Metabolites

16 pages, 3088 KB

Open AccessArticle

Seminal Plasma Metabolomic Profiling Reveals Key Metabolic Signatures Linked to Spermatogenic Potential in Non-Obstructive Azoospermia with Cryptorchidism

by Jianxing Cheng, Yanlin Tang, Qiancheng Zhao, Jiaming Weng, Zishui Fang, Yanan Qi, Hui Jiang and Zhe Zhang

Metabolites 2026, 16(2), 147; https://doi.org/10.3390/metabo16020147 - 23 Feb 2026

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Abstract

Background/Objectives: Cryptorchidism is a common cause of male infertility and often results in azoospermia. However, the metabolic perturbations underlying cryptorchidism complicated with azoospermia and their association with surgical sperm retrieval outcomes remain poorly defined. Methods: A total of 35 patients with cryptorchidism and [...] Read more.

Background/Objectives: Cryptorchidism is a common cause of male infertility and often results in azoospermia. However, the metabolic perturbations underlying cryptorchidism complicated with azoospermia and their association with surgical sperm retrieval outcomes remain poorly defined. Methods: A total of 35 patients with cryptorchidism and azoospermia, as well as 40 controls with normal semen parameters, were enrolled in the study. Seminal plasma samples from all participants were subjected to metabolomic analysis. Additionally, some patients underwent micro-TESE; the association between metabolomic features and the success or failure of surgical sperm retrieval was further analyzed. Results: A total of 931 differential metabolites were identified between patients and controls, primarily enriched in lipid metabolism and amino acid metabolism pathways. Lipid metabolites were broadly downregulated in patients, while several inflammation-related metabolites, including Prostaglandin E2, were upregulated. Routine clinical parameters showed no significant differences between patients with successful and failed micro-TESE. However, metabolomic profiles effectively distinguished these two subgroups. These differential metabolites between the two subgroups were mainly involved in three key pathways: phenylalanine–tyrosine–tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, and folate biosynthesis. Most metabolites in the first two pathways were downregulated in the successful retrieval group, while those in the folate biosynthesis pathway showed the opposite regulatory trend. Four metabolites, including Leucine, 7,8-Dihydroneopterin, L-Tyrosine and Pterin, exhibited robust predictive value for micro-TESE outcomes. Conclusions: This study reveals distinct metabolic signatures in patients of cryptorchidism with azoospermia. The identified metabolic biomarkers provide valuable references for clinical decision-making regarding micro-TESE, facilitating a personalized assessment of sperm retrieval feasibility. Full article

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

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23 pages, 1690 KB

Open AccessArticle

Unveiling the Antidiabetic Potential of Parmentiera edulis: From Polyphenols to Molecular Interaction

by Alexis Emus Medina, Cress L. Santos-Ballardo, Carlos B. Castro-Tamayo, Ramón I. Castillo-López, Miguel A. Angulo-Escalante, Jesús J. Portillo-Loera and J. Basilio Heredia

Metabolites 2026, 16(2), 146; https://doi.org/10.3390/metabo16020146 - 22 Feb 2026

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Abstract

Background/Objectives: Parmentiera edulis, traditionally called “cuajilote”, is a medicinal plant used to treat infections, indigestion, kidney problems, and diabetes. Although all parts of the plant are utilized, there is little scientific evidence available on its phytochemical composition to explain its medicinal properties. [...] Read more.

Background/Objectives: Parmentiera edulis, traditionally called “cuajilote”, is a medicinal plant used to treat infections, indigestion, kidney problems, and diabetes. Although all parts of the plant are utilized, there is little scientific evidence available on its phytochemical composition to explain its medicinal properties. This exploratory study aims to characterize and identify phytochemicals in hydromethanolic extracts of leaves, stems, and fruits; determine their antioxidant capacity, and evaluate in vitro and in silico inhibition of α-glucosidase and α-amylase, enzymes involved in glycemic control. Methods: Total phenolic and flavonoid contents were determined, and antioxidant capacity was evaluated using different assays. Phenolic acids were tentatively identified by UPLC-qTOF-MS/MS. Enzyme inhibition assays against α-glucosidase and α-amylase were performed in vitro, and molecular docking was used to explore enzyme–ligand interactions. Results: The total phenolic content was significantly higher in the fruit (552.9 mg GAE/100 g dw), while flavonoids were more abundant in leaves (119.84 mg QE/100 g dw). Antioxidant capacity varied among plant parts, depending on the assay used. Caffeic, chlorogenic, coumaric, ferulic, gallic, and quinic acids were identified. The highest concentrations were observed for chlorogenic, ferulic, and quinic acids. Among the analyzed parts, leaf extracts showed the most potent inhibitory effect on α-glucosidase (IC₅₀: 0.85 mg/mL) and α-amylase (IC₅₀: 1.38 mg/mL). Molecular docking revealed that chlorogenic and quinic acids interacted with the catalytic sites of α-amylase (Glu233, Asp197, and Asp300), whereas in α-glucosidase, interactions were observed at allosteric sites. Conclusions: These results suggest that Parmentiera edulis possesses bioactive compounds that could explain its therapeutic use. Full article

(This article belongs to the Special Issue Functional Foods and Natural Bioactive Compounds: Strategies to Face Metabolic Syndrome and Related Non-Communicable Diseases—2nd Edition)

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19 pages, 776 KB

Open AccessReview

Lipoprotein Metabolism in Hematological Malignancies: A Role in Shaping the Tumor Cell Microenvironment?

by Manal Sellam, Mélanie Lambert, Nadine Varin-Blank and Kevin Saitoski

Metabolites 2026, 16(2), 145; https://doi.org/10.3390/metabo16020145 - 20 Feb 2026

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Abstract

The tumor microenvironment (TME) plays a key role in driving tumor progression, metastasis, and resistance to therapy. The TME is a highly variable ecosystem composed of both cancer and surrounding normal cells, immune survey cells and the extracellular matrix, also composed of signaling [...] Read more.

The tumor microenvironment (TME) plays a key role in driving tumor progression, metastasis, and resistance to therapy. The TME is a highly variable ecosystem composed of both cancer and surrounding normal cells, immune survey cells and the extracellular matrix, also composed of signaling molecules that mediate interactions between them. Blood cancer cells pose a unique challenge because of their circulation and widespread distribution along with their capacity to invade various niches, interacting with a wide range of host cells such as fibroblasts, immune cells, endothelial cells, and adipocytes. Metabolism reprogramming in this tumor context, notably referring to elevated cholesterol and fatty acid metabolism, emerges as a crucial event in shaping an immune-suppressive microenvironment that promotes tumor progression. Cholesterol and fatty acids are supplied by both de novo biosynthesis and exogenous uptake from lipoproteins. Lipoproteins are pseudo-micellar structures, designed to transport essential water-insoluble metabolites, including triacylglycerols and cholesterol, in the plasma, lymph, and interstitial fluids. A number of studies have reported abnormal circulating lipoprotein levels in leukemic patients and have suggested that lipoproteins are key for cancer cells to thrive. However, the role of lipoprotein metabolism in cancer cells in the context of the TME is still incompletely discussed so far. The aim of this review is to consider the importance of lipoprotein metabolism in shaping the tumor microenvironment in the context of hematological malignancies. Full article

(This article belongs to the Special Issue Metabolic Crosstalk in the Tumor Microenvironment)

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32 pages, 7354 KB

Open AccessArticle

Different Associations of Plasma Lipopolysaccharide and Lipopolysaccharide-Binding Protein Concentrations with the Deterioration of Energy Metabolism from Healthy Individuals to Patients with Non-Alcoholic Fatty Liver Disease

by Nobuo Fuke, Yosui Tamaki, Kazunobu Aso, Yu Ota, Shin Otake and Shigenori Suzuki

Metabolites 2026, 16(2), 144; https://doi.org/10.3390/metabo16020144 - 20 Feb 2026

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Abstract

Background: Energy metabolism progressively deteriorates from a healthy state to non-alcoholic fatty liver disease (NAFLD), and circulating lipopolysaccharide (LPS) may contribute to this process. However, previous studies have analyzed healthy individuals and NAFLD patients together, leaving stage-specific associations unclear. Whether LPS and [...] Read more.

