Metabolites

22 pages, 3716 KB

Open AccessArticle

Precision Probiotics Regulate Blood Glucose, Cholesterol, Body Fat Percentage, and Weight Under Eight-Week High-Fat Diet

by Jinhua Chi, Jeffrey S. Patterson, Lingjun Li, Nicole Lalime, Daniella Hawley, Kyle Joohyung Kim, Li Liu, Julia Yue Cui, Dorothy D. Sears, Paniz Jasbi and Haiwei Gu

Metabolites 2025, 15(10), 642; https://doi.org/10.3390/metabo15100642 (registering DOI) - 25 Sep 2025

Abstract

Background/Objectives: Poor glycemic control is reaching an epidemic prevalence globally. It is associated with significantly morbid health concerns including retinopathy, neuropathy, nephropathy, cancer, and cardiovascular disease. Probiotics have shown promise in reducing health complications associated with poor blood glucose control. We tested [...] Read more.

Background/Objectives: Poor glycemic control is reaching an epidemic prevalence globally. It is associated with significantly morbid health concerns including retinopathy, neuropathy, nephropathy, cancer, and cardiovascular disease. Probiotics have shown promise in reducing health complications associated with poor blood glucose control. We tested a novel approach to designing a precision probiotic cocktail for improving blood glucose homeostasis. Methods: We tested the in vitro glucose consumption rate of twelve mouse microbiome bacterial strains and selected three with the greatest glucose consumption for the probiotic cocktail. The in vivo metabolic impact of ingesting the selected probiotic cocktail was evaluated in twelve C57BL/6J male mice fed a high-fat diet for eight weeks. Results: Compared to a control group, the probiotic group (L. rhamnosus, L. reuteri, and L. salivarius) exhibited significantly lower blood glucose levels, body weight, and body fat percentage. Moreover, the probiotic cocktail also demonstrated the ability to reduce serum insulin, total cholesterol, very-low-density lipoprotein/low-density lipoprotein cholesterol, and total cholesterol to high-density lipoprotein ratio. For further mechanistic investigation, untargeted metabolomics analyses uncovered overall downregulations in energy substrates and producing pathways like gluconeogenesis, acylcarnitine synthesis, glycolysis, the mitochondrial electron transport chain, the TCA cycle, and the building blocks for ATP formation. Partial least squares-discriminant analyses also confirmed clear group differences in metabolic activity. 16S rRNA sequencing from extracted gut microbiota also showed significant increases in Faith’s phylogenetic diversity, Lachnospiraceae bacterium 609-strain, and the genus Muribaculaceae as well as group β-diversity differences after probiotic intake. Conclusions: As such, we successfully developed a blend of three probiotics to effectively reduce blood glucose levels in male mice, which could further mitigate adverse health effects in the host. Full article

(This article belongs to the Special Issue Role of Nutraceuticals in Metabolic Disorders: Mechanisms and Benefits)

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13 pages, 1004 KB

Open AccessArticle

Matched Metabolic Stress Preserves Myokine Responses Regardless of Mechanical Load: A Randomized, Controlled Crossover Trial

by Yuji Maki, Hiroo Matsuse, Ryuki Hashida, Norika Matsukuma, Hiroshi Tajima, Eriko Baba, Yuji Kaneyuki, Sohei Iwanaga, Masayuki Omoto, Yoshio Takano, Matsuo Shigeaki, Takeshi Nago and Koji Hiraoka

Metabolites 2025, 15(10), 641; https://doi.org/10.3390/metabo15100641 - 25 Sep 2025

Abstract

Background/Objectives: Skeletal muscle functions as an endocrine organ by secreting myokines in response to exercise, with interleukin-6 (IL-6) recognized as a representative intensity-dependent biomarker that rapidly increases immediately after exercise and is strongly dependent on exercise intensity. However, it is unclear how [...] Read more.

Background/Objectives: Skeletal muscle functions as an endocrine organ by secreting myokines in response to exercise, with interleukin-6 (IL-6) recognized as a representative intensity-dependent biomarker that rapidly increases immediately after exercise and is strongly dependent on exercise intensity. However, it is unclear how changes in mechanical stress affect the response of myokines after exercise. This randomized crossover study aimed to investigate the effect of mechanical stress on acute myokine secretion during matched metabolic exercise under different mechanical stress. Methods: Ten healthy adult males performed 30 min of cycling at 60% of peak

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O₂ in both semi-recumbent position and side-lying positions. Blood samples were collected before, immediately after, and at 30 and 60 min post-exercise to evaluate IL-6, brain-derived neurotrophic factor (BDNF), and lactate. Results: BDNF and lactate levels peaked immediately after exercise, and IL-6 reached its peak at 30 min post-exercise in both the semi-recumbent position and side-lying positions. All markers showed significant elevations in response to exercise. However, no significant differences were found between the two postures in any of the measured variables. Conclusions: These findings suggest that reduced mechanical load does not impair endocrine responses when the intensity of metabolic stress is maintained. This study provides scientific evidence that, regardless of posture or environment, sufficient exercise intensity can induce adequate IL-6 and BDNF secretion, through which the beneficial effects of exercise may be expected. Full article

(This article belongs to the Special Issue Muscle Metabolic Response and Adaptation to Exercise, Diet, and Environment: 2nd Edition)

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12 pages, 1928 KB

Open AccessArticle

Chemometric Discrimination of Korean and Chinese Kimchi Using Untargeted Metabolomics

by Quynh-An Nguyen, Dong-Shin Kim, Hyo-Dong Kim, Kyu-Bin Kim, Kyung-Sik Ham, Yonghoon Lee and Hyun-Jin Kim

Metabolites 2025, 15(10), 640; https://doi.org/10.3390/metabo15100640 - 25 Sep 2025

Abstract

Background/Objectives: Kimchi has gained global recognition for its unique taste and health benefits, but its quality is totally different according to its geographical origin of materials and production methods. Methods: In this study, differences between Korean (53 samples) and Chinese kimchi (72 samples) [...] Read more.

