection. The analysis was performed by using gas chromatography–mass spectrometry (GC-MS) to explore the role of volatile organic compounds (VOCs) in plant immunity against this pathogen. Results: Our results revealed distinct volatile profiles associated with plant immunity, where RNAi_S5H-resistant plants showed significantly enhanced production of monoterpenoids upon viroid infection. Moreover, viroid-susceptible NahG plants emitted a broad range of VOCs, whilst viroid-tolerant RNAi_S5H plants exhibited less variation in VOC emission. Conclusions: This study demonstrates that SA levels significantly influence metabolic responses and immunity in tomato plants infected by CEVd. The identification of differential emitted VOCs upon CEVd infection could allow the development of biomarkers for disease or strategies for disease control. Full article
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25 pages, 2912 KiB  
Review
Metabolic Objectives and Trade-Offs: Inference and Applications
by Da-Wei Lin, Saanjh Khattar and Sriram Chandrasekaran
Metabolites 2025, 15(2), 101; https://doi.org/10.3390/metabo15020101 - 6 Feb 2025
Viewed by 313
Abstract
Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and [...] Read more.
Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and environmental constraints. While rapidly proliferating cells like tumors are often assumed to prioritize biomass production, mammalian cell types can exhibit objectives beyond growth, such as supporting tissue functions, developmental processes, and redox homeostasis. Methods: This review addresses the challenge of determining metabolic objectives and trade-offs from multiomics data. Results: Recent advances in single-cell omics, metabolic modeling, and machine/deep learning methods have enabled the inference of cellular objectives at both the transcriptomic and metabolic levels, bridging gene expression patterns with metabolic phenotypes. Conclusions: These in silico models provide insights into how cells adapt to changing environments, drug treatments, and genetic manipulations. We further explore the potential application of incorporating cellular objectives into personalized medicine, drug discovery, tissue engineering, and systems biology. Full article
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32 pages, 821 KiB  
Review
Practical Recommendations in the Treatment of Acute and Chronic Life-Threatening Infectious Diseases in Patients with Acute Hepatic Porphyria
by Bruno de Mattos Lombardi Badia, Paulo de Lima Serrano, João Paulo Barile, Daniel Delgado Seneor, Patrícia Marques Mendes, Renan Brandão Rambaldi Cavalheiro, Kaliny Oliveira Peixoto, Igor Braga Farias, Roberta Ismael Lacerda Machado, Wladimir Bocca Vieira de Rezende Pinto, Acary Souza Bulle Oliveira and Paulo Sgobbi
Metabolites 2025, 15(2), 99; https://doi.org/10.3390/metabo15020099 - 5 Feb 2025
Viewed by 276
Abstract
Background: Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical [...] Read more.
Background: Acute hepatic porphyrias (AHPs) represent inherited metabolic disorders of the heme biosynthesis pathway, leading to neurological and systemic impairment. Despite the presence of well-recognized chronic symptoms and signs, acute neurological, both neuromuscular and central neurological complications pose a significant challenge in clinical practice, with a potential risk of greater severity and mortality during acute decompensation episodes of AHPs. Care related to the prescription of medications, considering the risk of porphyrinogenicity, is a major and recurring concern in the acute and chronic management of AHP patients. Infectious clinical complications are significant issues in both outpatient and hospital settings for patients with AHPs. It is crucial to identify therapeutic regimens with the best safety and efficacy profiles for treating such infectious complications in AHP patients. The scarcity of structured knowledge available in guidelines and recommendations often leads to the use of therapeutic options with higher potential risks in treating patients with AHPs. Objectives: This review article aims to provide practical recommendations for managing the most significant infectious complications in clinical practice, with a focus on their impact on the clinical care of patients with AHPs. Full article
(This article belongs to the Special Issue The Comorbidity of Neurodegenerative and Metabolic Diseases)
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18 pages, 7537 KiB  
Article
Investigation on Rational Utilization of Medicinal Plant Semiliquidambar cathayensis Chang Leaf and Bark at Different Developmental Stages
by Juanling Li, Zhaopeng Geng, Yuanyuan Yuan, Minjuan Wang, Yanan Zhang and Junli Wang
Metabolites 2025, 15(2), 98; https://doi.org/10.3390/metabo15020098 - 5 Feb 2025
Viewed by 314
Abstract
Background: Semiliquidambar cathayensis Chang is an extremely valuable and endangered medicinal plant. To investigate the exploitation and rational utilization of S. cathayensis, this study conducted metabolomics analysis of the leaves and bark of artificially cultivated S. cathayensis at different developmental stages. [...] Read more.
Background: Semiliquidambar cathayensis Chang is an extremely valuable and endangered medicinal plant. To investigate the exploitation and rational utilization of S. cathayensis, this study conducted metabolomics analysis of the leaves and bark of artificially cultivated S. cathayensis at different developmental stages. Methods: These metabolites were detected and identified by Ultra-Performance Liquid Chromatography–tandem Mass Spectrometry (UPLC-MS/MS) technology, and then univariate statistical analyses, multivariate pattern analyses, and pathway analyses were carried out. Results: As a result, a total of 801 metabolites were detected in S. cathayensis; differential metabolites in leaves at different developmental stages were mainly enriched in pathways related to flavonoids, whereas differential metabolites in bark at different developmental stages were mainly aromatic compounds, amino acids, and flavonoids, among others. This study revealed that young leaves are ideal for use in treating rheumatism, regulating blood pressure, and lowering blood glucose, while old leaves are better suited for skincare products and extracting materials to prevent neurodegenerative diseases and support women’s ovarian health. As for bark, four-year-old S. cathayensis bark is optimal for extracting myricetin. If the pharmaceutical, chemical, food, and industrial fields require extensive extraction of L-phenylalanine, trans-3-hydroxycinnamate, and 4-hydroxyphenylacetate, and if the medical field needs to extract anti-allergy, liver protection, and anti-coagulant ingredients, the two-year-old S. cathayensis bark is the best choice. Conclusions: Thus, this study established a solid theoretical framework for the rational, effective, and sustainable utilization of S. cathayensis leaves and bark. Full article
(This article belongs to the Section Plant Metabolism)
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16 pages, 6875 KiB  
Article
Metabolomic-Based Assessment of Earthworm (Eisenia fetida) Exposure to Different Petroleum Fractions in Soils
by Meiyu Liu, Mutian Wang, Xiaowen Fu, Fanyong Song, Fangyuan Zhou, Tianyuan Li and Jianing Wang
Metabolites 2025, 15(2), 97; https://doi.org/10.3390/metabo15020097 - 5 Feb 2025
Viewed by 387
Abstract
Background/Objectives: Petroleum contamination in soil exerts toxic effects on earthworms (Eisenia fetida) through non-polar narcotic mechanisms. However, the specific toxicities of individual petroleum components remain insufficiently understood. Methods: This study investigates the effects of four petroleum components—saturated hydrocarbons, aromatic hydrocarbons, resins, [...] Read more.