Background: Energy metabolism progressively deteriorates from a healthy state to non-alcoholic fatty liver disease (NAFLD), and circulating lipopolysaccharide (LPS) may contribute to this process. However, previous studies have analyzed healthy individuals and NAFLD patients together, leaving stage-specific associations unclear. Whether LPS and its surrogate marker, lipopolysaccharide-binding protein (LBP), show similar relationships during NAFLD development also remains unknown. This study evaluated the associations between plasma LPS and LBP concentrations with clinical parameters in healthy individuals and NAFLD patients. Methods: We conducted a cross-sectional study of 31 healthy individuals (median age [IQR]: 31 (26–43) years) and 31 NAFLD patients (59 (54–70) years). Plasma LPS and LBP concentrations and clinical parameters were measured. Correlations were assessed using Spearman’s rank analysis, followed by multivariate regression adjusting for age, sex, and BMI. Results: Plasma LPS and LBP concentrations were significantly higher in NAFLD patients compared to healthy individuals. Additionally, in the univariate regression analysis for all study participants, plasma LPS concentrations were correlated with obesity, blood pressure, liver function, lipid metabolism, and glucose metabolism. Plasma LBP concentrations were also correlated with age, obesity, blood pressure, liver function, lipid metabolism, glucose metabolism, and inflammatory cytokines. In healthy individuals, LPS correlated positively with triglycerides (TG), remaining significant after adjustment and exclusion of participants with any clinical test values outside the normal range. This association was not observed in NAFLD patients. Plasma LBP did not correlate with TG in either group; however, it was inversely associated with hepatic fat fraction in NAFLD patients, although this association was attenuated after adjusting for alanine aminotransferase. Conclusions: Plasma LPS correlates with TG even in clinically healthy individuals, suggesting LPS may influence lipid metabolism before NAFLD onset. Full article

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

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22 pages, 12922 KB

Open AccessArticle

Acute High-Intensity Noise Exposure Induces Cognitive Impairment and Arachidonic Acid Metabolism-Related Molecular Alterations in Rats: A Multi-Omics Study

by Yane Liu, Mengping Diao, Yihan Hao, Zhongqi Liu, Hao Ma, Yong Zou, Lizhen Ma, Lifeng Wang, Weijia Zhi and Qiong Yu

Metabolites 2026, 16(2), 143; https://doi.org/10.3390/metabo16020143 - 20 Feb 2026

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Abstract

Background: Acute high-intensity noise exposure represents a critical environmental stressor; however, its impact on brain function and the underlying mechanisms remain incompletely understood. This study aimed to investigate the effects of acute high-intensity noise exposure on cognitive function in rats, utilizing multi-omics [...] Read more.

Background: Acute high-intensity noise exposure represents a critical environmental stressor; however, its impact on brain function and the underlying mechanisms remain incompletely understood. This study aimed to investigate the effects of acute high-intensity noise exposure on cognitive function in rats, utilizing multi-omics analysis to explore potential mechanisms. Methods: Rats were exposed to acute noise at 120 dB, and brain function was evaluated using the novel object recognition (NOR) test, recordings of electroencephalographic activity, and histopathological examination. Longitudinal serum metabolomics and fecal metagenomics were performed on samples collected at 0 h, 7, 14, and 28 days post-exposure. Quantitative profiling of oxylipins and proteomics were conducted at a critical time point, followed by integrative multi-omics network analysis. Results: Acute high-intensity noise exposure significantly reduced the recognition index in the NOR test, increased theta-band power, and induced hippocampal neuronal damage. Multi-omics analyses revealed time-dependent alterations in gut microbiota and metabolic profiles, identifying day 7 as the critical response window, with arachidonic acid (AA)-derived metabolites consistently downregulated across omics layers. Integrated analysis revealed a coordinated microbiota–oxylipins–proteins network, highlighting key AA-derived oxylipins (e.g., 8-HETE, 12-HETE) that correlated with specific gut microbiota and proteins involved in lipid metabolism and inflammation. Conclusions: Acute high-intensity noise exposure induces cognitive impairment and systemic molecular disturbances. AA-centered lipid metabolism acts as a key hub linking gut microbiota dysbiosis with inflammatory and metabolic protein alterations, providing multi-omics evidence for coordinated microbiota–lipid–protein dysregulation underlying noise-induced neurobiological dysfunction. Full article

(This article belongs to the Special Issue Environmental Metabolites Insights into Health and Disease)

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15 pages, 1117 KB

Open AccessArticle

An Untargeted Metabolomic Approach to Characterize the Emerging Kernel Disorder “Orange Spot” in Walnut (Juglans regia L.) cv. Chandler

by Ignacia Hernández, Excequel Ponce, Juan Vidal, Gerardo Núñez-Lillo, Flavia Dorochesi, Romina Pedreschi and Claudia Fuentealba

Metabolites 2026, 16(2), 142; https://doi.org/10.3390/metabo16020142 - 19 Feb 2026

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Abstract

Background/Objectives: The physiological disorder known as “orange spot” in Juglans regia L. cv. Chandler is an emerging kernel quality issue of increasing concern for the Chilean walnut industry. Characterized by a localized orange discoloration of the embryo, its etiology remains unknown. This study [...] Read more.

Background/Objectives: The physiological disorder known as “orange spot” in Juglans regia L. cv. Chandler is an emerging kernel quality issue of increasing concern for the Chilean walnut industry. Characterized by a localized orange discoloration of the embryo, its etiology remains unknown. This study aimed to determine whether orange spot is associated with bacterial infection and to elucidate the metabolic alterations underlying its development, testing the hypothesis that it results from oxidative imbalance and lipid disorganization. Methods: Untargeted metabolomic profiling and fatty acid methyl ester (FAME) analysis were applied to compare affected (orange) and unaffected (white) walnut kernels collected from a commercial orchard in Melipilla, Chile, during the 2018 and 2022 seasons. Bacterial DNA was screened by PCR amplification of the 16S rRNA gene (799F/1193R). Results: Orange spot incidence reached 31–34% across seasons. No bacterial-sized amplicons were detected in either kernel type, indicating the absence of detectable bacterial DNA under the analyzed conditions. Metabolomic analyses revealed significant alterations in glyoxylate and dicarboxylate metabolism, glutamate-related pathways, and glycerophospholipid metabolism. Affected kernels exhibited reduced levels of L-glutamic acid and antioxidant-associated metabolites, alongside increased gluconic, citric and quinic acid, consistent with the redox imbalance and membrane oxidative degradation. FAME analysis showed higher total fatty acid content in affected kernels, suggesting intensified lipid turnover associated under oxidative stress. Conclusions: Orange spot is a physiological, non-infectious disorder linked to premature oxidative stress and lipid disorganization, negatively affecting walnut kernel quality. Full article

(This article belongs to the Section Food Metabolomics)

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9 pages, 219 KB

Open AccessArticle

Circulating Gremlin-1 Reflects Age-Associated Metabolic Changes in Women

by Rahma M. Alyami and Khalid Al-Regaiey

Metabolites 2026, 16(2), 141; https://doi.org/10.3390/metabo16020141 - 19 Feb 2026

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Abstract

Background: Menopause is accompanied by hormonal alterations that are closely linked to changes in body composition, insulin sensitivity, and cardiovascular risk in women. Gremlin-1 has recently been identified as an adipokine involved in metabolic and reproductive aging; however, its associations with endocrine and [...] Read more.

Background: Menopause is accompanied by hormonal alterations that are closely linked to changes in body composition, insulin sensitivity, and cardiovascular risk in women. Gremlin-1 has recently been identified as an adipokine involved in metabolic and reproductive aging; however, its associations with endocrine and lipid biomarkers across the menopausal transition remain incompletely defined. Objectives: To evaluate the relationships between plasma Gremlin-1 and IGF-1, HDL cholesterol, estradiol, and age in reproductive-aged and postmenopausal women. Methods: This cross-sectional study included 88 women aged 18–65 years, stratified by menopausal status (reproductive-aged vs. postmenopausal). Plasma concentrations of Gremlin-1, growth hormone, IGF-1, insulin, estradiol (E2), glucose, HbA1c, and a standard lipid profile were measured. Results: Plasma Gremlin-1 concentrations were significantly higher in postmenopausal women compared with reproductive-aged women (p < 0.001). Age (p = 0.013), but not menopause status (p = 0.874), was associated with Gremlin-1 levels. Gremlin-1 showed a strong inverse association with IGF-1 (p = 0.003) and a negative correlation with HDL cholesterol (p = 0.03) in non-obese women; however this association disappeared after adjustment for age. Conclusion: Circulating Gremlin-1 primarily reflects chronological aging and associated endocrine–metabolic changes rather than menopausal status or adiposity per se. While unadjusted associations with metabolic biomarkers are detectable, these relationships are largely attributable to aging. Gremlin-1 may therefore serve as a marker of systemic aging-related endocrine–metabolic remodeling rather than a specific indicator of ovarian aging or adipose tissue dysfunction. Full article

(This article belongs to the Special Issue Changes in Body Composition (Bone, Muscle, Adipose Tissue) with Age and Accompanying Biomarkers for Each Tissue)

25 pages, 5514 KB

Open AccessArticle

Topological and Functional Diversity of Gut Microbiota Metabolism Across the Human Lifespan

by Benjamí Pérez-Rocher, Mariana Reyes-Prieto, Susana Ruiz-Ruiz, Pere Palmer-Rodríguez, José Aurelio Castro, Andrés Moya and Mercè Llabrés-Segura

Metabolites 2026, 16(2), 140; https://doi.org/10.3390/metabo16020140 - 19 Feb 2026

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Abstract

Background: The human gut microbiota plays a central role in host physiology by influencing digestion, immune function, and metabolism. Characterizing age-associated differences in the organization of microbial metabolism may provide insights into functional variation in the gut microbiome across the human lifespan. Methods: [...] Read more.