Background/Objectives: Kimchi has gained global recognition for its unique taste and health benefits, but its quality is totally different according to its geographical origin of materials and production methods. Methods: In this study, differences between Korean (53 samples) and Chinese kimchi (72 samples) were investigated through comprehensive metabolomic analysis using gas chromatography–mass spectrometry (GC-MS) and ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS). Results: Multivariate statistical analyses revealed a clear separation between the two groups. Thirty-four metabolites contributing to the separation were identified. Korean kimchi was enriched in sucrose, quinic acid, sinapic acid derivatives, rutin, capsicosin, and capsianoside, while Chinese kimchi contained higher levels of trihydroxy octadecenoic acid, 2-hydroxypalmitic acid, pinellic acid, maltose, glucuronic acid, and corchorifatty acid F. In particular, the univariate Bayesianlogistic regression analysis revealed that among these metabolites, rutin, capsicosin derivatives, and sinapic acid derivatives showed strong potential as origin-discriminant markers of kimchi, providing insights into how these metabolites influence its nutritional and sensory properties. Conclusions: These compositional differences may be attributed to variations in raw materials and production methods of kimchi. Full article

(This article belongs to the Section Food Metabolomics)

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11 pages, 255 KB

Open AccessReview

Vitamin D Metabolism and the Risk of Renal Stones: A Focus on PHPT

by Elena Castellano and Federica Saponaro

Metabolites 2025, 15(10), 639; https://doi.org/10.3390/metabo15100639 - 24 Sep 2025

Abstract

Primary hyperparathyroidism is nowadays a common endocrine disorder. Over time, the clinical manifestation has shifted from symptomatic cases to mostly asymptomatic diagnoses. Despite this, nephrolithiasis remains significant, often presenting as bilateral and recurrent, with the literature reporting prevalence rates of up to 40%. [...] Read more.

Primary hyperparathyroidism is nowadays a common endocrine disorder. Over time, the clinical manifestation has shifted from symptomatic cases to mostly asymptomatic diagnoses. Despite this, nephrolithiasis remains significant, often presenting as bilateral and recurrent, with the literature reporting prevalence rates of up to 40%. The nephrolithiasis pathogenesis in PHPT is multifactorial and not fully understood. While elevated PTH increases urinary calcium load, additional urinary abnormalities and demographic factors, including age and sex, influence the risk. Vitamin D status has also been explored as a possible contributor to stone formation both in the general population and in PHPT patients. The relationship between serum 25OHD levels and nephrolithiasis remains unclear, and the impact of vitamin D supplementation on stone risk in PHPT is still under investigation. The relationship between vitamin D status, supplementation and renal stones in PHPT is explored in the present review. Full article

(This article belongs to the Special Issue Primary Hyperparathyroidism: Mechanisms and Treatment)

18 pages, 1886 KB

Open AccessArticle

Effect of β-Caryophyllene on PPAR-γ, NF-κB, and CNR2: Implications for Gut–Brain Axis Communication in a Murine Model of Diet-Induced Obesity

by Cristina Pech-Jiménez, Lucrecia Carrera-Quintanar, Juan Manuel Viveros-Paredes, Yolanda Fabiola Marquez-Sandoval, Luis Felipe Jave-Suárez, Adelaida Sara Minia Zepeda-Morales, Gilberto Velázquez-Juárez and Rocio Ivette López-Roa

Metabolites 2025, 15(10), 638; https://doi.org/10.3390/metabo15100638 - 24 Sep 2025

Abstract

Background /Objectives: The rising prevalence of metabolic disorders, such as obesity, is linked to increased consumption of high-calorie foods and sedentary lifestyles. While conventional treatments rely on lifestyle modifications and pharmaceuticals, these often have limitations and adverse effects. As an alternative, natural compounds [...] Read more.

Background /Objectives: The rising prevalence of metabolic disorders, such as obesity, is linked to increased consumption of high-calorie foods and sedentary lifestyles. While conventional treatments rely on lifestyle modifications and pharmaceuticals, these often have limitations and adverse effects. As an alternative, natural compounds like β-caryophyllene (BCP), found in spices such as black pepper and cloves, have gained interest due to their anti-inflammatory and metabolic properties. This study investigated the effects of BCP on the gut–brain axis in obese C57BL/6J mice. Methods: Quantitative real-time PCR (RT-qPCR) was performed using a Rotor-GeneQ thermocycler (Qiagen). Relative gene expression levels were normalized to the reference gene’s transcript levels (2^−∆∆Ct method). Results: BCP was found to modulate key receptors, including FFAR3, LEPR, and GHSR, which are involved in appetite regulation and insulin sensitivity. Its action on the CNR2 (CB2 receptor) suggests additional benefits in energy balance and anorexigenic activity. Conclusions: These findings support BCP’s potential as a complementary therapy for obesity, though further studies are needed to confirm its efficacy in humans. Its safety profile and multifactorial effects make it a promising alternative to conventional treatments. Full article

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

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0 pages, 6097 KB

Open AccessArticle

Hexavalent Chromium Induces Defense Responses, Hepatocellular Apoptosis, and Lipid Metabolism Alterations in New Zealand Rabbit Livers

by Junzhao Yuan, Lei Zhang, Xiuqing Li, Xinfeng Li, Pandeng Zhao, Xiaoli Ren and Yuzhen Song

Metabolites 2025, 15(10), 637; https://doi.org/10.3390/metabo15100637 - 23 Sep 2025

Abstract

Background: Hexavalent chromium (Cr(VI)) can migrate into soil and water, posing risks to animal health. However, it remains unclear whether Cr(VI) perturbs essential trace elements and antioxidant gene expression, triggers apoptosis, or disrupts hepatic lipid metabolism in New Zealand rabbits. Methods: [...] Read more.