Background/Objectives: Petroleum contamination in soil exerts toxic effects on earthworms (Eisenia fetida) through non-polar narcotic mechanisms. However, the specific toxicities of individual petroleum components remain insufficiently understood. Methods: This study investigates the effects of four petroleum components—saturated hydrocarbons, aromatic hydrocarbons, resins, and asphaltenes—on earthworms in artificially contaminated soil, utilizing a combination of biochemical biomarker analysis and metabolomics to uncover the underlying molecular mechanisms. Results: The results revealed that aromatic hydrocarbons are the most toxic fraction, with EC50 concentrations significantly lower than those of other petroleum fractions. All tested fractions triggered notable metabolic disturbances and immune responses in earthworms after 7 days of exposure, as evidenced by significant changes in metabolite abundance within critical pathways such as arginine synthesis, a-linolenic acid metabolism, and the pentose phosphate pathway. According to the KEGG pathway analysis, saturated hydrocarbon fractions induced marked changes in glycerophospholipid metabolism, and arginine and proline metabolism pathways, contributing to the stabilization of the protein structure and membrane integrity. Aromatic hydrocarbon fractions disrupted the arachidonic acid metabolic pathway, leading to increased myotube production and enhanced immune defense mechanisms. The TCA cycle and riboflavin metabolic pathway were significantly altered during exposure to the colloidal fraction, affecting energy production and cellular respiration. The asphaltene fraction significantly impacted glycolysis, accelerating energy cycling to meet stress-induced increases in energy demands. Conclusions: Aromatic hydrocarbons accounted for the highest level of toxicity among the four components in petroleum-contaminated soils. However, the contributions of other fractions to overall toxicity should not be ignored, as each fraction uniquely affects key metabolic pathways and biological functions. These findings emphasize the importance of monitoring metabolic perturbations caused by petroleum components in non-target organisms such as earthworms. They also reveal the specificity of the toxic metabolic effects of different petroleum components on earthworms. Full article
(This article belongs to the Section Environmental Metabolomics)
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8 pages, 477 KiB  
Brief Report
Effectiveness of Pemafibrate Dose Escalation on Metabolic Dysfunction-Associated Steatotic Liver Disease Refractory to Standard Dose
by Satoshi Shinozaki, Kouichi Miura, Toshiyuki Tahara and Hironori Yamamoto
Metabolites 2025, 15(2), 100; https://doi.org/10.3390/metabo15020100 - 5 Feb 2025
Viewed by 329
Abstract
Background and Aim: Controlling the hepatic inflammation of metabolic dysfunction-associated steatotic liver disease (MASLD) is important to prevent serious condition. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has demonstrated effectiveness at a standard dose (0.2 mg daily). The aim of this study is [...] Read more.
Background and Aim: Controlling the hepatic inflammation of metabolic dysfunction-associated steatotic liver disease (MASLD) is important to prevent serious condition. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has demonstrated effectiveness at a standard dose (0.2 mg daily). The aim of this study is to evaluate the effectiveness of pemafibrate dose escalation from 0.2 mg to 0.4 mg daily in patients with MASLD who are refractory to standard-dose therapy. Methods: This study included patients with MASLD who had a persistent elevation of alanine aminotransferase (ALT) levels despite more than one year of standard-dose pemafibrate therapy (0.2 mg daily). All patients underwent dose escalation to 0.4 mg once daily. Hepatic inflammation was assessed using serum ALT levels, hepatic function was evaluated with the albumin–bilirubin score, and hepatic fibrosis was estimated using Mac-2 binding protein glycosylation isomer (M2BPGi) levels. A one-year treatment period was investigated, including six months before dose escalation and six months after dose escalation. Results:Eleven patients were included. The median treating period with standard-dose pemafibrate was 3.2 years. Weight did not show significant change throughout the observation period. Regarding the hepatobiliary enzyme, the aspartate aminotransferase, ALT, and γ-glutamyl transpeptidase levels significantly improved six months after the dose escalation. Specifically, ALT improved in all patients, and the ALT levels normalized in four patients (36%). The lipid profiles, the albumin–bilirubin score, and M2BPGi did not significantly change after the dose escalation. Conclusions: The dose escalation of pemafibrate from 0.2 mg to 0.4 mg daily may improve hepatic inflammation in patients with MASLD refractory to standard-dose therapy. Full article
(This article belongs to the Special Issue Metabolic Syndrome and Non-Alcoholic Liver Disease)
30 pages, 6408 KiB  
Article
Metabolomic Insights into Smoking-Induced Metabolic Dysfunctions: A Comprehensive Analysis of Lipid and Amino Acid Metabolomes
by Muhammad Amtiaz Aslam, Hajra Iqbal, Kainat Ilyas, Kanwal Rehman, Amjad Hussain, Muhammad Sajid Hamid Akash, Mudassar Shahid and Shuqing Chen
Metabolites 2025, 15(2), 96; https://doi.org/10.3390/metabo15020096 - 4 Feb 2025
Viewed by 356
Abstract
Background: Cigarette smoking is a leading cause of preventable mortality, largely due to the absence of effective, non-invasive biomarkers for early disease detection. Profiling serum metabolomics to identify metabolic changes holds the potential to accelerate the detection process and identify individuals at risk [...] Read more.