Background: The human gut microbiota plays a central role in host physiology by influencing digestion, immune function, and metabolism. Characterizing age-associated differences in the organization of microbial metabolism may provide insights into functional variation in the gut microbiome across the human lifespan. Methods: Gut microbiota metabolic organization was analyzed in a cohort of 30 individuals spanning three age groups (infants, adults, and elderly individuals) and comprising 156 stool samples. Community metabolic networks were reconstructed using the metabolic Directed Acyclic Graph (m-DAG) framework derived from KEGG Ortholog annotations. Network topology was characterized to assess whether the resulting networks conform to previously described global structural patterns and to examine age-associated variability. Pairwise m-DAG dissimilarities were computed, and hierarchical clustering was applied to evaluate similarities among samples. Results: All samples revealed a conserved global network organization, alongside marked variability in specific structural features. Hierarchical clustering did not strictly reflect chronological age. A homogeneous cluster composed exclusively of adult samples was identified, whereas elderly samples were distributed across two clusters, one grouping with adults and the other with infants. Exploratory discriminative analyses identified functional reactions contributing to the separation between the adult cluster and the remaining samples, indicating age-associated differences in metabolic network organization. Conclusions: Gut microbiota metabolic networks in adults tend to exhibit lower redundancy and structural complexity, whereas those in infant and elderly samples display more heterogeneous network configurations. This network-based analysis provides a functional perspective on age-associated variation in gut microbiota metabolism and offers a framework for future integrative studies. Full article

(This article belongs to the Topic Application of Analytical Technology in Metabolomics)

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15 pages, 1894 KB

Open AccessArticle

The “Movie Theater” Study: Acute Cardiometabolic Effects of a Cinema-Style Meal

by Jenna K. Schifferer, Alexis R. Quirk, Morgan E. Higgins, Sarah E. Fruit, Natalie G. Keirns and Bryant H. Keirns

Metabolites 2026, 16(2), 139; https://doi.org/10.3390/metabo16020139 - 18 Feb 2026

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Abstract

Background/Objectives: Meals eaten at movie theaters may have acute, negative health effects due to high refined sugar and moderate sodium content. We aimed to characterize the cardiometabolic response to movie-theater-style meals independently (fasting) and after high-fat meal consumption. Methods: Participants (N [...] Read more.

Background/Objectives: Meals eaten at movie theaters may have acute, negative health effects due to high refined sugar and moderate sodium content. We aimed to characterize the cardiometabolic response to movie-theater-style meals independently (fasting) and after high-fat meal consumption. Methods: Participants (N = 10; 5M/5F; 18–45 y) completed two meal trials (randomized). At both trials, participants ate a movie-theater-style meal (popcorn, candy, and soda; 884 kcal, 150 g sugar, and 700 mg sodium). At one trial, the movie theater meal was consumed while fasting (Fasting Trial). At the other trial, a high-fat meal (820 kcal; 56 g fat) was consumed 3.5 h prior to the movie theater meal (Fed Trial). Blood was collected (0, 0.5, 1, 2, 3, and 4 h) and endothelial function (i.e., flow-mediated dilation or FMD) was assessed (0, 2, and 4 h) at both trials. Serum metabolic markers (glucose, insulin, triglycerides, and HDL-C) and biomarkers of intestinal permeability (sCD14 and LBP) were measured. Mixed-model ANOVAs (meal × time) and change scores (Δ) were used to compare responses between trials. Results: At both trials, glucose, insulin, and triglycerides increased, while HDL-C decreased (p_time’s ≤ 0.05). ΔInsulin (p = 0.02), but not Δglucose, was higher at Fasting versus Fed. Peak glucose (range = 86–178 mg/dL) and insulin (range = 28.3–307.6 mU/L) were highly variable between participants across trials. Absolute and percent FMD tended to decrease, regardless of trial (p_time’s ≥ 0.08). Conclusions: Overall, the movie theater meal impacted a number of cardiometabolic factors when consumed independently and after a high-fat meal, although there was notable inter-individual variability. Full article

(This article belongs to the Special Issue Effects of Nutrition and Exercise on Cardiometabolic Health)

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18 pages, 4423 KB

Open AccessArticle

Metabolomics and Microbiomics Reveal the Cultivation-Dependent Divergence in Ginsenoside Biosynthesis and Rhizosphere Ecology of Panax ginseng

by Siqi Liu, Dehua Wu, Wenqi Ma, Tielin Wang, Binbin Yan, Yang Ge, Feng Xiong, Hongyang Wang and Chuanzhi Kang

Metabolites 2026, 16(2), 138; https://doi.org/10.3390/metabo16020138 - 18 Feb 2026

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Abstract

Background: Cultivation environments impose distinct abiotic and biotic stresses that act as primary drivers reshaping the metabolic profile and microbiome assembly of medicinal plants. This study investigates the impact of simulative habitat versus arched greenhouse cultivation on the synthesis of bioactive ginsenosides and [...] Read more.

Background: Cultivation environments impose distinct abiotic and biotic stresses that act as primary drivers reshaping the metabolic profile and microbiome assembly of medicinal plants. This study investigates the impact of simulative habitat versus arched greenhouse cultivation on the synthesis of bioactive ginsenosides and the associated root microbiome structure in Panax ginseng. Methods: A combined metabolomics and microbiomics approach was applied to compare ginsenoside accumulation and rhizosphere microbial community composition under the two cultivation modes. Results: Ginseng from simulative habitat cultivation exhibited significantly higher ginsenoside content, particularly ginsenoside Re, compared to arched greenhouse cultivation, with this advantage being more pronounced in long-term cultivation. Microbiome profiling revealed that specific taxa, including Bradyrhizobium, were strongly enriched in simulative habitats and positively correlated with enhanced ginsenoside accumulation, suggesting a microbiome-mediated mechanism for metabolic plasticity. In contrast, arched greenhouse cultivation was associated with a more complex microbial structure characterized by increased negative interactions, which may compromise metabolic quality. Conclusions: These findings, utilizing multi-omics correlations, provide a theoretical basis for optimizing Panax ginseng quality through ecological cultivation strategies that leverage stress-responsive microbe–metabolite interactions. Full article

(This article belongs to the Special Issue Multi-Omics Insights into Stress-Induced Metabolism of Bioactive Plant Compounds)

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14 pages, 2831 KB

Open AccessArticle

Untargeted Metabolomics of Human Airway Epithelium Reveals Neuroactive Signatures Linked to Pulmonary Neuroendocrine Cell Enrichment and Allergen Exposure

by Ritu Mann-Nüttel, Ayshna Diya and Paul Forsythe

Metabolites 2026, 16(2), 137; https://doi.org/10.3390/metabo16020137 - 17 Feb 2026

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Abstract

Background: Pulmonary neuroendocrine cells (PNECs) are rare airway sensory cells implicated in amplifying allergic inflammation, yet due to their scarcity, the contribution of PNECs to the metabolic programs and responses of the airway epithelium remains poorly defined. Using a newly developed PNEC-enriched human [...] Read more.