Background: Hexavalent chromium (Cr(VI)) can migrate into soil and water, posing risks to animal health. However, it remains unclear whether Cr(VI) perturbs essential trace elements and antioxidant gene expression, triggers apoptosis, or disrupts hepatic lipid metabolism in New Zealand rabbits. Methods: To address this knowledge gap, twenty-four 30-day-old New Zealand rabbits were randomly allocated to one control and three Cr(VI)-treated groups (differing in Cr(VI) concentration) and maintained for 28 days. Livers were then harvested for analysis. Total Cr and essential trace elements were quantified by ICP-OES. Hematoxylin–eosin staining and transmission electron microscopy were employed to assess histopathological and ultrastructural alterations, respectively. Hepatic lipid accumulation was visualized with Oil Red O staining. QRT-PCR was used to determine the expression of antioxidant and lipid-metabolism-related genes. Results: Cr(VI) was detectable in liver tissue at all exposure levels and was accompanied by significant decreases in four essential trace elements (Fe, Mn, Zn, and Se); Cu displayed a biphasic response, rising at lower Cr(VI) doses before declining at higher doses. Histopathological and ultrastructural analyses revealed overt hepatic injury. Notably, all Cr(VI) treatments elevated antioxidant gene expression, indicating activation of hepatic defense pathways. Lipid metabolism was also disrupted, evidenced by increased lipid deposition and up-regulation of genes governing hepatic fat metabolism. Conclusions: Collectively, these findings demonstrate that Cr(VI) elicits dose-dependent activation of hepatic antioxidant defenses, promotes apoptosis, and induces lipid-metabolic disorders in New Zealand rabbit hepatocytes. This study provides novel mechanistic insights into Cr(VI)-induced hepatotoxicity and offers a valuable reference for evaluating the hepatic risks of environmental Cr(VI) exposure in this species. Full article

(This article belongs to the Special Issue Animal Nutritional Metabolism and Toxicosis Disease, 2nd Edition)

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0 pages, 2668 KB

Open AccessArticle

NAD⁺-Dependent Lysine Acetylation Regulates Glucose Uptake and Fatty Acid Oxidation in Cardiomyocytes

by Ettore Vanni and Christophe Montessuit

Metabolites 2025, 15(10), 636; https://doi.org/10.3390/metabo15100636 - 23 Sep 2025

Abstract

Background/Objectives: Stimulation of glucose uptake in response to ischemic stress is important for cardiomyocyte post-ischemic function and survival. In the diabetic myocardium chronically exposed to an excess of circulating lipids, this mechanism is impaired, making the myocardium more sensitive to ischemia–reperfusion injury (IRI). [...] Read more.

Background/Objectives: Stimulation of glucose uptake in response to ischemic stress is important for cardiomyocyte post-ischemic function and survival. In the diabetic myocardium chronically exposed to an excess of circulating lipids, this mechanism is impaired, making the myocardium more sensitive to ischemia–reperfusion injury (IRI). In vitro studies have shown that exposure to fatty acids (FAs) reduces basal and stimulated glucose uptake in cardiomyocytes. Preliminary results indicate reduced NAD⁺ levels and increased protein lysine acetylation in FA-exposed cardiomyocytes. This study aims to investigate whether intracellular NAD⁺ reduction is responsible for FA-induced increase in protein acetylation and impaired glucose uptake. Methods: Primary rat cardiomyocytes were chronically treated with the sirtuin deacetylase inhibitor nicotinamide (NAM) in absence of FAs to induce protein acetylation. Conversely, we replenished NAD⁺ concentration using nicotinamide riboside (NR) to induce protein deacetylation in FA-exposed cardiomyocytes. Results: Similar to FA exposure, NAM treatment increased protein acetylation and impaired metabolic-stress-stimulated glucose uptake in cardiomyocytes. In contrast, NR supplementation reduced protein acetylation and improved metabolic-stress-stimulated glucose uptake in FA-exposed cardiomyocytes. Neither NAM nor NR influenced insulin-stimulated glucose uptake. Both NAM and FAs induced hydroxyacyl-CoA dehydrogenase trifunctional enzyme subunit α (HADHA) acetylation on lysine residues K¹⁶⁶ and K²¹⁴ and enhanced palmitate oxidation. Conversely, NR treatment induced HADHA deacetylation and reduced palmitate uptake and oxidation in FA-exposed cardiomyocytes. Conclusions: In cardiomyocytes, protein hyperacetylation, resulting from either FA exposure or sirtuin inhibition, impairs metabolic-stress-stimulated glucose uptake and is associated with increased FA oxidation. Full article

(This article belongs to the Section Cell Metabolism)

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17 pages, 3157 KB

Open AccessArticle

Deciphering the Role of Different Ceramide Synthases in the Human Cardiomyocyte Hypertrophic Response

by Alexandra M. Wiley, Melissa A. Krueger, Nona Sotoodehnia, Jason G. Umans, Andrew N. Hoofnagle, Rozenn N. Lemaitre, Rheem A. Totah and Sina A. Gharib

Metabolites 2025, 15(9), 635; https://doi.org/10.3390/metabo15090635 - 22 Sep 2025

Abstract

Background/Objectives: Recent studies suggest that plasma ceramide levels may be better predictors of CVD risk than LDL cholesterol. Ceramides are part of the sphingolipid class of lipids and are the central intermediates in complex sphingolipid biosynthesis. Sphingolipids are crucial for cellular structure [...] Read more.