Background: Cigarette smoking is a leading cause of preventable mortality, largely due to the absence of effective, non-invasive biomarkers for early disease detection. Profiling serum metabolomics to identify metabolic changes holds the potential to accelerate the detection process and identify individuals at risk of developing smoking-related diseases. Objectives: This study investigated the biochemical and metabolomic changes induced by nicotine exposure, with a focus on disruptions in amino acid, lipid, and carbohydrate metabolism. Methods: Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was employed to observe significant disruptions in lipid and amino acid metabolism, along with alterations in key metabolic pathways. A total of 400 smokers and 100 non-smokers were included to evaluate the biomarkers related to insulin resistance, blood lipid profile, inflammation, and kidney and liver function. Results: The results demonstrated significantly elevated (p < 0.05) levels of glycemic markers in smokers, including fasting blood glucose; glycated hemoglobin (HbA1c); and inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Smokers also exhibited dyslipidemia, with increased total cholesterol (154.888 ± 35.565) and LDL levels (117.545 ± 24.138). Impaired liver and kidney function was evident, with significantly higher levels (p < 0.05) of AST, ALP, ALT, blood urea nitrogen, and creatinine in smokers. A total of 930 metabolites were identified, of which 343 exhibited significant alterations (p < 0.05) in smokers compared to non-smokers. Among these, 116 metabolites were upregulated, and 127 were downregulated. Metabolomic pathway analysis revealed eight significant pathways. The study also identified three lipid metabolites specific to smokers and seven unique to non-smokers. Through LC-MS/MS, fragments of phenylalanine, tryptophan, valine, histidine, carnitine, and sphinganine were detected. Several lipidomic changes associated with insulin resistance and cardiovascular complications were observed. Cadmium (Cd) levels were higher in smokers than non-smokers (1.264 ppb vs. 0.624 ppb) and showed a strong negative correlation (R2 = 0.8061, p-value = 0.015) with serum zinc (Zn), likely due to Cd displacing Zn in proteins and causing nephrotoxicity through accumulation. Conclusions: This study highlights the distinct metabolic disruptions caused by smoking that could serve as potential biomarkers for the early detection of metabolic diseases. It emphasizes the importance of metabolomics in identifying systemic indicators of smoking-related health issues, providing new opportunities for preventive and therapeutic interventions. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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13 pages, 2703 KiB  
Article
Identification of Plasma Metabolites Responding to Oxycodone Exposure in Rats
by Thao Vu, Suneeta Godbole, Lieselot L. G. Carrette, Lisa Maturin, Olivier George, Laura M. Saba and Katerina Kechris
Metabolites 2025, 15(2), 95; https://doi.org/10.3390/metabo15020095 - 4 Feb 2025
Viewed by 351
Abstract
Background: Oxycodone has an elevated abuse liability profile compared to other prescription opioid medications. However, many human and rodent metabolomics studies have not been specifically focused on oxycodone. Objectives: Investigating metabolomics changes associated with oxycodone exposure can provide insights into biochemical mechanisms of [...] Read more.
Background: Oxycodone has an elevated abuse liability profile compared to other prescription opioid medications. However, many human and rodent metabolomics studies have not been specifically focused on oxycodone. Objectives: Investigating metabolomics changes associated with oxycodone exposure can provide insights into biochemical mechanisms of the addiction cycle and prognosis prediction. Methods: Plasma samples from 16 rats at pre-exposure and intoxication time points were profiled on the Metabolon platform. A total of 941 metabolites were characterized. We employed a k-Nearest Neighbor imputation to impute metabolites with low levels of missingness and binarized metabolites with moderate levels of missingness, respectively. Results: Of the 136 binarized metabolites, 6 showed differential abundance (FDR < 0.05), including 5 that were present at pre-exposure but absent at intoxication (e.g., adenine), while linoleamide (18:2n6) exhibited the opposite behavior. Among the 798 metabolites with low levels of missingness, 364 showed significant changes between pre-exposure and intoxication (FDR < 0.01), including succinate, oleamide, and sarcosine. We identified four pathways, including tryptophan metabolism, that were nominally enriched among the metabolites that change with oxycodone exposure (p < 0.05). Furthermore, we identified several metabolites that showed nominal correlations with the Addiction Index (composite of oxycodone behaviors): 17 at pre-exposure and 8 at intoxication. In addition, the changes in abundance between pre-exposure and intoxication time points of 9 metabolites were nominally correlated with the Addiction Index, including sphingomyelins, methylhistidines, and glycerols. Conclusions: In summary, not only were we able to capture oxy-induced changes in metabolic pathways using easily accessible blood samples, but we also demonstrated the potential of blood metabolomics to better understand addiction liability. Full article
(This article belongs to the Section Pharmacology and Drug Metabolism)
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18 pages, 1581 KiB  
Article
Metabolites and Free Fatty Acids in Japanese Black Beef During Wet Aging
by Shuji Ueda, Yuka Yoshida, Yuka Tateoka, Biniam Kebede, Masakazu Shinohara, Hiroki Nakanishi, Itsuko Fukuda and Yasuhito Shirai
Metabolites 2025, 15(2), 94; https://doi.org/10.3390/metabo15020094 - 3 Feb 2025
Viewed by 364
Abstract
Abstract: Background: Japanese Black beef is known for its high intramuscular fat content, an important factor in its distinctive Wagyu aroma. Wet aging, which involves vacuum-packing meat and storing it at low temperatures, enhances flavor, texture, and tenderness and is essential [...] Read more.
Abstract: Background: Japanese Black beef is known for its high intramuscular fat content, an important factor in its distinctive Wagyu aroma. Wet aging, which involves vacuum-packing meat and storing it at low temperatures, enhances flavor, texture, and tenderness and is essential for maintaining and improving meat quality. In this study, changes in metabolites and lipid profiles were investigated during the wet aging of Japanese Black and Holstein beef. Methods/Results: Gas chromatography–mass spectrometry identified 113 metabolites in Japanese Black beef and 94 in Holstein beef, with significant increases in metabolites like aspartic acid and maleic acid over the aging period. Regarding lipid composition, total free fatty acids significantly increased with wet aging, with Japanese Black beef showing significantly higher concentrations of oleic and linoleic acids than Holstein beef. Additionally, lipid analysis by liquid chromatography–mass spectrometry revealed a reduction in specific phospholipids, particularly lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), with notable decreases in LPC (18:1), LPC (18:2), LPE (18:1), and LPE (18:2). Conclusions: These results suggest that wet aging influences the stability of membrane lipids, facilitating the degradation of phospholipids into free fatty acids, and improving the flavor of Japanese Black beef. Full article
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17 pages, 3371 KiB  
Article
In-Depth Investigation on Potential Mechanism of Forest-Grown Ginseng Alleviating Alzheimer’s Disease via UHPLC-MS-Based Metabolomics
by Huazhou Niu, Meng Zhang, Kaiyue Zhang, Saibire Aishan, Hui Li and Wei Wu
Metabolites 2025, 15(2), 93; https://doi.org/10.3390/metabo15020093 - 3 Feb 2025
Viewed by 362
Abstract
Background: Alzheimer’s disease is a central nervous system degenerative disease closely related to age with a complex pathogenesis. As a natural medicinal plant, forest-grown ginseng (GSF) contains abundant ginsenosides and offers significant neuroprotective effects. Methods: In this study, we comprehensively investigated the effect [...] Read more.