Background: Pulmonary neuroendocrine cells (PNECs) are rare airway sensory cells implicated in amplifying allergic inflammation, yet due to their scarcity, the contribution of PNECs to the metabolic programs and responses of the airway epithelium remains poorly defined. Using a newly developed PNEC-enriched human airway epithelial model (ePNEC), we investigated the influence of PNECs on neuroendocrine and immune-modulatory metabolite production in response to the common aeroallergen of the house dust mite (HDM). Methods: Human bronchial epithelial cells (HBECs) and ePNEC cultures were differentiated at the air–liquid interface. Global untargeted metabolomics was performed to quantify metabolite abundance at baseline and following stimulation with HDMs. Differential expression, overlap significance, metabolite class enrichment, and pathway analyses were used to define PNEC-specific metabolic programs. Results: Principal component analysis (PCA) demonstrated strong baseline separation between ePNECs and HBECs, with HDMs inducing additional within-cell-type shifts. ePNECs displayed broader and more pronounced metabolite changes than HBECs. Baseline differences were largely preserved following allergen exposure, with significant overlap in both up- and down-regulated metabolites. ePNECs exhibited enriched neurotransmitter-linked metabolites—including serotonin, L-noradrenaline, dopamine, and histamine—at baseline and after HDM exposure. Amino acid–centered metabolism dominated the dataset, with enhanced histidine and tryptophan pathway activity in ePNECs. Pathway analysis revealed significant enrichment of phenylalanine, tyrosine, tryptophan, glutathione, and arginine–proline metabolism in ePNECs, whereas HBECs showed no significant pathway-level enrichment after HDM exposure. Conclusions: Human ePNECs engage a distinct, neuroactive metabolic program that is amplified upon HDM exposure. These findings provide a metabolic framework for how PNECs shape epithelial and neuroimmune responses to inhaled allergens. Full article

(This article belongs to the Section Cell Metabolism)

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17 pages, 2825 KB

Open AccessArticle

Targeting Heightened Inflammatory Tone in IUGR Neonatal Lambs via Daily Oral Supplementation of ω-3 PUFA Improved Growth Rates, Muscle Mass, and Adiponectin Signaling

by Melanie R. White, Rachel L. Gibbs, Pablo C. Grijalva, Zena M. Herrera, Shelley A. Curry, Haley N. Beer, Eileen S. Marks-Nelson and Dustin T. Yates

Metabolites 2026, 16(2), 136; https://doi.org/10.3390/metabo16020136 - 17 Feb 2026

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Abstract

Background/Objectives: Circulating inflammatory cytokines and tissue sensitivity are both elevated following heat stress-induced intrauterine growth restriction (IUGR). Cytokines disrupt myoblast function and muscle growth, and thus we hypothesized that suppressing inflammatory tone in IUGR-born lambs by supplementing anti-inflammatory nutraceuticals would improve early [...] Read more.

Background/Objectives: Circulating inflammatory cytokines and tissue sensitivity are both elevated following heat stress-induced intrauterine growth restriction (IUGR). Cytokines disrupt myoblast function and muscle growth, and thus we hypothesized that suppressing inflammatory tone in IUGR-born lambs by supplementing anti-inflammatory nutraceuticals would improve early postnatal growth. Methods: IUGR lambs produced by maternal heat stress were supplemented daily with 42 mg/kg oral omega-3 polyunsaturated fatty acid (ω-3 PUFA) Ca²⁺ salts or placebo from birth to 28 days of age. Results: By day 28, the 21% lighter bodyweights for IUGR lambs were fully resolved by ω-3 PUFA due to the complete recovery of average daily gain. Subcutaneous fat deposition and visceral organ growth were modestly diminished in IUGR-born lambs, but skeletal muscle mass was more markedly restricted. This coincided with 63% less muscle AdipoR2 but 27% greater circulating adiponectin. ω-3 PUFA reduced or eliminated deficits in subcutaneous fat, visceral organs, and five of the six individual muscles assessed, which corresponded with rescue of myoblast populations and AdipoR2 content. In turn, asymmetric growth restriction was resolved at one month of age. Conclusions: These findings show that targeting heightened inflammatory tone during the neonatal period in IUGR-born offspring can recover early growth in skeletal muscle and other soft tissues. Full article

(This article belongs to the Section Animal Metabolism)

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30 pages, 1740 KB

Open AccessArticle

Untargeted Metabolomics Profiling of a PFAS-Exposed Flemish Population

by María del Mar Delgado-Povedano, Haesong Sher, Leen Jacobs, Maria van de Lavoir, Rani Robeyns, Ann Colles, Eva Govarts, Elly Den Hond, Giulia Poma, Alexander L. N. van Nuijs and Adrian Covaci

Metabolites 2026, 16(2), 135; https://doi.org/10.3390/metabo16020135 - 15 Feb 2026

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Abstract

Background/Objectives: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that accumulate in humans through everyday exposure pathways, raising concern about long-term metabolic health effects in exposed populations. This study aimed to characterize PFAS-associated serum metabolic alterations in a Flemish population residing [...] Read more.

Background/Objectives: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that accumulate in humans through everyday exposure pathways, raising concern about long-term metabolic health effects in exposed populations. This study aimed to characterize PFAS-associated serum metabolic alterations in a Flemish population residing within a 3 km radius of a PFAS production facility using untargeted metabolomics and lipidomics. Methods: A cohort of 82 adults was stratified into high-exposure (n = 41, median total PFAS = 162.0 ng/mL) and low-exposure (n = 41, median total PFAS = 7.2 ng/mL) groups. Serum metabolic profiling was performed using four liquid chromatography–high-resolution mass spectrometry (LC-HRMS)-based platforms. Univariate and multivariate statistics were conducted to identify metabolites that were differentially expressed between both exposure groups. Results: The analysis revealed 38 altered metabolites. Overall, high PFAS exposure was characterized by upregulation of phosphatidylglycerols (PG), phosphatidylinositols, phosphatidylethanolamines (PE), and triacylglycerols (TG) and downregulation of sphingomyelins, with differential regulation of ceramides, hexosylceramides (HexCer), and phosphatidylcholines. Glycerophospholipid metabolism as well as sphingolipid metabolism pathways were identified as perturbed. Seven lipids and one amino acid showed weak-to-strong correlations (|r|= 0.23–0.61) with PFAS levels. A panel of five metabolites was selected to explore whether they collectively form a potential metabolic signature associated with PFAS exposure. This panel, including L-aspartic acid, PG 18:0_18:2, HexCer (d18:1/14:0), PE 16:0_18:3, and TG 16:0_20:5_22:6, showed moderate discrimination between residents with high and low PFAS levels (area under the curve, AUC = 0.753). Conclusions: This study identifies coordinated lipid metabolic changes associated with PFAS exposure and highlights a small, exploratory metabolite panel that may provide complementary insight into the biological effects of PFAS. Full article

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

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17 pages, 1810 KB

Open AccessArticle

Toxicometabolomics Characterization of Two N1-Sulfonated Dimethyltryptamine Derivatives in Zebrafish Larvae and Human Liver S9 Fractions Using Liquid Chromatography–High-Resolution Mass Spectrometry

by Prajwal Punnamraju, Sascha K. Manier, Selina Hemmer, Matthias Grill, Philip Schippers, Jennifer Herrmann and Markus R. Meyer

Metabolites 2026, 16(2), 134; https://doi.org/10.3390/metabo16020134 - 14 Feb 2026

Viewed by 597

Abstract

Introduction: The availability of toxicokinetic data is critical for detecting and monitoring the intake of psychoactive substances. Timely characterization of novel psychoactive substances (NPS) is particularly important to assess their abuse potential and inform public health responses. Methods: Toxicometabolomics offers a [...] Read more.

Introduction: The availability of toxicokinetic data is critical for detecting and monitoring the intake of psychoactive substances. Timely characterization of novel psychoactive substances (NPS) is particularly important to assess their abuse potential and inform public health responses. Methods: Toxicometabolomics offers a powerful approach to characterize xenobiotic metabolism through high-resolution profiling of biochemical transformations. It thus allows the finding of exogenous biomarkers, such as new drug metabolites, and endogenous biomarkers, which could be indications of acute drug ingestions or sample manipulation, as well as offering information on the mode of action of drugs. In this study, we applied a liquid chromatography–high-resolution mass spectrometry workflow to investigate the toxicometabolomics of two N1-sulfonated N,N-dimethyltryptamine derivatives with potential for both therapeutic use and recreational abuse. Results: Zebrafish (Danio rerio), an increasingly valuable model for preclinical pharmacology and toxicology studies, along with pooled human liver S9 fractions were used to elucidate metabolic pathways and identify key phase I and phase II biotransformations. Furthermore, untargeted metabolomics revealed significant downregulation of L-threonine associated with compound exposure. Conclusions: These findings advance the current understanding of tryptamine metabolism and underscore the utility of toxicometabolomics in the analytical evaluation of NPS. Full article

(This article belongs to the Special Issue Drug Metabolism, Interactions and Toxicity: Advances in Metabolomics Approaches)

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17 pages, 5292 KB

Open AccessArticle

Metabolome Reprogramming During Fruit Ripening and Post-Harvest Storage in Ten Crop Species

by Michael Wittenberg, Yanitsa Ilieva and Tsanko Gechev

Metabolites 2026, 16(2), 133; https://doi.org/10.3390/metabo16020133 - 13 Feb 2026

Cited by 1 | Viewed by 688

Abstract

Background/Objectives: Plants alter metabolites of their fruits during the ripening process, leading to improved nutritional properties and taste. In addition, metabolite compositions continue to change on the shelf after harvest. However, the dynamics of these important processes are species-specific and so this study [...] Read more.