Background/Objectives: Recent studies suggest that plasma ceramide levels may be better predictors of CVD risk than LDL cholesterol. Ceramides are part of the sphingolipid class of lipids and are the central intermediates in complex sphingolipid biosynthesis. Sphingolipids are crucial for cellular structure and have important biological roles as complex signaling lipids, structurally and functionally differentiated by their acylated fatty acid. Higher plasma concentrations of 16:0 ceramide are associated with increased risk of heart failure. In contrast, higher concentrations of 22:0 plus 24:0 ceramide are associated with lower risk. We aim to address how alterations in these lipids can affect the human cardiac hypertrophic response. Methods: We silenced the ceramide synthase genes (CERS) responsible for the production of 16:0 ceramide (CERS5/6) or 22:0 and 24:0 ceramide (CERS2) in immortalized human ventricular cardiomyocytes and examined the altered cardiac hypertrophic response to phorbol 12-myristate 13-acetate treatment by examining changes in the transcriptome. Results: We discovered that silencing CERS2 or CERS5/6 drastically altered the cardiac cell hypertrophic response. We demonstrated that human cardiomyocytes with silenced CERS2 appeared to have an exacerbated hypertrophy response, while cardiomyocytes with silenced CERS5/6 had a more favorable response, suggesting that CERS2 and CERS5/CERS6 and their gene product metabolites may have opposing roles in the development and progression of CVD. Conclusions: The exact mechanisms through which various ceramides contribute to CVD progression are still unknown. This study will help elucidate the role of specific ceramides during cardiac hypertrophy and suggests that drugs targeting specific sphingolipids can potentially be a viable treatment option for the prevention of CVD. Full article

(This article belongs to the Special Issue Lipid Biomarkers and Cardiometabolic Diseases—2nd Edition)

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11 pages, 1024 KB

Open AccessArticle

Reducing False Positives in Newborn Screening: The Role of Perinatal Factors in the Dutch NBS Program

by Nils W. F. Meijer, Rose E. Maase, Patricia L. Hall, Wouter F. Visser, Klaas Koop, Annet M. Bosch, M. Rebecca Heiner-Fokkema, Monique G. M. de Sain‐van der Velden and the CLIR-NBS Group

Metabolites 2025, 15(9), 634; https://doi.org/10.3390/metabo15090634 - 22 Sep 2025

Abstract

Background/Objectives: Dutch newborn screening is an important public health program designed to detect conditions early in life, enabling timely interventions that can prevent mortality, morbidity, and long-term disabilities. However, the program also faces certain challenges. One such issue is obtaining and maintaining [...] Read more.

Background/Objectives: Dutch newborn screening is an important public health program designed to detect conditions early in life, enabling timely interventions that can prevent mortality, morbidity, and long-term disabilities. However, the program also faces certain challenges. One such issue is obtaining and maintaining a high positive predictive value (PPV); another is that newborn screening (NBS) in the Netherlands is intended for all newborn babies until the age of six months. This means comparing infants at different ages may introduce variability that complicates data interpretation. To support the optimization of the program, we systematically analyzed population-level tandem mass spectrometry (MS/MS) data to explore postnatal metabolic changes. Methods: We evaluated the impact of covariates—including birth weight, gestational age, age at blood collection, and biological sex—on metabolite profiles using retrospective newborn screening (NBS) data. Special emphasis was placed on the combined effects of these covariates. The analysis was based on data from 985,629 newborns collected between 2018 and 2024. Results: Specifically, (extremely) preterm infants exhibit altered levels of several amino acids and acylcarnitines. Moreover, we observed multiplicative effects of gestational age and birth weight on several metabolic markers. Biological sex however, does not have an impact. The largest impact of the age of sampling was observed on the C0/C16+C18 ratio, which may impact screening performance for CPT1 deficiency. Conclusions: Covariate-adjusted reference values could improve the performance of the Dutch newborn screening. Full article

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

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18 pages, 4789 KB

Open AccessArticle

Combination of Metabolomic Analysis and Transcriptomic Analysis Reveals Differential Mechanism of Phenylpropanoid Biosynthesis and Flavonoid Biosynthesis in Wild and Cultivated Forms of Angelica sinensis

by Yuanyuan Wang, Jialing Zhang, Yiyang Chen, Juanjuan Liu, Ke Li and Ling Jin

Metabolites 2025, 15(9), 633; https://doi.org/10.3390/metabo15090633 - 22 Sep 2025

Abstract

Objectives: Angelica sinensis is a type of traditional Chinese medicine (TCM) used primarily as a blood tonic. The chemical components that exert their efficacy are mainly bioactive metabolites, such as ferulic acid, flavonoids, and volatile oils. The resources of wild Angelica sinensis (WA) [...] Read more.

Objectives: Angelica sinensis is a type of traditional Chinese medicine (TCM) used primarily as a blood tonic. The chemical components that exert their efficacy are mainly bioactive metabolites, such as ferulic acid, flavonoids, and volatile oils. The resources of wild Angelica sinensis (WA) are very scarce, and almost all the market circulation of TCM formulations relies on cultivated Angelica sinensis (CA). Some studies have shown that WA and CA differ in morphological features and chemical composition, but the reasons and mechanisms behind the differences have not been studied deeply. Methods: Herein, metabolomics analysis (MA) and transcriptomics analysis (TA) were used to reveal the differences in bioactive metabolites and genes between WA and CA. Expression of key genes was verified by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Results showed that 12,580 differential metabolites (DMs) and 1837 differentially expressed genes (DEGs) were identified between WA and CA. Fourteen DMs (e.g., cinnamic acid, caffeic acid, ferulic acid, p-coumaroylquinic acid, and phlorizin) and 27 DEGs (e.g., cinnamic acid 4-hydroxylase (C4H), 4-coumarate-CoA ligase (4CL), shikimate O-hydroxycinnamoyltransferase (HCT), caffeic acid-O-methyltransferase (COMT), cinnamyl-alcohol dehydrogenase (CAD), flavonol synthase (FLS)) were screened in phenylpropanoid biosynthesis and flavonoid biosynthesis. A combined analysis of MA and TA was performed, and a network map of DMs regulated by DEGs was plotted. The results of real-time RT-qPCR showed that the transcriptome data were reliable. Conclusions: These findings provide a reference for further optimization of the development of WA cultivation and breeding of CA varieties. Full article