Background: Alzheimer’s disease is a central nervous system degenerative disease closely related to age with a complex pathogenesis. As a natural medicinal plant, forest-grown ginseng (GSF) contains abundant ginsenosides and offers significant neuroprotective effects. Methods: In this study, we comprehensively investigated the effect of GSF on the cell viability of PC12 cells in an AD model alongside metabolic changes in the serum and brains of mice, combined with an efficacy evaluation of PC12 cells in vitro and UHPLC-MS-based metabolomics in vivo. The goal of this study is to clarify the potential mechanism of GSF in treating AD. Results: The PC12 cell results showed that GSF can promote the proliferation of PC12 cells, reduce the content of IL-8, increase the activity of SOD, and alleviate the inflammation and oxidative stress induced by Aβ25~35. The immunohistochemical results for the mouse brain tissue also showed that GSF could reduce the inflammatory response of mouse brain tissue by reducing the overexpression of IBa1. AD was alleviated by reducing Aβ protein deposition in the mouse brain tissue. An untargeted metabolomics analysis was performed using UHPLC-Q-Exactive MS and principal component analysis (PCA) to identify the differentially expressed metabolites in the serum and brain tissue of AD mice after treatment. Twenty and seventeen different metabolites were identified in the serum and brain tissue, respectively. The pathway enrichment analysis of differential metabolites showed that GSF could treat AD by up-regulating succinic acid semialdehyde, carbamoyl phosphate, Sphingosine 1-phosphate, L-cystathionine, 2-ketobutyric acid, Vanillylmandelic acid, and D-Ribose to regulate sphingomyelin metabolism, the synthesis and metabolism of neurotransmitters and precursors, and energy metabolism. Conclusions: GSF can reduce neuroinflammation and alleviate Alzheimer’s disease by regulating the metabolic disorders of amino acids, sphingolipids, unsaturated fatty acids, and arachidonic acid in mice serum and brain tissue metabolites. These results suggest a link between metabolite imbalance and AD, and reveal the basis for the mechanism of ginsenosides in AD treatment. Full article
(This article belongs to the Section Plant Metabolism)
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14 pages, 2983 KiB  
Article
Identification and Characterization of Two Se6OMTs from Stephania epigaea Offer Novel Insights into the Biosynthetic Pathway of Cepharanthine
by Jingyi Gan, Wenlong Shi, Qishuang Li, Xinyi Li, Xingyu Zhao, Junhao Tang, Ying Ma, Jian Wang, Shukun Gong, Xiaohui Ma and Juan Guo
Metabolites 2025, 15(2), 92; https://doi.org/10.3390/metabo15020092 - 3 Feb 2025
Viewed by 381
Abstract
Background/Objectives: Stephania epigaea is a plant from the Menispermaceae family. Its root is an important traditional folk medicine, which is called Diburong in China. Diburong is rich in benzylisoquinoline alkaloids (BIAs), including cepharanthine, which has been demonstrated to exhibit significant anti-inflammatory, antiviral, antineoplastic, [...] Read more.
Background/Objectives: Stephania epigaea is a plant from the Menispermaceae family. Its root is an important traditional folk medicine, which is called Diburong in China. Diburong is rich in benzylisoquinoline alkaloids (BIAs), including cepharanthine, which has been demonstrated to exhibit significant anti-inflammatory, antiviral, antineoplastic, and anti-SARS-CoV-2 activities, as well as raising leukocytes. Cepharanthine is composed of (R)- and (S)-1-benzylisoquinoline alkaloid (1-BIA). (S)-norcoclaurine-6-O-methyltransferase (6OMT) is a rate-limiting enzyme in BIA biosynthesis. However, its role in the cepharanthine biosynthetic pathway, particularly with the (R) stereoisomer substrate, remains largely unexplored. This study aimed to identify Se6OMTs involved in the cepharanthine biosynthetic pathway and elucidate the O-methyltransferases (OMTs) responsible for the production of (R)- and (S)-stereoisomer BIAs. Methods: In this study, three OMTs were cloned from S. epigaea and functionally characterized using nine 1-BIAs of (R)- and (S)-configurations as substrates. Results: Two O-methyltransferases, Se6OMT1 and Se6OMT3, showed efficient catalytic activity at the C6 position of both (R)- and (S)-norcoclaurine. Furthermore, Se6OMT3 demonstrated high catalytic activity at the C7 and C4′ positions of other (R)- and (S)-configuration 1-BIAs, which resulted in the generation of multiple products. Conclusions: This study focused on 6OMT enzymes in S. epigaea, identifying Se6OMTs involved in the cepharanthine biosynthetic pathway, determining the OMTs involved in the production of (R)- and (S)-stereoisomer BIAs. This research provides valuable insights into the substrate promiscuity of Se6OMTs on (R)- and (S)-configured 1-BIAs in S. epigaea and highlights the genetic components necessary for the metabolic engineering and synthetic biology approaches to cepharanthine production. Full article
(This article belongs to the Section Plant Metabolism)
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13 pages, 709 KiB  
Article
Endothelial Markers in Type 2 Diabetic Patients with Acute Decompensated Heart Failure: A Pilot Study
by Martin Jozef Péč, Jakub Jurica, Tomáš Bolek, Ingrid Škorňová, Monika Péčová, Marek Cingel, Simona Horná, Lucia Stančiaková, Ján Staško, Štefan Tóth, Juraj Sokol, Peter Galajda, Marián Mokáň and Matej Samoš
Metabolites 2025, 15(2), 91; https://doi.org/10.3390/metabo15020091 - 3 Feb 2025
Viewed by 445
Abstract
Background: Impaired endothelial function has been associated with vascular complications in type 2 diabetes (T2D), but its role in T2D-related heart failure (HF) remains indeterminate. The aim of this study was to assess selected markers of endothelial function in T2D patients with acute [...] Read more.