Background/Objectives: Plants alter metabolites of their fruits during the ripening process, leading to improved nutritional properties and taste. In addition, metabolite compositions continue to change on the shelf after harvest. However, the dynamics of these important processes are species-specific and so this study aimed to contrast the ripening dynamics of ten different fruit species simultaneously. Methods: Plant material was collected from the fruits of apple, banana, blueberry, kiwifruit, pear, plum, peach, strawberry, raspberry, and tomato at three different stages: unripe, fully ripe, and overripe fruits. Comparative metabolome analysis by GCMS was performed to identify differentially abundant metabolites across the species of this study and to examine their dynamics across ripening and post-harvest storage. These results were complemented by elemental compositions derived from a literature search. Results: In a first, this study demonstrated that both baseline metabolite abundances and their dynamics across ripening clustered species vary largely according to their phylogeny. Comparisons across ripe fruit identified differences in nutritional properties, highlighting species such as banana to be of especially high nutritional value and blueberry and peach to be prominent sources of antioxidants. Comparing the ripening dynamics of all species identified common patterns, such as the conversion of organic acids to sugars and cell wall dynamics, although species-specific responses were also acknowledged, in particular, kiwi and the Rosaceae berries, which may explain differences in post-harvest shelf-life. Conclusions: The observed inter- and intra-specific variation in nutritionally relevant metabolites and elements serves as a reference for both producers and consumers and emphasizes that consuming a variety of fruits, not only across species but also across cultivars within a species, can maximize the intake of beneficial phytonutrients, sugars, amino acids, and antioxidants. Full article

(This article belongs to the Special Issue Metabolic Changes During Pre- and Post-Harvest Fruit and Vegetable Decay, Ripening and Senescence—2nd Edition)

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18 pages, 1643 KB

Open AccessArticle

Anti-Obesity Effects of a Standardized Prunus persica Flower Extract (HT099) Through the Regulation of Lipid Metabolism in High-Fat Diet-Induced Obese Mice

by Se-Young Kim, Minju Kim, Young-Woong Choi, Mi-Yeon Kim, Kun Yun, Young-Sik Kim and Hocheol Kim

Metabolites 2026, 16(2), 132; https://doi.org/10.3390/metabo16020132 - 13 Feb 2026

Viewed by 452

Abstract

Background: Obesity is one of the most prevalent metabolic disorders worldwide, and its long-term management remains challenging due to the limited efficacy and adverse effects of current pharmacological treatments. Accordingly, there is growing interest in safe and effective anti-obesity strategies based on [...] Read more.

Background: Obesity is one of the most prevalent metabolic disorders worldwide, and its long-term management remains challenging due to the limited efficacy and adverse effects of current pharmacological treatments. Accordingly, there is growing interest in safe and effective anti-obesity strategies based on natural compounds. This study aimed to evaluate the anti-obesity effects of HT099, an extract derived from Prunus persica (peach blossom), and to investigate molecular changes associated with its metabolic effects in a high-fat diet (HFD)-induced obesity mouse model. Methods: Male C57BL/6N mice were fed an HFD and orally administered HT099 (50 or 100 mg/kg) or the positive control orlistat (40 mg/kg) for 12 weeks. Body weight, adipose tissue accumulation, food efficiency ratio, glucose tolerance, serum lipid profiles, and hepatic gene expression related to lipid metabolism were evaluated. Results: HT099 supplementation significantly attenuated body weight gain and reduced white adipose tissue accumulation while improving food efficiency ratio. HT099 also ameliorated HFD-induced glucose intolerance and favorably modulated serum lipid profiles, including reduced triglyceride levels, increased HDL-cholesterol levels, and improved non-HDL cholesterol indices. At the molecular level, HT099 administration was associated with an increased hepatic AMPKα1 mRNA expression and decreased expression of adipogenic and lipogenic genes, including C/EBPα, PPARγ, FAS, and SREBP-1c. Conclusions: These findings indicate that HT099 exerts anti-obesity effects in HFD-induced obese mice, accompanied by improvements in lipid and glucose metabolism and changes in adipogenesis- and lipogenesis-related gene expression. Collectively, the results support the potential of HT099 as a natural bioactive agent for obesity management. Full article

(This article belongs to the Special Issue Bioactive Compounds in Obesity and Its Metabolic Complications)

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19 pages, 1468 KB

Open AccessArticle

Metabolomic Signatures and Advanced Echocardiography Highlight Clinical Risk and Early Cardiac Changes in Systemic Lupus Erythematosus: Six-Year Follow-Up

by Nicola Campana, Michele Migliari, Antonio Deidda, Martino Deidda, Luca Fazzini, Gianmario Usai, Giulia Anna Maria Luigia Costanzo, Antonio Noto, Cristina Piras, Davide Firinu, Stefano Del Giacco, Luigi Atzori and Christian Cadeddu Dessalvi

Metabolites 2026, 16(2), 131; https://doi.org/10.3390/metabo16020131 - 13 Feb 2026

Viewed by 514

Abstract

Background/Objectives: Cardiovascular involvement drives morbidity and mortality in systemic lupus erythematosus (SLE). Echocardiography has limited predictive value for long-term outcomes, and subclinical right ventricular (RV) remodeling is poorly characterized. Metabolic dysregulation may influence immune activation and myocardial injury. This study investigates whether baseline [...] Read more.

Background/Objectives: Cardiovascular involvement drives morbidity and mortality in systemic lupus erythematosus (SLE). Echocardiography has limited predictive value for long-term outcomes, and subclinical right ventricular (RV) remodeling is poorly characterized. Metabolic dysregulation may influence immune activation and myocardial injury. This study investigates whether baseline metabolomic profiles are associated with longitudinal RV changes and disease progression in SLE. Methods: In this prospective, single-center study, patients with established SLE and no known cardiac disease underwent baseline clinical assessment, plasma metabolomic profiling, and advanced echocardiography, including 3D RV analysis. Echocardiography was repeated after 6 years. Metabolomics was performed using NMR spectroscopy and GC–MS. Disease progression was assessed via the SLICC/ACR damage index (SDI), defining clinical stability as ΔSDI = 0 and worsening as ΔSDI ≥ 1. Results: Twenty-five patients completed the follow-up (88% female; mean age 51 ± 13 years). Despite normal echocardiographic values, subtle but significant RV changes were observed, remaining within reference ranges, including mild declines in fractional area change and septal longitudinal strain (p < 0.05). Clinically worsened patients showed reduced TAPSE, while stable patients had slight increases (p < 0.05). Multivariate metabolomic analysis distinguished stable from worsened patients (R²Y = 0.772; Q² = 0.483), primarily driven by higher 2-aminoheptanedioic acid values in those with progression (p < 0.05), along with trends toward higher fumarate and lower fructose and glucopyranose. Conclusions: Baseline metabolomic and advanced echocardiographic profiling may identify SLE patients at risk of disease progression. Longitudinal echocardiography enables monitoring of subtle RV changes, supporting personalized surveillance to detect early subclinical trajectories before overt dysfunction develops. Full article

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

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15 pages, 8491 KB

Open AccessArticle

Transcriptomics and Metabolomics Analysis Reveal the Mechanism of Petal Number Variation in Gardenia jasminoides

by Bo Gao, Yi Lu, Wenhuan Lai, Yiwen Liao, Liang Dong, Qigong Zhang, Shuangquan Zou and Xiaoxing Zou

Metabolites 2026, 16(2), 130; https://doi.org/10.3390/metabo16020130 - 13 Feb 2026

Viewed by 427

Abstract

Background/Objectives: This study was based on the joint analysis of transcriptome and metabolome to explore the key genes and metabolic pathways of gardenia single flower petal number variation and to explore the possible mechanism of floral organ variation. Methods: Five, six, [...] Read more.

Background/Objectives: This study was based on the joint analysis of transcriptome and metabolome to explore the key genes and metabolic pathways of gardenia single flower petal number variation and to explore the possible mechanism of floral organ variation. Methods: Five, six, and seven petals of single-flower gardenia were selected as test materials for transcriptome and metabolome determination to excavate the key genes in regulating petal number in gardenia. Results: Metabolomic analysis identified triethylamine, succinic acid, succinylaldehyde, 2-phenylethanol, and o-xylene as the top five differentially expressed metabolites affecting petal number variation in gardenia. In the KEGG enrichment analysis, gardenia five, six, and seven DEGs were mainly enriched in amphetamine biosynthesis, the biosynthesis of plant secondary metabolites; transcriptome results showed that the identified differential transcription factors mainly come from NAC, ERF, C2H2, MYB, and MADS-box gene families; the expression of GjMADS50, GjMADS59, and GjERF28 changed with the increase in petal number. The commonality between gardenia five, six, and seven flowers exceeded the difference, and the expression pattern of MADS-box and ERF gene family members was the upregulation of GjERF28, GjERF39, and GjMADS67 and downregulation of GjMADS50, GjMADS59, and GjMADS60. Conclusions: We propose that ERF transcription factors may determine the initial number of petal primordia by mediating gibberellin biosynthesis or signaling, thereby coordinately regulating floral meristem activity and specific metabolic states. Full article

(This article belongs to the Special Issue The Influencing Factors of Nutrients and Metabolites in Plants)

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17 pages, 6076 KB

Open AccessArticle

Multi-Modal Metabolomics Deciphers Pan-Cancer Metabolic Landscapes and Spatial-Niche-Specific Alternations

by Tingze Feng, Hai-Long Piao and Di Chen

Metabolites 2026, 16(2), 129; https://doi.org/10.3390/metabo16020129 - 13 Feb 2026

Viewed by 577

Abstract

Background: Metabolic reprogramming is a hallmark of cancer and supports tumor growth and adaptation within the tumor microenvironment (TME). The complexity of this reprogramming manifests as both distinct variations across cancer types and spatial heterogeneity within individual tumors. The specificity of these metabolic [...] Read more.