(This article belongs to the Section Plant Metabolism)

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16 pages, 1623 KB

Open AccessArticle

Non-Invasive Detection of Nasopharyngeal Carcinoma Using Volatile Organic Compounds

by Chuan Hao Gui, Zhunan Jia, Alex Chengyao Tham, Khai Beng Chong, Zihao Xing, Fuchang Zhang, Fang Du, Yaw Khian Chong, Hao Li, Ernest Weizhong Fu, Jereme Yijin Gan, Agnes Si Qi Chew and Ming Yann Lim

Metabolites 2025, 15(9), 632; https://doi.org/10.3390/metabo15090632 - 22 Sep 2025

Abstract

Background: Nasopharyngeal carcinoma (NPC) is a leading head and neck cancer in Asia, where late-stage presentation contributes to poor survival. Non-invasive diagnostic strategies such as breath analysis may improve early detection. Objectives: This study aimed to investigate whether volatile organic compound (VOC) features [...] Read more.

Background: Nasopharyngeal carcinoma (NPC) is a leading head and neck cancer in Asia, where late-stage presentation contributes to poor survival. Non-invasive diagnostic strategies such as breath analysis may improve early detection. Objectives: This study aimed to investigate whether volatile organic compound (VOC) features in exhaled breath, detected using proton transfer reaction mass spectrometry (PTR-MS), can distinguish NPC patients from healthy controls. Methods: Breath samples were collected from 50 NPC patients and 40 healthy controls. PTR-TOF-MS was used to measure exhaled VOC features. Group comparisons were performed using univariate analysis, while multivariable regression was adjusted for age, sex, BMI, smoking, and medication use. Multivariate methods, including principal component analysis (PCA) and random forest classification, were used to assess discriminatory potential. Results: Seven distinct VOC features (measured as m/z values) showed significant differences between NPC patients and healthy controls, with m089 and m175 emerging as the strongest markers of distinction. PCA after normalization revealed clearer separation between NPC patients and controls. Random forest models incorporating significant VOCs achieved moderate classification accuracy, and the results remained robust after adjusting for confounders. Conclusions: PTR-MS breath analysis can detect disease-specific VOC features in NPC and shows promise as a non-invasive diagnostic tool. Larger validation studies and definitive compound identification are needed to confirm clinical utility. Full article

(This article belongs to the Special Issue Multiomics and Metabolism in Infectious Diseases and Cancer: Unveiling Novel Mechanisms and Biomarkers)

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28 pages, 7524 KB

Open AccessArticle

Ambient Mass Spectrometry Imaging Reveals Spatiotemporal Brain Distribution and Neurotransmitter Modulation by 1,8-Cineole: An Epoxy Monoterpene in Mongolian Medicine Sugmel-3

by Jisiguleng Wu, Qier Mu, Junni Qi, Hasen Bao and Chula Sa

Metabolites 2025, 15(9), 631; https://doi.org/10.3390/metabo15090631 - 22 Sep 2025

Abstract

Background/Objectives: 1,8-Cineole, an epoxy monoterpene, is a key volatile component of Sugmel-3, a traditional Mongolian medicine used for treating insomnia. Although previous studies suggest that 1,8-Cineole can cross the blood–brain barrier (BBB), its precise spatiotemporal distribution in the brain and its in situ [...] Read more.

Background/Objectives: 1,8-Cineole, an epoxy monoterpene, is a key volatile component of Sugmel-3, a traditional Mongolian medicine used for treating insomnia. Although previous studies suggest that 1,8-Cineole can cross the blood–brain barrier (BBB), its precise spatiotemporal distribution in the brain and its in situ association with alterations in neurotransmitter (NT) levels remain unclear. This study utilized ambient mass spectrometry imaging (AFADESI-MSI) to investigate the dynamic brain distribution of 1,8-Cineole and its major metabolite, as well as their correlation with NT levels. Methods: Sprague Dawley rats (n = 3 per time point) received oral administration of 1,8-Cineole (65 mg/kg). Brain tissues were harvested 5 min, 30 min, 3 h, and 6 h post dose and analyzed using AFADESI-MSI. The spatial and temporal distributions of 1,8-Cineole, its metabolite 2-hydroxy-1,8-Cineole, key neurotransmitters (e.g., 5-HT, GABA, glutamine, melatonin), and related endogenous metabolites were mapped across 13 functionally distinct brain microregions. Results: AFADESI-MSI demonstrated rapid brain entry of 1,8-Cineole and its metabolite, with distinct spatiotemporal pharmacokinetics. The metabolite exhibited higher brain exposure, with 1,8-Cineole predominant in the cortex (CTX) and hippocampus (HP), while its metabolite showed pronounced accumulation in the pineal gland (PG), alongside CTX/HP. Region-dependent alterations in neurotransmitter levels (notably in PG, HP) correlated with drug concentrations, with observed increases in key molecules of the serotonergic and GABAergic pathways. Conclusions: Using AFADESI-MSI, this study provides the first spatiotemporal map of 1,8-Cineole and its metabolite in the brain. The correlation between their region-specific distribution and local neurotransmitter alterations suggests a direct mechanistic link to Sugmel-3′s sedative–hypnotic efficacy, guiding future target identification. Full article

(This article belongs to the Special Issue Mass Spectrometry Imaging and Spatial Metabolomics)

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20 pages, 2219 KB

Open AccessArticle

Metabolomic Profiling Reveals Distinct Signatures in Primary and Secondary Polycythemia

by Murat Yıldırım, Batuhan Erdoğdu, Selim Sayın, Ozan Kaplan, Emine Koç, Mine Karadeniz, Bülent Karakaya, Mustafa Güney, Mustafa Çelebier and Meltem Aylı

Metabolites 2025, 15(9), 630; https://doi.org/10.3390/metabo15090630 - 22 Sep 2025

Abstract

Background/Objectives: The differential diagnosis between primary polycythemia vera (PV) and secondary polycythemia (SP) presents significant clinical challenges owing to substantial phenotypic overlap. This investigation utilized untargeted metabolomic approaches to elucidate disease-specific metabolic perturbations and evaluate the metabolic consequences of cytoreductive therapeutic interventions. [...] Read more.