Background: Impaired endothelial function has been associated with vascular complications in type 2 diabetes (T2D), but its role in T2D-related heart failure (HF) remains indeterminate. The aim of this study was to assess selected markers of endothelial function in T2D patients with acute decompensated HF. Methods: A pilot prospective study on patients with acute decompensated HF requiring in-hospital admission was carried out. The vascular endothelial growth factor (VEGF), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were assessed at admission and after decongestion. Subsequently, differences in these markers between T2D and non-diabetic (ND) patients were studied. Results: In total, 39 patients (21 with T2D and 18 ND patients) were enrolled. Twenty-eight patients presented with preserved ejection fraction (EF), and 11 presented with reduced EF. Looking at the VEGF levels in T2D patients, on admission, a median of 233.0 pg/mL (1.7–598 pg/mL) was found compared to 106.0 pg/mL (1.7–888 pg/mL) in ND individuals; the differences reached statistical significance (p = 0.04). There were no significant differences in VEGF levels after decongestion, and in VCAM-1 (2237 ± 1195 vs. 2699 ± 1093 ng/mL, p = 0.37) and ICAM-1 (596 ± 268 vs. 638 ± 437 ng/mL, p = 0.79) levels between T2D and ND patients upon admission and after decongestion. The value of EF (preserved or reduced) affected the VEGF levels upon admission. Conclusions: This study identified significantly higher VEGF levels upon admission due to acute decompensated HF in T2D patients. Full article
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14 pages, 2061 KiB  
Article
Exploring the Antineoplastic Properties of the Lebanese Jania rubens Against Colorectal Cancer
by Mariam Rifi, Zeina Radwan, Nouha Sari-Chmayssem, Rayan Kassir, Ziad Fajloun, Abir Abdel Rahman, Marwan El-Sabban, Corinne Prévostel, Zeina Dassouki and Hiba Mawlawi
Metabolites 2025, 15(2), 90; https://doi.org/10.3390/metabo15020090 - 2 Feb 2025
Viewed by 623
Abstract
Background/Objective: Colon cancer poses a significant health burden, with current treatments often associated with severe side effects and limited effectiveness for some patients. Natural products are gaining interest as adjuvant therapies, potentially reducing side effects and improving responses to conventional treatments. We previously [...] Read more.
Background/Objective: Colon cancer poses a significant health burden, with current treatments often associated with severe side effects and limited effectiveness for some patients. Natural products are gaining interest as adjuvant therapies, potentially reducing side effects and improving responses to conventional treatments. We previously highlighted the potent antineoplastic effects of organic extracts derived from the Lebanese red algae Jania rubens. This study, investigated the anticancer activities of polysaccharide, protein, and lipid extracts from J. rubens, which may serve as adjuvant therapies to enhance conventional treatments. Methods: we employed colorimetric assays, wound healing assays, and cell cycle analysis to evaluate the anticancer activities of the extracts. The polysaccharide extract was characterized for sulfate content and structure using barium chloride-gelatin and FT-IR methods. Results: All J. rubens extracts exhibited significant anticancer effects, with the polysaccharide extract showing particularly strong cytotoxicity, apoptosis induction, and antiproliferative and anti-migratory activities. Conclusion: These findings confirm that J. rubens is a source of bioactive compounds with anticancer potential. Further investigations are needed to elucidate the molecular pathways targeted by J. rubens extracts in cancer cells. Full article
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17 pages, 665 KiB  
Review
Metabolic Syndrome Spectrum in Children with Classic Congenital Adrenal Hyperplasia—A Comprehensive Review
by Sanja Panic Zaric, Tatjana Milenkovic, Sladjana Todorovic, Katarina Mitrovic, Dimitrije Cvetkovic, Maja Cehic, Jelena Vekic, Katja Dumic and Rade Vukovic
Metabolites 2025, 15(2), 89; https://doi.org/10.3390/metabo15020089 - 2 Feb 2025
Viewed by 440
Abstract
Children with a classic form of congenital adrenal hyperplasia (CCAH) have a potentially increased risk of unfavorable cardiometabolic events due to the interplay of corticosteroid treatment, hyperandrogenism, and other factors. Although readily recognized in adults, these aspects are frequently overlooked in children and [...] Read more.
Children with a classic form of congenital adrenal hyperplasia (CCAH) have a potentially increased risk of unfavorable cardiometabolic events due to the interplay of corticosteroid treatment, hyperandrogenism, and other factors. Although readily recognized in adults, these aspects are frequently overlooked in children and youth with CCAH; Aim: To review the evidence available from studies regarding cardiometabolic health outcomes in CCAH patients; Methods: A review of the literature was performed following PRISMA guidelines, including studies published between 2000 and 2024. We included studies reporting cardiometabolic outcomes in children and adolescents (<18 years) with CCAH. Where pediatric data were sparse, additional data were obtained from studies with older adolescents and young adults (15–25 years). Cardiometabolic outcomes included risk factors, such as obesity, insulin resistance, lipids, blood pressure, and vascular markers; Results: Twenty-five studies were analyzed. The prevalence of obesity was found to be higher in children with CCAH, as well as of increased visceral adiposity. Higher indices of insulin resistance were also a frequent finding in children with CCAH. CCAH patients had higher systolic blood pressure and more frequently loss of nocturnal blood pressure dipping, particularly among salt-wasting subtypes and in younger children. Subclinical atherosclerosis was indicated by increased carotid intima–media thickness, elevated hs-CRP, and impaired endothelial function. Other findings suggested changes in lipid profiles, particularly decreased HDL-c and increased triglycerides, although the findings were less consistent; Conclusions: Compared with the general pediatric population, children with CCAH were found to have an increase in multiple cardiometabolic risk factors. It is therefore vital to monitor these risk factors in pediatric CCAH, as well as tailoring treatment with cardiometabolic health in mind, to achieve better long-term cardiovascular and metabolic outcomes. Future research should focus on longitudinal studies of cardiometabolic outcomes and innovative therapeutic approaches to reduce these risks in patients with CCAH. Full article
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13 pages, 1615 KiB  
Article
Clustering-Based Identification of BMI-Associated Metabolites with Mechanistic Insights from Network Analysis in Korean Men
by JooYong Park, Jihyun Kang, Ji-Yeoun Lee, Daehee Kang, Joo-Youn Cho and Ji-Yeob Choi
Metabolites 2025, 15(2), 88; https://doi.org/10.3390/metabo15020088 - 2 Feb 2025
Viewed by 505
Abstract
Background: Epidemiological studies using metabolomics often encounter challenges due to metabolite profiles being influenced by multiple modifiable behavioral factors, including regular exercise, smoking, drinking, and weight control. This study aimed to identify modifiable behavioral factors reflected in metabolites by clustering subjects based on [...] Read more.