Background: Metabolic reprogramming is a hallmark of cancer and supports tumor growth and adaptation within the tumor microenvironment (TME). The complexity of this reprogramming manifests as both distinct variations across cancer types and spatial heterogeneity within individual tumors. The specificity of these metabolic alterations, whether to cancer type, spatial niche, or as shared features, remains unclear, highlighting a critical gap in our systematic, pan-cancer understanding of metabolic reprogramming. Methods: We integrated bulk metabolomics and spatial metabolomics to investigate pan-cancer metabolic features and used blood-based metabolomics and spatial transcriptomics data to validate key findings. Metabolic differences were compared between tumor and normal tissues across multiple cancer types at the bulk level to identify metabolic modules shared across cancers or specific to individual cancer types. A two-step clustering framework was applied to identify both local and global TME-associated spatial metabolic modules of spatial metabolomics data from various tumor tissue slices. Results: We have identified a spectrum of metabolic features, including those specific to individual cancer types or spatial architectures and others shared across cancers, with some features emerging only at bulk-level and others uniquely discernible through spatial metabolomics. Integrative analyses also identified 19 metabolites consistently altered in both bulk and spatial data, especially carnitine species, which also showed concordant changes in blood samples and spatial associations with genes involved in fatty acid metabolism. Conclusions: This pan-cancer, multi-scale integrative analysis highlights substantial metabolic heterogeneity within the TME and across cancer types and identifies metabolites with consistent alterations across analytical layers, providing candidate features for future studies of tumor metabolism and potential metabolic biomarkers. Full article

(This article belongs to the Topic Multi-Omics in Precision Medicine)

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19 pages, 6059 KB

Open AccessArticle

Shared Plasma Fatty Acid Profiles in Four Cancer Types Enable Diagnosis and Discrimination of Gastrointestinal and Lung Cancers

by Ahad Hussain, Kangwe Shen, Yan Yan, Xuejun Kang and Li Xie

Metabolites 2026, 16(2), 128; https://doi.org/10.3390/metabo16020128 - 12 Feb 2026

Viewed by 394

Abstract

Background: Cancer is a leading cause of mortality worldwide, characterized by metabolic reprogramming, including alterations in fatty acid (FA) metabolism. Plasma FA profiles hold promise as non-invasive biomarkers for the diagnosis and classification of cancer. Objectives: This study aimed to investigate the diagnostic [...] Read more.

Background: Cancer is a leading cause of mortality worldwide, characterized by metabolic reprogramming, including alterations in fatty acid (FA) metabolism. Plasma FA profiles hold promise as non-invasive biomarkers for the diagnosis and classification of cancer. Objectives: This study aimed to investigate the diagnostic potential of plasma FA profiles across four major cancers and to identify shared and cancer-type-specific metabolic alterations. Methods: We examine comprehensive FA profiling of plasma samples from 368 individuals, including patients with colorectal (CRC, n = 94), gastric (GC, n = 55), esophageal (EC, n = 53), and lung cancer (LC, n = 73), alongside 93 healthy controls (HCs) by gas chromatography–mass spectrometry. Data were analyzed using univariate statistics and multivariate modeling analysis. Results: Univariate analysis showed a shared set of altered FAs across the cancer types, demonstrating a shared pan-cancer metabolic shift. A comprehensive comparison revealed a remarkable shared pattern within the gastrointestinal (GI) cancers (GC, CRC, EC), while LC showed opposite trends for most FAs. Partial Least Squares Discriminant Analysis (PLS-DA) models on a 70% training set excellently discriminated each cancer type from HCs. The cross-validation of the model demonstrated robust internal performance with Q² = 0.675 (LC), 0.559 (GC), 0.774 (CRC), and 0.628 (EC). This is followed by assessing the diagnostic accuracy on a 30% hold-out test set, with area under the curve (AUC) values of 0.686 (LC), 0.926 (GC), 0.905 (CRC), and 0.843 (EC). Conclusions: Plasma FA profiles may provide a potential source of biomarkers, capturing both shared cancer markers and distinct tissue-specific metabolic alterations. These findings highlight the high diagnostic and classificatory potential of FAs alterations in oncology. Full article

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

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29 pages, 3515 KB

Open AccessArticle

Genotype × Environment Shapes Fig Seed Oil Metabolic Fingerprinting

by Charaf Ed-dine Kassimi, Souhaila Hadday, Souhaila Bouchelta, Ahmed Irchad, Ibtissame Guirrou, Karim Houmanat, Fedoua Diai, Lhoussain Hajji and Lahcen Hssaini

Metabolites 2026, 16(2), 127; https://doi.org/10.3390/metabo16020127 - 12 Feb 2026

Viewed by 594

Abstract

Background/Objectives: Fig (Ficus carica L.) seed oil represents an underexplored by-product with considerable nutraceutical potential. However, systematic evaluation of genotype × environment (G × E) interactions affecting its biochemical composition remains limited. This study assessed compositional variability across fig varieties, identified metabolic [...] Read more.

Background/Objectives: Fig (Ficus carica L.) seed oil represents an underexplored by-product with considerable nutraceutical potential. However, systematic evaluation of genotype × environment (G × E) interactions affecting its biochemical composition remains limited. This study assessed compositional variability across fig varieties, identified metabolic trade-offs, and developed rapid authentication protocols using FTIR-ATR spectroscopy to support predictive G × E models and marker-assisted selection. Methods: Thirty-seven fig varieties were evaluated across two consecutive harvest years (2023–2024) in Morocco. Conventional biochemical analyses measured total phenolic content (TPC), total flavonoid content (TFC), DPPH and ABTS antioxidant activities, and oil yield. FTIR-ATR spectroscopy characterized spectral variations, with ANOVA assessing effects of year, variety, and G × E interactions. Principal Component Analysis (PCA) discriminated genotypes and years. Results: TPC varied substantially (16.5–115.1 mg GAE/100 g oil), declining 36% from 2023 (48.7 ± 16.6 mg GAE/100 g) to 2024 (31.2 ± 16.6 mg GAE/100 g; F = 1372.84, p < 0.001), with TFC showing parallel trends (15.6 vs. 11.8 mg QCE/100 g). DPPH activity increased 34% in 2024 (58.5% vs. 43.7%), while ABTS activity decreased 18.6% from 32.34 ± 14.28% to 26.31 ± 6.10% (p < 0.001). Oil yield decreased from 26.7% to 21.2% and negatively correlated with phenolic accumulation (r = −0.49, p < 0.001). FTIR-ATR identified diagnostic peaks (e.g., 3012, 2928 cm⁻¹), with significant G × E effects (p < 0.001). PCA captured 75.4–84.5% variance, discriminating genotypes and years. Stable high-value cultivars included ‘Dottato Perguerolles’, ‘VCR 276/49’, and ‘Ferqouch Jmel’. Conclusions: Genotypic differences and year-to-year environmental conditions significantly influence fig seed oil composition. The observed negative correlation between oil yield and phenolic content indicates a trade-off between lipid biosynthesis and secondary metabolism. FTIR-ATR spectroscopy coupled with multivariate analysis enables reliable variety discrimination and year differentiation, supporting the development of stable cultivars for nutraceutical applications. Full article

(This article belongs to the Special Issue The Influencing Factors of Nutrients and Metabolites in Plants)

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15 pages, 452 KB

Open AccessArticle

Sixty Years After a Coal Mine Disaster: Serum Metabolomic Profiles in Older Adults with Long-Term Sequelae of Carbon Monoxide Poisoning: A Cross-Sectional Study

by Eriko Baba, Hiroo Matsuse, Ryuki Hashida, Norika Matsukuma, Yuji Maki, Masayuki Omoto, Yoshio Takano, Makiko Motooka and Hiromichi Motooka

Metabolites 2026, 16(2), 126; https://doi.org/10.3390/metabo16020126 - 12 Feb 2026

Viewed by 479

Abstract

Background: Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike–Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor [...] Read more.