Background/Objectives: The differential diagnosis between primary polycythemia vera (PV) and secondary polycythemia (SP) presents significant clinical challenges owing to substantial phenotypic overlap. This investigation utilized untargeted metabolomic approaches to elucidate disease-specific metabolic perturbations and evaluate the metabolic consequences of cytoreductive therapeutic interventions. Methods: Plasma specimens obtained from PV patients (n = 40) and SP patients (n = 25) underwent comprehensive metabolomic profiling utilizing liquid chromatography–mass spectrometry (LC-MS) platforms. Multivariate statistical analyses, including principal component analysis (PCA), were employed in conjunction with pathway enrichment analyses to characterize disease-associated metabolic dysregulation. Additionally, receiving treatment (tPV) (n = 25) and not receiving treatment (ntPV) (n = 15) PV patients were compared to assess therapeutic metabolic effects. Results: Comprehensive metabolomic analysis identified 67 significantly altered metabolites between PV and SP patients, with 36 upregulated and 31 downregulated in PV. Key upregulated metabolites in PV included thyrotropin-releasing hormone, 3-sulfinoalanine, nicotinic acid adenine dinucleotide, and protoporphyrin IX, while 4-hydroxyretinoic acid and deoxyuridine were notably downregulated. Pathway enrichment analysis revealed disruptions in taurine, glutamate, nicotinate, and cysteine metabolism in PV. ntPV patients exhibited higher glucose and octanoyl-CoA levels compared to treated patients, indicating the normalization of glucose and fatty acid metabolism with cytoreductive therapy. ntPV was also associated with altered B-vitamin metabolism, including decreased nicotinic acid adenine dinucleotide and increased nicotinamide ribotide levels. Cross-comparison analysis revealed overlapping pathway enrichment in glutamate metabolism, nicotinate and nicotinamide metabolism, and cysteine metabolism between both comparisons. Conclusions: This study demonstrates that PV and SP exhibit fundamentally distinct metabolic signatures, providing novel insights into disease pathogenesis and potential diagnostic biomarkers. The identification of oxidative stress signatures, disrupted energy metabolism, and altered B-vitamin cofactor pathways distinguishes PV from SP at the molecular level. Cytoreductive therapy significantly normalizes metabolic dysregulation, particularly glucose and nucleotide metabolism, validating current therapeutic approaches while revealing broader systemic treatment effects. The metabolic signatures identified, particularly the combination of deoxyuridine, thyrotropin-releasing hormone, and oxidative stress metabolites, may serve as complementary diagnostic tools to traditional morphological and molecular approaches. These findings advance our understanding of myeloproliferative neoplasm pathophysiology and provide a foundation for developing metabolically targeted therapeutic strategies and precision medicine approaches in PV management. Full article

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

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15 pages, 1757 KB

Open AccessReview

Using Caprylic Acid for the Prevention and Treatment of Helicobacter pylori Infection and Gastric Cancer: A Review

by Alexandra Balderrama-Gómez, Victor Manuel Muñoz-Pérez, Mario I. Ortiz, Raquel Cariño-Cortés, Javier Castro-Rosas, Abigail Betanzos, Eduardo Fernández-Martínez and Israel Castillo-Juárez

Metabolites 2025, 15(9), 629; https://doi.org/10.3390/metabo15090629 - 22 Sep 2025

Abstract

The present study investigates the bactericidal and anticancer potential of caprylic acid (CA) against Helicobacter pylori infection, a major global risk factor for gastric cancer. Several chronic inflammatory processes, bacterial virulence factors, and carcinogenic mechanisms—capable of inducing DNA damage in gastric epithelial cells, [...] Read more.

The present study investigates the bactericidal and anticancer potential of caprylic acid (CA) against Helicobacter pylori infection, a major global risk factor for gastric cancer. Several chronic inflammatory processes, bacterial virulence factors, and carcinogenic mechanisms—capable of inducing DNA damage in gastric epithelial cells, promoting genomic instability, and contributing to the development of gastritis or peptic ulcer disease in susceptible individuals—remain incompletely understood. CA, a medium-chain fatty acid naturally found in plant and animal sources such as coconut oil and goat’s milk, possesses notable biological properties that may confer gastroprotective effects against gastric cancer induced by H. pylori. Despite advances in medical management, no universally effective strategy currently exists for the treatment or prevention of H. pylori–associated gastric cancer. Conventional therapies, including surgery, radiotherapy, and chemotherapy, often entail long-term complications that may affect patients’ nutritional status. In brief, further elucidation of the mechanisms underlying medium-chain fatty acid metabolism, particularly that of CA in gastric cancer cells, may yield valuable insights for the development of innovative therapeutic approaches. Consequently, the integration of CA into therapeutic dietary regimens and the formulation of nutraceuticals targeting H. pylori infection and related gastric pathologies warrant consideration. Therefore, CA could be considered a potential adjuvant in the preventive treatment of H. pylori–induced gastritis and its associated complications. However, further in vitro and in vivo studies are needed to confirm its beneficial use for this pathology. Full article

(This article belongs to the Section Plant Metabolism)

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13 pages, 1881 KB

Open AccessArticle

Analysis of FsTyDC1 Gene from Forsythia suspensa in Response to Drought and Salt Stress Treatment

by Jiaqi Xu, Jiaxi Chen, Meng Yuan, Panpan Wang, Wenwen Li, Yilong Li, Chong Yang, Shufang Lv, Zhanqiang Ma, Hongxiao Zhang, Huawei Xu, Xingli Zhao, Ting Wang and Dianyun Hou

Metabolites 2025, 15(9), 628; https://doi.org/10.3390/metabo15090628 - 19 Sep 2025

Abstract

Background: Forsythia suspensa (Thunb.) Vahl is a perennial deciduous shrub of the Oleaceae family. Its dried mature fruits are used as medicine and hold an important position in traditional Chinese medicine. Tyrosine decarboxylase (TyDC) is a key enzyme involved in the synthesis [...] Read more.