Background: Epidemiological studies using metabolomics often encounter challenges due to metabolite profiles being influenced by multiple modifiable behavioral factors, including regular exercise, smoking, drinking, and weight control. This study aimed to identify modifiable behavioral factors reflected in metabolites by clustering subjects based on their metabolite profiles. Networks of metabolites were constructed to visualize their relationships and the differences between clustering groups. Methods: Sixty-four healthy men were included in this study. Information on regular exercise, smoking, and drinking was collected by questionnaires, and body mass index (BMI), an indicator of weight control, was calculated based on measured height and weight. Through targeted metabolomics, the concentrations of 149 metabolites were quantified. Subjects were clustered using the k-means method based on metabolite composition. Correlation-based networks were constructed for each cluster using Cytoscape software, followed by network analysis. Results: The subjects were divided into two clusters, with BMI identified as a distinguishing feature. Four lyso-phosphatidylcholines (PCs), six diacyl-PCs, and one acyl-alkyl-PC were positively associated with BMI. In the constructed network, acyl-alkyl-PCs exhibited the highest degrees, suggesting their central role in BMI-associated metabolic pathways. Conclusions: These findings suggest that metabolites can reflect behavioral factors, with BMI exerting a significant influence on metabolite profiles, particularly through its associations with phosphatidylcholines. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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23 pages, 3870 KiB  
Article
Separate and Combined Effects of Moderate-Intensity Exercise Training and Detraining with Protocatechuic Acid (PCA) on Myokines and Insulin-Signaling Pathways in Male Wistar Rats: A Preclinical Randomized Study
by Hira Shakoor, Jaleel Kizhakkayil, Yauhen Statsenko and Carine Platat
Metabolites 2025, 15(2), 87; https://doi.org/10.3390/metabo15020087 - 1 Feb 2025
Viewed by 486
Abstract
Background: Exercise training positively modulates myokine secretion and improves glucose metabolism. Herein, we analyzed the effect of moderate-intensity training, detraining, and Protocatechuic Acid (PCA) supplementation on myokine secretions and regulation of insulin-signaling pathways. Methods: A five-arm study was conducted on 47 healthy [...] Read more.
Background: Exercise training positively modulates myokine secretion and improves glucose metabolism. Herein, we analyzed the effect of moderate-intensity training, detraining, and Protocatechuic Acid (PCA) supplementation on myokine secretions and regulation of insulin-signaling pathways. Methods: A five-arm study was conducted on 47 healthy male Wistar rats, trained at a moderate intensity level for four weeks (T0-T4). Animals were randomly classified into groups according to PCA supplementation and exercise durations: four weeks of Aerobic Training with or without PCA (AT4, AT4-PCA), eight weeks of Aerobic Training with or without PCA (AT8, AT8-PCA), and PCA Vehicle Control (VC). The animals were followed up until week 12 (T12). We decapitated six rats at T0 and T4, four rats per group at T8, and three rats per group at T12. Myokines (IGF-1, IL-6, FGF-21, myostatin, and irisin) were analyzed with ELISA. Western blot analysis measured protein expression of insulin-signaling pathways and GLUT-4 in the gastrocnemius muscle. Results: The IL-6 levels increased significantly (p < 0.01) with 8-week training in AT8 by 34% and AT8-PCA by 32%, compared to groups trained for only 4 weeks (AT4 and AT4-PCA). Similarly, the PI3K, and GLUT-4 expression improved in AT8 and AT8-PCA at T8. Training for 4 weeks improved IGF-1 levels, but a further 14% improvement was observed with 8-week training in AT8 at T8. Myostatin level significantly dropped by 27% even with 4-week training (p < 0.001). However, detraining increased the myostatin levels in all groups, but in AT8-PCA with PCA dose, myostatin reduced by 11% compared to AT8 at T12. PCA supplementation reduced the FGF-21 levels by 54% during detraining at T12 in AT8-PCA compared to AT8. However, the irisin level did not change markedly in any group. Conclusions: Physical training (with and without PCA) modulates myokine production and improves glucose metabolism, but the benefits are lost after detraining. Full article
(This article belongs to the Special Issue Diet and Nutrition in Relation to Metabolic Health)
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15 pages, 285 KiB  
Review
Metabolomics in Pathogenic Pathways and Targeted Therapies for Diabetic Neuropathy: A Comprehensive Review
by Cornelia Bala, Adriana Rusu, Dana Mihaela Ciobanu, Gabriela Roman and Anca Elena Crăciun
Metabolites 2025, 15(2), 86; https://doi.org/10.3390/metabo15020086 - 1 Feb 2025
Viewed by 398
Abstract
Introduction and objective: This literature review aims to provide an overview of the progress in metabolomic assessment in animal and cell models and in humans with diabetic neuropathy (DN). Methods: Metabolomics has emerged as an important approach for investigating, identifying, and describing biomarkers [...] Read more.
Introduction and objective: This literature review aims to provide an overview of the progress in metabolomic assessment in animal and cell models and in humans with diabetic neuropathy (DN). Methods: Metabolomics has emerged as an important approach for investigating, identifying, and describing biomarkers related to DN. None has yet been validated for use in clinical practice. Results: DN induced significant alterations in energy metabolism and carbohydrates, lipids, amino acids, peptides, and proteins. Several treatments for DN, evaluated using metabolomics, were proved to have promising results. Conclusions: The ideal metabolite or set of metabolites that could be used as biomarkers should identify patients with diabetes prone to develop DN or those prone to progress to severe forms of sensory loss, associated with risk of ulcerations and amputation. Another potential use of a metabolite might be as an indicator of treatment response in clinical trials using agents with potential disease-modifying properties. Full article
24 pages, 602 KiB  
Review
Optimised Skeletal Muscle Mass as a Key Strategy for Obesity Management
by Thomas M. Barber, Stefan Kabisch, Andreas F. H. Pfeiffer and Martin O. Weickert
Metabolites 2025, 15(2), 85; https://doi.org/10.3390/metabo15020085 - 1 Feb 2025
Viewed by 417
Abstract
The ‘Body Mass Index’ (BMI) is an anachronistic and outdated ratio that is used as an internationally accepted diagnostic criterion for obesity, and to prioritise, stratify, and outcome-assess its management options. On an individual level, the BMI has the potential to mislead, including [...] Read more.