Background: Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike–Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor (BDNF). Methods: In this cross-sectional case–control study, outpatients with chronic CO-poisoning sequelae (CO; n = 14) and former miners without CO exposure (CON; n = 16), all aged ≥ 75 years, underwent targeted serum metabolomics (1183 metabolites) and clinical assessments. Between-group differences were evaluated using Welch’s t-test, and age-matched propensity-score matching (1:1) served as a sensitivity analysis. BDNF was additionally compared using a linear regression/ analysis of covariancemodel adjusting for age and Mini–Mental State Examination (MMSE). Results: Relative to controls, the CO group showed higher valine, alanine, and betaine and lower 3-hydroxybutyric acid, inosine, and hypoxanthine; these contrasts persisted with concordant direction after matching. Serum BDNF was lower in the CO group (unadjusted trend) and was significantly reduced after age/MMSE adjustment (p = 0.0252). Exploratory correlations between clinical measures and selected metabolites/BDNF were attenuated after accounting for group. Conclusions: Six decades after exposure, chronic CO sequelae were associated with a reproducible serum profile combining amino-acid elevations with relative suppression of ketone-body and purine-related metabolites, suggesting enduring alterations in systemic substrate handling and bioenergetics. If replicated in larger cohorts, such signatures—potentially alongside BDNF—should be regarded as hypothesis-generating; biomarker development would require external validation, longitudinal tracking, and assessment of intervention responsiveness before any clinical use is considered. Full article

(This article belongs to the Special Issue Metabolomics Insights into Environmental Pollution: Unraveling Metabolic Responses to Contaminants)

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1 pages, 132 KB

Open AccessCorrection

Correction: Zhou et al. The Positive Regulatory Effect of DBT on Lipid Metabolism in Postpartum Dairy Cows. Metabolites 2025, 15, 58

by Zheng Zhou, Kang Yong, Zhengzhong Luo, Zhenlong Du, Tao Zhou, Xiaoping Li, Xueping Yao, Liuhong Shen, Shumin Yu, Yixin Huang and Suizhong Cao

Metabolites 2026, 16(2), 125; https://doi.org/10.3390/metabo16020125 - 12 Feb 2026

Viewed by 267

Abstract

The authors would like to make the following correction to their published paper [...] Full article

(This article belongs to the Section Animal Metabolism)

13 pages, 578 KB

Open AccessArticle

The Impact of Nutritional Management on Fat-Soluble Nutrient Status in Patients with Fatty Acid Oxidation Disorders: A Cross-Sectional Study

by Maria Wasiewicz-Gajdzis, Małgorzata Jamka, Łukasz Kałużny, Natalia Wichłacz-Trojanowska, Anna Blask-Osipa, Monika Duś-Żuchowska, Joanna Jagłowska, Szymon Kurek, Anna Miśkiewicz-Chotnicka and Jarosław Walkowiak

Metabolites 2026, 16(2), 124; https://doi.org/10.3390/metabo16020124 - 11 Feb 2026

Viewed by 651

Abstract

Background: Fatty acid oxidation disorders (FAOD) are rare inborn errors of metabolism that impair mitochondrial β-oxidation and energy production. Management includes fasting avoidance for all FAOD types. Patients with long-chain FAOD are advised to restrict long-chain triglycerides (LCTs) to 10% of total energy [...] Read more.

Background: Fatty acid oxidation disorders (FAOD) are rare inborn errors of metabolism that impair mitochondrial β-oxidation and energy production. Management includes fasting avoidance for all FAOD types. Patients with long-chain FAOD are advised to restrict long-chain triglycerides (LCTs) to 10% of total energy intake and supplement medium-chain triglycerides (MCTs). The impact of such dietary modification on fat-soluble vitamin status has not yet been studied. Methods: In this cross-sectional study, serum concentrations of vitamins A, 25(OH)D, E, and β-carotene were measured in 36 FAOD patients and 36 healthy controls matched for age and sex. Vitamins A, E, and β-carotene were quantified using high-performance liquid chromatography and vitamin 25(OH)D through an immunoassay. FAOD patients were further divided into fat-modified (LCT-restricted) and standard-fat diet subgroups based on dietary management. Results: FAOD patients had significantly higher vitamin A concentrations than controls (p < 0.05), while there was no difference in vitamins 25(OH)D, E, and β-carotene. Within the FAOD cohort, the fat-modified group had higher levels of vitamins A and 25(OH)D but lower levels of vitamin E and β-carotene than the standard-fat group (all p < 0.05). Vitamin 25(OH)D deficiency (<20 ng/mL) was more frequent in the standard-fat group (p = 0.03). Conclusions: Fat-modified diets influence fat-soluble vitamin status in FAOD, emphasising the importance of ongoing monitoring and tailored supplementation. Future work should focus on optimising nutritional management, including modifications to formula composition, and on addressing the currently limited evidence on nutritional status and vitamin deficiencies in patients with FAOD. Full article

(This article belongs to the Section Nutrition and Metabolism)

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1 pages, 131 KB

Open AccessCorrection

Correction: Hernández-Miranda et al. Impacts of Phenolic Compounds and Their Benefits on Human Health: Germination. Metabolites 2025, 15, 425

by Jonathan Hernández-Miranda, Karen Argelia Reyes-Portillo, Abigail García-Castro, Esther Ramírez-Moreno and Alma Delia Román-Gutiérrez

Metabolites 2026, 16(2), 123; https://doi.org/10.3390/metabo16020123 - 11 Feb 2026

Viewed by 296

Abstract

The authors would like to make the following correction to their published paper [...] Full article

(This article belongs to the Special Issue Plants and Plant-Based Foods for Metabolic Disease Prevention)

19 pages, 957 KB

Open AccessArticle

Metabolic and Lactation Effects of Rumen-Protected Choline Supplementation in Peripartum Dairy Cows and Its Effects on Calf Growth Until Weaning

by Ugur Serbester and Melisa Topaktas

Metabolites 2026, 16(2), 122; https://doi.org/10.3390/metabo16020122 - 10 Feb 2026

Viewed by 499

Abstract

Background: This study evaluated the effects of rumen-protected choline (RUPCHOL) supplementation in dairy cows from 21 days before calving to 28 days postpartum. The objective was to determine how RUPCHOL influences metabolic status, milk composition, and subsequent calf growth until weaning. Methods: Twenty-seven [...] Read more.

Background: This study evaluated the effects of rumen-protected choline (RUPCHOL) supplementation in dairy cows from 21 days before calving to 28 days postpartum. The objective was to determine how RUPCHOL influences metabolic status, milk composition, and subsequent calf growth until weaning. Methods: Twenty-seven pregnant Holstein cows were assigned to a Control group (n = 13) or an RUPCHOL group (n = 14), both receiving a total mixed ration (TMR), with the RUPCHOL group supplemented with 15 g/day of choline chloride. Cows were monitored during prepartum, calving, and postpartum periods for body weight, body condition score, dry matter intake, rectal temperature, milk yield and composition, and blood metabolites. Results: RUPCHOL supplementation tended to reduce serum aspartate aminotransferase and lowered concentrations of non-esterified fatty acids and β-hydroxybutyrate, indicating improved metabolic status. Milk total solids, fat, and protein percentages were higher in RUPCHOL-fed cows, suggesting enhanced milk quality. Maternal supplementation did not affect colostrum immunoglobulin G (IgG) content or calf body weight and body measurements (heart girth, wither height, hip height, and body length) from birth to weaning. Conclusions: In summary, RUPCHOL supplementation improved indicators of metabolic health and milk composition of dairy cows during the peripartum period without altering calf growth outcomes. Full article

(This article belongs to the Section Animal Metabolism)

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17 pages, 1833 KB

Open AccessArticle

Carbohydrate and Fat Oxidation in Muscle Assessed with Exercise Calorimetry in 6465 Subjects

by Jean-Frédéric Brun, Emmanuel Varlet, Justine Myzia, Emmanuelle Varlet-Marie, Eric Raynaud de Mauverger and Jacques Mercier

Metabolites 2026, 16(2), 121; https://doi.org/10.3390/metabo16020121 - 9 Feb 2026

Viewed by 815

Abstract

Background/Objectives: Exercise calorimetry provides a means to quantify the relative contributions of lipid and carbohydrate (CHO) oxidation across a range of exercise intensities. Although lipid oxidation capacity has been widely studied—particularly in relation to exercise prescription for individuals with obesity—the factors governing CHO [...] Read more.