Background: Forsythia suspensa (Thunb.) Vahl is a perennial deciduous shrub of the Oleaceae family. Its dried mature fruits are used as medicine and hold an important position in traditional Chinese medicine. Tyrosine decarboxylase (TyDC) is a key enzyme involved in the synthesis of dopamine in Forsythia suspensa. At the same time, it also affects the growth and development of this species under biotic stress. Methods: This study examined the expression and function of FsTyDC1 under drought and salt stress. The TyDC gene identified in F. suspensa, termed FsTyDC1, has an open reading frame (ORF) of 1518 bp. Results: qRT-PCR and subcellular localization analyses indicated that FsTyDC1 is highly expressed in F. suspensa fruit and its protein is located in the cytoplasm. The gene was silenced using a pTRV2-FsPDS/FsTyDC1 vector with virus-induced gene silencing. Following exposure to drought and salt stress, the leaves of FsTyDC1-silenced plants exhibited increased curling and wilting. Conclusions: The results indicate that FsTyDC1 responds to both salt and drought stress, which provides a foundation for further investigation into the function of FsTyDC1. Full article

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

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27 pages, 1416 KB

Open AccessReview

The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV

by Yusnier Lázaro Díaz-Rodríguez, Elsa Janneth Anaya-Ambriz, Paula Catalina Méndez-Ríos, Jaime F. Andrade-Villanueva, Luz A. González-Hernández, Tania Elisa Holguín-Aguirre, Pedro Martínez-Ayala, Vida V. Ruiz-Herrera, Monserrat Alvarez-Zavala and Karina Sánchez-Reyes

Metabolites 2025, 15(9), 627; https://doi.org/10.3390/metabo15090627 - 19 Sep 2025

Abstract

Background/Objectives: HIV infection has been associated with an increased incidence of non-communicable comorbidities, including metabolic disorders. This phenomenon has been linked to gut microbiota dysbiosis, which involves not only changes in bacterial composition but also functional alterations in metabolite production. The objective of [...] Read more.

Background/Objectives: HIV infection has been associated with an increased incidence of non-communicable comorbidities, including metabolic disorders. This phenomenon has been linked to gut microbiota dysbiosis, which involves not only changes in bacterial composition but also functional alterations in metabolite production. The objective of this study was to describe the impact of intestinal microbial metabolomics on the development of type 2 diabetes in people living with HIV. Methods: This study provides a narrative synthesis of current evidence addressing the role of gut microbiota-derived metabolites in immunometabolic regulation and their implications in HIV-associated type 2 diabetes. Results: Microbial metabolites play a fundamental role in regulating key physiological processes such as intestinal permeability, systemic immune activation, and glucose metabolism. Compounds such as short-chain fatty acids, tryptophan catabolites, secondary bile acids, trimethylamine N-oxide, and imidazole propionate have been shown to significantly influence immunometabolic balance. In people living with HIV, these microbial products may exert diverse effects depending on their chemical nature and the molecular pathways they activate in peripheral tissues. The interaction between dysbiosis, chronic low-grade inflammation, and HIV-associated metabolic disturbances may contribute to the early onset of type 2 diabetes beyond traditional risk factors. Conclusions: Recognizing the role of microbial metabolites in the context of HIV infection is essential to broaden our pathophysiological understanding of associated metabolic comorbidities. It also opens opportunities to develop more comprehensive diagnostic and therapeutic strategies that include modulation of the gut microbiota and its metabolic activity for the prevention and management of type 2 diabetes in this population. Full article

(This article belongs to the Special Issue Targeting Microbiota and Metabolites for Prevention and Treatment of Human Diseases)

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26 pages, 1439 KB

Open AccessArticle

Essential Amino Acid Supplementation May Attenuate Systemic Inflammation and Improve Hypoalbuminemia in Subacute Hemiplegic Stroke Patients

by Mirella Boselli, Roberto Aquilani, Roberto Maestri, Paolo Iadarola, Alessandro Magistroni, Chiara Ferretti, Antonia Pierobon, Matteo Cotta Ramusino, Alfredo Costa, Daniela Buonocore, Marco Peviani, Federica Boschi and Manuela Verri

Metabolites 2025, 15(9), 626; https://doi.org/10.3390/metabo15090626 - 19 Sep 2025

Abstract

Background: Post-stroke inflammation and hypoalbuminemia can negatively affect neurocognitive recovery. This study evaluated whether oral amino acid (AA) supplementation with prevalently essential amino acids (EAAs, 82.1%) could improve inflammation and albumin levels in post-stroke patients undergoing neurorehabilitation. Methods: Sixty-four patients with subacute stroke [...] Read more.