The ‘Body Mass Index’ (BMI) is an anachronistic and outdated ratio that is used as an internationally accepted diagnostic criterion for obesity, and to prioritise, stratify, and outcome-assess its management options. On an individual level, the BMI has the potential to mislead, including inaccuracies in cardiovascular risk assessment. Furthermore, the BMI places excessive emphasis on a reduction in overall body weight (rather than optimised body composition) and contributes towards a misunderstanding of the quiddity of obesity and a dispassionate societal perspective and response to the global obesity problem. The overall objective of this review is to provide an overview of obesity that transitions away from the BMI and towards a novel vista: viewing obesity from the perspective of the skeletal muscle (SM). We resurrect the SM as a tissue hidden in plain sight and provide an overview of the key role that the SM plays in influencing metabolic health and efficiency. We discuss the complex interlinks between the SM and the adipose tissue (AT) through key myokines and adipokines, and argue that rather than two separate tissues, the SM and AT should be considered as a single entity: the ‘Adipo–Muscle Axis’. We discuss the vicious circle of sarcopenic obesity, in which aging- and obesity-related decline in SM mass contributes to a worsened metabolic status and insulin resistance, which in turn further compounds SM mass and function. We provide an overview of the approaches that can mitigate against the decline in SM mass in the context of negative energy balance, including the optimisation of dietary protein intake and resistance physical exercises, and of novel molecules in development that target the SM, which will play an important role in the future management of obesity. Finally, we argue that the Adipo–Muscle Ratio (AMR) would provide a more clinically meaningful descriptor and definition of obesity than the BMI and would help to shift our focus regarding its effective management away from merely inducing weight loss and towards optimising the AMR with proper attention to the maintenance and augmentation of SM mass and function. Full article
(This article belongs to the Special Issue Obesity and Metabolic Health)
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30 pages, 6137 KiB  
Article
Comprehensive Metabolomics Profiling and Bioactivity Study of Lycium shawii (Awsaj) Extracts with Particular Emphasis on Potential Anti-Malarial Properties
by Ruba Al-Nemi, Mutaz Akkawi, Khalid Sawalha, Siska Andrina Kusumastuti, Nuralih, Susi Kusumaningrum, Tia Okselni, Vania Chlarisa Situmorang, Abdi Wira Septama, Mariusz Jaremko and Abdul-Hamid Emwas
Metabolites 2025, 15(2), 84; https://doi.org/10.3390/metabo15020084 - 1 Feb 2025
Viewed by 868
Abstract
Background/Objectives: Although malaria is one of the oldest known human diseases, it continues to be a major global health challenge. According to UNICEF, the global malaria mortality rate exceeded 600,000 annually in 2022, which includes more than 1000 children dying each day. This [...] Read more.
Background/Objectives: Although malaria is one of the oldest known human diseases, it continues to be a major global health challenge. According to UNICEF, the global malaria mortality rate exceeded 600,000 annually in 2022, which includes more than 1000 children dying each day. This study aimed to investigate the comprehensive chemical profile and biological activities, particularly the antimalarial activity, of Lycium shawii (Awsaj), a shrub traditionally used in the Arabian Peninsula, Middle East, India, and Africa to treat a myriad of ailments. Methods: Crude extracts of L. shawii were prepared using water, ethanol, methanol, and acetone. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) were utilized to perform untargeted metabolomics to maximize metabolite detection and tentatively identify bioactive phytochemicals. The total phenolic content (TPC) was measured for each extract, and bioassays were conducted to evaluate their antimalarial, antibacterial, and anti-inflammatory activities, particularly those of the water extract, which is the traditional method of consumption in Arabian folk medicine. Results: A total of 148 metabolites were detected, 45 of which were classified as phytochemicals. The bioassays revealed that the water extract that is traditionally used showed promising antimalarial potential by significantly inhibiting β-hematin formation in vitro at 1 mg/mL (with an absorbance of 0.140 ± 0.027). This is likely due to the rich presence of quinoline in the aqueous extract among several other bioactive phytochemicals, such as phenylpropanoids, alkaloids, flavonoids, and benzenoids. However, their anti-inflammatory and antibacterial activities were found to be weak, with only a minor inhibition of nitric oxide (NO) production in LPS-induced RAW 264.7 cells at a concentration of 500 µg/mL and weak antibacterial effects against pathogens like P. aeruginosa, MRSA, A. baumannii, and K. pneumoniae with an MIC of 500 μg/mL. The results also revealed that the methanolic extract had the highest TPC at 26.265 ± 0.005 mg GAE/g. Conclusions: The findings support the traditional medicinal use of L. shawii and highlight its potential as a source of novel therapeutic compounds, particularly for treating malaria. This study encourages further research to isolate and develop effective plant-based anti-malarial agents. Full article
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17 pages, 2777 KiB  
Article
Structural Analysis of Cardanol and Its Biological Activities on Human Keratinocyte Cells
by Shereen Basiouni, Nina Abel, Wolfgang Eisenreich, Helen L. May-Simera and Awad A. Shehata
Metabolites 2025, 15(2), 83; https://doi.org/10.3390/metabo15020083 - 30 Jan 2025
Viewed by 423
Abstract
Background/Objectives: Cashew nutshell liquid (CNSL) is obtained during the industrial processing of cashew nuts. It contains anacardic acid (2-hydroxy-6-n-pentadecylbenzoic acid) and cardanol (3-n-pentadecylphenol). Therefore, CNSL provides a rich source of phenolic lipids serving as natural antioxidants or precursors for industrial uses. Here, we [...] Read more.