Background/Objectives: Exercise calorimetry provides a means to quantify the relative contributions of lipid and carbohydrate (CHO) oxidation across a range of exercise intensities. Although lipid oxidation capacity has been widely studied—particularly in relation to exercise prescription for individuals with obesity—the factors governing CHO oxidation during exercise are less clearly defined. This study therefore aimed to investigate, within a large single-center cohort, not only the established determinants of maximal lipid oxidation (LIPOXmax) but also those influencing CHO oxidation. Methods: Exercise calorimetry was performed in a cohort of 6465 individuals (4561 women and 1904 men; mean age 46.5 years; mean BMI 33.6 kg/m²). Two principal physiological indices were derived: LIPOXmax, defined as the exercise intensity eliciting maximal rates of fat oxidation, and the carbohydrate cost of the watt (CCW), defined as the slope characterizing the relationship between CHO oxidation and power output. Results: LIPOXmax showed positive associations with lean and muscle mass, and negative associations with fat mass and age, supporting the notion that greater muscle mass enhances the capacity for fat oxidation. Although men demonstrated higher absolute maximal fat oxidation rates, adjustment for body composition revealed that women exhibited relatively higher lipid oxidation (+30%, p < 0.001), occurring at a greater percentage of

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O_2max (+9.2%, p < 0.001). Furthermore, the carbohydrate cost of the watt was significantly elevated in women (+17.8% compared with men). CCW was positively correlated with BMI, fat mass, and age, and negatively correlated with muscle mass, LIPOXmax, and the crossover point—that is, the exercise intensity at which CHO becomes the predominant substrate. Discussion and Conclusions: Individuals with higher adiposity exhibited a greater reliance on carbohydrate oxidation, whereas leaner individuals preferentially oxidized lipids at comparable exercise intensities. These observations reinforce the reciprocal interplay between lipid and carbohydrate metabolism during exercise and highlight the substantial influence of body composition, age, and sex. Notably, this study provides the first comprehensive characterization of the determinants of CHO oxidation during exercise, identifying sex, age, and adiposity as major contributing factors. This underexplored facet of metabolic flexibility may hold practical relevance in clinical contexts such as obesity or susceptibility to exercise-induced hypoglycemia. Full article

(This article belongs to the Special Issue Interactions Between Exercise Physiology and Metabolism)

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12 pages, 406 KB

Open AccessReview

The Significance of the Heterogeneity of Cancer-Associated Fibroblasts in Tumor Microenvironments

by Daiki Imanishi, Hinano Nishikubo, Dongheng Ma, Hongdong Gao, Tomoya Sano, Canfeng Fan, Takashi Sakuma, Yurie Yamamoto and Masakazu Yashiro

Metabolites 2026, 16(2), 120; https://doi.org/10.3390/metabo16020120 - 9 Feb 2026

Viewed by 561

Abstract

The tumor heterogeneity that is frequently observed in cancer tissues comprises not only cancer cells but also stromal cells in the tumor microenvironment. One of the major components of tumor stroma, i.e., cancer-associated fibroblasts (CAFs), play crucial roles in tumor progression and the [...] Read more.

The tumor heterogeneity that is frequently observed in cancer tissues comprises not only cancer cells but also stromal cells in the tumor microenvironment. One of the major components of tumor stroma, i.e., cancer-associated fibroblasts (CAFs), play crucial roles in tumor progression and the tumor response to chemotherapy. The known subtypes of CAFs are antigen-presenting CAFs (apCAFs), myofibroblastic CAFs (myCAFs), and inflammatory CAFs (iCAFs). It has been speculated that (i) the heterogeneity of CAF subtypes might contribute to tumor progression; (ii) cell-to-cell interactions among CAF subtypes in tumors might be associated with the development of various types of carcinomas, and (iii) juxtracrine and/or paracrine signaling from CAFs may play important roles in this development. A clarification of the mechanisms that underlie the tumoral heterogeneity of CAFs could contribute to cancer treatment as precision medicine. This review explains the significance of CAF heterogeneity in tumor microenvironments, especially concerning the CAF subtypes. Full article

(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)

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24 pages, 6146 KB

Open AccessArticle

Transcriptomic Profiling Across Developmental Stages of Camellia petelotii (Merr.) Sealy Flower

by Yi Wang, Xing Chen, Shihui Zou, Xuemei Li, Wei Guo and Lijiao Ai

Metabolites 2026, 16(2), 119; https://doi.org/10.3390/metabo16020119 - 9 Feb 2026

Viewed by 450

Abstract

Background: The Camellia genus is widely recognized for its remarkable diversity in floral morphology and coloration, with Camellia petelotii (Merr.) Sealy being particularly notable for its rare golden-yellow flowers, which possess exceptional ornamental value. Despite its horticultural significance, the molecular mechanisms governing [...] Read more.

Background: The Camellia genus is widely recognized for its remarkable diversity in floral morphology and coloration, with Camellia petelotii (Merr.) Sealy being particularly notable for its rare golden-yellow flowers, which possess exceptional ornamental value. Despite its horticultural significance, the molecular mechanisms governing its flowering process remain poorly elucidated, presenting a substantial barrier to effective conservation and breeding initiatives. Methods: To address this knowledge gap, we conducted a comprehensive transcriptomic analysis, focusing on three distinct developmental stages of C. petelotii floral organs: the alabastrum stage (S1), the half-opened flower stage (S2), and the full bloom stage (S3). These samples were subjected to high-throughput sequencing using the Illumina platform. Following rigorous quality control and alignment with the reference genome, we performed transcript assembly and integrated comprehensive gene annotation data with quantitative gene expression profiles. Results: Our analysis identified 18,732 differentially expressed genes (DEGs) showing significant expression changes across developmental stages. Notably, we identified 134 DEGs as potential flowering-related genes, which were functionally associated with key pathways involved in floral regulation, including plant hormone signal transduction (e.g., AUX/IAA, ARF, SAUR, GH3, JAR4, GID1 and SOC1), starch (SS, SUS, BAM) and sucrose metabolism (HK, FrK, and GH32), circadian rhythm regulation (e.g., PIF3, ELF3, LHY, and PRR), and the Autonomous pathway. Building upon these findings, we have proposed a comprehensive model illustrating the regulatory network underlying flowering transition in C. petelotii. The reliability of the transcriptomic data was demonstrated through the validation of 11 genes using quantitative real-time PCR (qRT-PCR). Conclusions: These insights not only enhance our understanding of the molecular basis of flowering in this species but also provide a valuable theoretical framework for future genetic improvement and breeding programs of C. petelotii. Full article

(This article belongs to the Special Issue Metabolomics and Plant Defence, 2nd Edition)

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Open AccessArticle

Targeting Inflammation with Dietary ω-3 Polyunsaturated Fatty Acids Improved Lipid Mobilization and Flux in Heat-Stressed Wether Lambs

by Shelley A. Curry, Melanie R. White, Micah S. Most, Pablo C. Grijalva, Rachel L. Gibbs, Eileen S. Marks-Nelson, Ty B. Schmidt and Dustin T. Yates

Metabolites 2026, 16(2), 118; https://doi.org/10.3390/metabo16020118 - 9 Feb 2026

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Abstract

Background/Objectives: Chronic heat stress impairs lipid mobilization from adipocytes, which reduces substrate availability for muscle metabolism. Systemic inflammation is a key facilitative response to heat stress, and we sought to determine if mitigating inflammation in heat-stressed wether lambs would improve lipid flux. Methods: [...] Read more.

Background/Objectives: Chronic heat stress impairs lipid mobilization from adipocytes, which reduces substrate availability for muscle metabolism. Systemic inflammation is a key facilitative response to heat stress, and we sought to determine if mitigating inflammation in heat-stressed wether lambs would improve lipid flux. Methods: Two cohorts of commercial feedlot lambs were heat stressed for 30 days. In study 1, heat-stressed lambs received dexamethasone injections every 3 days, fish oil capsules twice daily, or no intervention. In study 2, heat-stressed lambs received daily boluses of ω-3 polyunsaturated fatty acid Ca²⁺ salts (ω-3 PUFA) or no intervention. Results: In both studies, heat stress reduced ex vivo epinephrine-stimulated free fatty acid and glycerol mobilization from visceral adipose tissue. These deficits were partially resolved by fish oil and fully resolved by ω-3 PUFA. In study 1, fish oil recovered heat stress-induced deficits in circulating triglycerides and HDL-cholesterol but not in circulating free fatty acids. Fish oil and dexamethasone resolved the increase in muscle PPARα, indicating less lipid utilization for metabolism. In study 2, ω-3 PUFA resolved heat stress-induced deficits in muscle CD36 and PPARγ, indicating improved lipid uptake capacity. However, interventions did not resolve reduced intramuscular lipid content in either study. Conclusions: We conclude that inflammation was a primary facilitator of impaired lipid mobilization in heat-stressed lambs but was not the sole driver of lipid dysregulation. Nevertheless, targeting inflammation was a beneficial strategy for improving lipid flux during chronic heat stress. Full article

(This article belongs to the Section Animal Metabolism)

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Metabolites, Volume 16, Issue 2 (February 2026) – 58 articles

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