Background: Post-stroke inflammation and hypoalbuminemia can negatively affect neurocognitive recovery. This study evaluated whether oral amino acid (AA) supplementation with prevalently essential amino acids (EAAs, 82.1%) could improve inflammation and albumin levels in post-stroke patients undergoing neurorehabilitation. Methods: Sixty-four patients with subacute stroke (less than three 3 months from acute event) and elevated inflammation markers (C-reactive protein, CRP > 0.5 mg/dL) were enrolled. All underwent anthropometric assessments and blood tests for CRP (normal value < 0.5 mg/dL), albumin (normal range: 3.5–4.76 g/dL), prealbumin (18–32 mg/dL), and white blood cell count. Participants were randomly assigned to receive either oral EAAs (8.4 g/day) or placebo (maltodextrin, 8.4 g/day) for 55 days. Measurements were taken at baseline (T0) and at discharge (T1), approximately two months later. Results: At baseline, both groups had comparable levels of systemic inflammation, albumin and prealbumin: CRP, 2.13 ± 1.82 mg/dL (placebo) vs. 2.89 ± 2.12 mg/dL (EAAs), p = 0.13; albumin, 3.10 ± 0.46 g/dL (placebo) vs. 3.07 ± 0.57 g/dL (EAAs), p = 0.82; prealbumin, 18.3 ± 6.2 mg/dL (placebo) vs. 16.9 ± 3.9 mg/dL (EAAs), p = 0.28. During rehabilitation, only the EAA group showed significant reductions in CRP (p = 0.036 vs. placebo) and improvements in albumin (p = 0.033 vs. placebo) and prealbumin levels (p = 0.05 vs. placebo). However, full normalization of CRP and albumin was not achieved. Conclusions: This study demonstrates that a physiological dose of supplemented EAAs may attenuate, but not fully resolve, post-stroke inflammation and hypoalbuminemia. Further research is needed to determine whether higher EAA doses and/or modifications in EAA composition could enhance or normalize systemic inflammation. Full article

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

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11 pages, 763 KB

Open AccessArticle

Impact of Salivary Amino Acid Concentrations on 8 km Running Performance in Male Undergraduate Students: A Prospective Observational Study Based on HPLC

by Hai Zhao, Kangwei Shen, Wei Fan, Mengjie Li and Xuejun Kang

Metabolites 2025, 15(9), 625; https://doi.org/10.3390/metabo15090625 - 19 Sep 2025

Abstract

Purpose: To explore the potential relationship between salivary amino acid concentrations and 8 km running performance in male undergraduate students. Methods: Thirty male undergraduate students were recruited. Participants completed an 8 km run while wearing smart bracelets. Saliva samples were collected before, immediately [...] Read more.

Purpose: To explore the potential relationship between salivary amino acid concentrations and 8 km running performance in male undergraduate students. Methods: Thirty male undergraduate students were recruited. Participants completed an 8 km run while wearing smart bracelets. Saliva samples were collected before, immediately after, and 24 h after the run. Ultra-High Performance Liquid Chromatography (UHPLC) was used to quantify salivary amino acids. Results: The fast group (average speed > 12.80 km/h) had a significantly shorter running time (35.66 ± 1.30 min, p < 0.001) and higher speed (13.59 ± 0.46 km/h, p < 0.001) than the slow group. Before the run, salivary serine concentration (20.19 µg/mL, p = 0.013) was higher in the fast group. After 24 h, salivary glutamine concentration (6.65 µg/mL, p = 0.047) was lower in the fast group. Salivary threonine concentration was positively correlated with running speed. For every 1 µg/mL increase in salivary threonine concentration, average running speed increased by 0.011 km/h, and this correlation persisted after adjusting for age and heart rate. Conclusions: This study found a positive correlation between salivary threonine and 8 km running speed, along with differences in serine and glutamine concentrations among runners with different speeds. These findings provide preliminary evidence for the relationship between salivary amino acid concentrations and running performance, though further research with larger samples and diverse exercise types is needed. Full article

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

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36 pages, 505 KB

Open AccessReview

Dietary Modulation of Metabolic Health: From Bioactive Compounds to Personalized Nutrition

by Aleksandra Leziak, Julia Lipina, Magdalena Reclik and Piotr Kocelak

Metabolites 2025, 15(9), 624; https://doi.org/10.3390/metabo15090624 - 19 Sep 2025

Abstract

Metabolic health is a dynamic equilibrium influenced by diet and lifestyle. This review synthesizes evidence on how specific dietary patterns and bioactive nutrients modulate metabolic disorders. Diets like the Mediterranean and DASH plans consistently improve cardiometabolic markers: a Mediterranean diet can halve metabolic [...] Read more.

Metabolic health is a dynamic equilibrium influenced by diet and lifestyle. This review synthesizes evidence on how specific dietary patterns and bioactive nutrients modulate metabolic disorders. Diets like the Mediterranean and DASH plans consistently improve cardiometabolic markers: a Mediterranean diet can halve metabolic syndrome prevalence (~52% reduction) in as little as 6 months, while the DASH diet typically lowers systolic blood pressure by ~5–7 mmHg and modestly improves lipid profiles (LDL-C by ~3–5 mg/dL). Plant-based diets (vegetarian/vegan) are associated with lower BMI, improved insulin sensitivity, and reduced inflammation. Ketogenic diets induce rapid weight loss (~12% body weight vs. 4% on control diets) and improve glycemic control (reducing HbA1c and triglycerides), though long-term effects (elevated LDL) warrant caution. Bioactive compounds present in these diets play critical roles: polyphenols improve insulin signaling and reduce oxidative stress (resveratrol supplementation reduced HOMA-IR by ~0.5 units and fasting glucose by ~0.3 mmol/L); omega-3 fatty acids (fish oil) reduce triglycerides by ~25–30% and inflammation; and probiotic interventions modestly enhance glycemic control (lowering HOMA-IR and HbA1c) and gut health. Personalized nutrition approaches, which account for genetic and microbiome differences, are emerging to maximize these benefits. In conclusion, evidence-based dietary strategies rich in fiber, unsaturated fats, and phytochemicals can substantially improve metabolic health outcomes, underscoring the potential of tailored nutrition in preventing and managing obesity-related metabolic disorders. Full article

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

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