Background/Objectives: Cashew nutshell liquid (CNSL) is obtained during the industrial processing of cashew nuts. It contains anacardic acid (2-hydroxy-6-n-pentadecylbenzoic acid) and cardanol (3-n-pentadecylphenol). Therefore, CNSL provides a rich source of phenolic lipids serving as natural antioxidants or precursors for industrial uses. Here, we have analyzed in detail a commercial sample of cardanol by nuclear magnetic resonance (NMR) spectroscopy and its biological activities in the human keratinocyte cell line (HaCaT cells). Methods: The cytotoxic effects, genotoxicity, cell proliferation, and healing properties on HaCaT cells were studied using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, comet assay, proliferation assay, and scratch assay, respectively. Additionally, the modulatory effect of cardanol on the cellular fatty acid profile of HaCaT cells was analyzed by gas chromatography. Results: NMR showed the structure of cardanol as a mixture of the 8′-monoene (42%), the 8′,11′-diene (22%), and the 8′,11′,14′-triene (36%) for the pentadecyl side chain with all double bonds in Z configuration. The cytotoxic effects on HaCaT cells only occurred at high concentrations of cardanol (>10 µg/mL), which caused significant reductions in cell viability. Using the comet assay, a dose-dependent increase in DNA damage was found at concentrations above 10 µg/mL. Scratch assays revealed that cardanol achieved 99% wound closure of HaCaT cells treated with 1 µg/mL cardanol after 48 h. Cardanol at 1 and 0.1 µg/mL significantly enhanced HaCaT cell proliferation and promoted migration, contributing to accelerated wound healing processes. As shown by gas chromatography, 1 µg/mL cardanol increased the total amount of polyunsaturated fatty acids (PUFA), including ω-3, ω-6, and ω-9 fatty acids. Conclusions: Together, these findings suggest that concentrations of <10 µg/mL cardanol are safe and exhibit beneficial biological activities, particularly wound-healing effects on HaCaT cells. Further studies are necessary to explore additional potential applications of cardanol, to refine its formulations for clinical use, and to ensure its safety and action in other target cells and species. Full article
(This article belongs to the Section Cell Metabolism)
14 pages, 3810 KiB  
Article
Methimazole-Induced Hypothyroidism Increases the Content of Glycogen and Changes the Expression of LDH, GLUT4, and Aromatase in the Pregnant Uterus of Rabbits
by Marlen Espindola-Lozano, Maribel Méndez-Tepepa, Marlenne Castillo-Romano, Rubicela Rojas-Juárez, Leticia Nicolás-Toledo, Jorge Rodríguez-Antolín, Francisco Castelán and Estela Cuevas-Romero
Metabolites 2025, 15(2), 82; https://doi.org/10.3390/metabo15020082 - 30 Jan 2025
Viewed by 423
Abstract
Objective: To determine the impact of hypothyroidism on uterine glycogen accumulation during pregnancy. Methods: Non-pregnant and pregnant (days 5, 10, and 20) rabbits were grouped into control and methimazole (MMI) groups. In rabbits, serum concentrations of thyroxine (T4), triiodothyronine, glucose, insulin, [...] Read more.
Objective: To determine the impact of hypothyroidism on uterine glycogen accumulation during pregnancy. Methods: Non-pregnant and pregnant (days 5, 10, and 20) rabbits were grouped into control and methimazole (MMI) groups. In rabbits, serum concentrations of thyroxine (T4), triiodothyronine, glucose, insulin, progesterone, and estradiol were quantified. In uterine inter- and implantation sites, the glycogen content and expression of lactate dehydrogenase (LDH), GLUT4, and aromatase were quantified via Western blot. Fetuses’ characteristics at 20 days of pregnancy were analyzed. Two-way ANOVA was used to compare variables between groups. Results: Pregnancy reduced T4 concentrations but not T3. In virgin groups, MMI treatment significantly reduced the concentrations of T4 and T3 and increased the expression of GLUT4 and aromatase in the uterus compared to the control group. In pregnant groups, T4, T3, glucose, insulin, progesterone, and estradiol levels were similar between control and MMI-treated rabbits. Compared to controls, MMI treatment in pregnant rabbits (a) reduced GLUT4 expression on inter-implantation sites on day 5; (b) increased glycogen content on implantation sites but reduced GLUT4 expression on inter-and implantation sites on day 10; (c) increased glycogen content and LDH and aromatase expression but reduced GLUT4 on inter-implantation sites; and (d) increased glycogen content and the expression of LDH, GLUT4, and aromatase on day 20 on implantation sites. Moreover, the fetus characteristics were similar between groups. Conclusions: MMI-induced hypothyroidism is associated with changes in the uterine content of glycogen and the expression of LDH, GLUT4, and aromatase during pregnancy. Full article
(This article belongs to the Special Issue Glucose Metabolism in Pregnancy)
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19 pages, 4391 KiB  
Article
Metabolomic and Transcriptomic Analyses Reveal the Factors Underlying Mature Fruit Pericarp Color Variations in the ‘Xinli No. 7’ Pear (Pyrus sinkiangensis)
by Yi Wang, Can Lu, Pan Yan, Shijie An, Ling Ma, Qiangqing Zheng, Yonghui Deng and Qiling Chen
Metabolites 2025, 15(2), 81; https://doi.org/10.3390/metabo15020081 - 30 Jan 2025
Viewed by 480
Abstract
Background/Objectives: The ‘Xinli No. 7’ pear is a new pear variety with the advantages of early ripening, high quality, high storage resistance, and a long shelf life. Peel color is an important appearance-related trait and an important indicator of fruit quality and [...] Read more.
Background/Objectives: The ‘Xinli No. 7’ pear is a new pear variety with the advantages of early ripening, high quality, high storage resistance, and a long shelf life. Peel color is an important appearance-related trait and an important indicator of fruit quality and commercial value. Methods: In this study, we investigated the polyphenol compound biosynthesis metabolic pathway in the fruit pericarp of ‘Xinli No. 7’ pear using metabolomic and transcriptomic approaches, and qRT–PCR was used for the relative expression analysis of 21 DEGs associated with flavonoid biosynthesis. Results: A total of 128 phenolic compounds were identified, along with 1850 differently expressed genes (DEGs) in peels of different colors. Caftaric acid, apigenin, astragalin, phlorizin, prunin, taxifolin, rutin, naringenin, and their derivatives were abundant in the peel of ‘Xinli No. 7’ pear. An integrated analysis of transcriptomic and metabolomic data revealed that one PGT1, one LAR, two ANS, three 4CL, one CHS, one DFR, and one CHI gene involved in flavonoid biosynthesis exhibited markedly different expression levels in the fruit pericarp of ‘Xinli No. 7’ pear. Metabolic profiling of pear skin led to the identification of polyphenol substances involved in the flavonoid biosynthetic process and revealed 16 flavonoid compounds with high accumulation in pear fruit with red skin (PR). Notably, MYBs (25), bHLHs (18), WRKYs (15), NACs (15), ERFs (15), and MADs (2) may also contribute to the accumulation of flavonoid metabolites and the biosynthesis of anthocyanins in the peel of ‘Xinli No. 7’. Conclusions: Therefore, our results demonstrate the key role of phenolic compounds and candidate transcription factors involved in the peel color formation of ‘Xinli No. 7’ pear fruit. Full article
(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites)
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