Metabolites

17 pages, 5524 KiB

Open AccessArticle

Osteopenia Metabolomic Biomarkers for Early Warning of Osteoporosis

by Jie Wang, Dandan Yan, Suna Wang, Aihua Zhao, Xuhong Hou, Xiaojiao Zheng, Jingyi Guo, Li Shen, Yuqian Bao, Wei Jia, Xiangtian Yu, Cheng Hu and Zhenlin Zhang

Metabolites 2025, 15(1), 66; https://doi.org/10.3390/metabo15010066 - 20 Jan 2025

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Abstract

Introduction: This study aimed to capture the early metabolic changes before osteoporosis occurs and identify metabolomic biomarkers at the osteopenia stage for the early prevention of osteoporosis. Materials and Methods: Metabolomic data were generated from normal, osteopenia, and osteoporosis groups with [...] Read more.

Introduction: This study aimed to capture the early metabolic changes before osteoporosis occurs and identify metabolomic biomarkers at the osteopenia stage for the early prevention of osteoporosis. Materials and Methods: Metabolomic data were generated from normal, osteopenia, and osteoporosis groups with 320 participants recruited from the Nicheng community in Shanghai. We conducted individual edge network analysis (iENA) combined with a random forest to detect metabolomic biomarkers for the early warning of osteoporosis. Weighted Gene Co-Expression Network Analysis (WGCNA) and mediation analysis were used to explore the clinical impacts of metabolomic biomarkers. Results: Visual separations of the metabolic profiles were observed between three bone mineral density (BMD) groups in both genders. According to the iENA approach, several metabolites had significant abundance and association changes in osteopenia participants, confirming that osteopenia is a critical stage in the development of osteoporosis. Metabolites were further selected to identify osteopenia (nine metabolites in females; eight metabolites in males), and their ability to discriminate osteopenia was improved significantly compared to traditional bone turnover markers (BTMs) (female AUC = 0.717, 95% CI 0.547–0.882, versus BTMs: p = 0.036; male AUC = 0.801, 95% CI 0.636–0.966, versus BTMs: p = 0.007). The roles of the identified key metabolites were involved in the association between total fat-free mass (TFFM) and osteopenia in females. Conclusion: Osteopenia was identified as a tipping point during the development of osteoporosis with metabolomic characteristics. A few metabolites were identified as candidate early-warning biomarkers by machine learning analysis, which could indicate bone loss and provide new prevention guidance for osteoporosis. Full article

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

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20 pages, 4662 KiB

Open AccessArticle

Metabolics-Based Study on the Therapeutic Mechanism Behind the Effect of Shenhuang Plaster Applied to the Shenque Acupoint on Gastrointestinal Motility in POI Mice

by Yanan Shi, Chenglei Wu, Ting Liu, Rongyun Wang, Bin Ding and Qiuhua Sun

Metabolites 2025, 15(1), 65; https://doi.org/10.3390/metabo15010065 - 20 Jan 2025

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Abstract

Background: Postoperative ileus (POI) is a common postoperative clinical complication that significantly affects postoperative rehabilitation and quality of life in patients and can even produce secondary complications, leading to serious consequences. External treatment using Shenhuang Plaster (SHP) (Shenque acupoint administration) has definite effects [...] Read more.

Background: Postoperative ileus (POI) is a common postoperative clinical complication that significantly affects postoperative rehabilitation and quality of life in patients and can even produce secondary complications, leading to serious consequences. External treatment using Shenhuang Plaster (SHP) (Shenque acupoint administration) has definite effects and unique advantages in the prevention and treatment of POI, but its mechanism is not completely clear. In this study, we investigated the therapeutic mechanism behind the effect of Shenhuang Plaster applied to the Shenque acupoint on gastrointestinal motility in POI mice based on metabolomics. Materials and Methods: C57BL/6 mice were divided into three groups: blank control (Ctrl), model (POI), and intervention (POI + SHP) groups. SHP treatment was started 3 days before modeling. We employed several behavioral tests and gastrointestinal transit function measurements and performed qRT-PCR analysis, 16S rRNA gene sequencing, and metabolomics analysis on serum metabolites. Results: We found that SHP could reduce the mRNA expression of inflammatory mediators in the smooth muscle tissue of the small intestine, regulate the structure and function of the intestinal microbiota, and modulate serum phenylalanine, carnitine, and glutamic acid levels. Conclusions: POI mice had obvious intestinal flora disorders and metabolic disorders of amino acids and their derivatives, and there was a significant correlation between differential flora and differential metabolites. SHP could effectively regulate the concentration of intestinal flora and serum metabolites and the metabolic pathway related to amino acids in vivo and, ultimately, achieve a therapeutic purpose in POI. In this study, it was found, for the first time, that applying SHP to the Shenque acupoint could effectively regulate the serum metabolites of phenylalanine, carnitine, and glutamate, and improve postoperative intestinal motile disturbance through association with the intestinal flora. Full article

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

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13 pages, 1792 KiB

Open AccessArticle

Changes in Phenylacetylglutamine Levels Provide Add-On Value in Risk Stratification of Hypertensive Patients: A Longitudinal Cohort Study

by Xuan Xu, Lixin Jia, Bokang Qiao, Yanyan Gong, Shan Gao, Yuan Wang and Jie Du

Metabolites 2025, 15(1), 64; https://doi.org/10.3390/metabo15010064 - 20 Jan 2025

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Abstract

Background: Despite antihypertensive treatment, some high-risk hypertensive patients still experience major adverse cardiovascular events (MACEs). Current risk stratification tools may underestimate the presence of metabolites in hypertension and thereby risk of MACEs. Objectives: We aimed to explore the potential value of gut microbiota-derived [...] Read more.

Background: Despite antihypertensive treatment, some high-risk hypertensive patients still experience major adverse cardiovascular events (MACEs). Current risk stratification tools may underestimate the presence of metabolites in hypertension and thereby risk of MACEs. Objectives: We aimed to explore the potential value of gut microbiota-derived metabolite phenylacetylglutamine (PAGln) in risk stratification of hypertension. Methods: We measured plasma PAGln levels using liquid chromatography tandem mass spectrometry in 1543 high-risk hypertensive patients, dividing them into a discovery cohort (n = 792) and a validation cohort (n = 751). After follow-up, the Kaplan–Meier curve and the Cox regression model were utilized to determine the correlation between PAGln and MACEs (death, non-fatal ischemic stroke and hemorrhagic stroke, non-fatal acute coronary syndrome and unplanned revascularization). We examined the predictive performance of PAGln in different subgroups and evaluated the incremental predictive value of PAGln as an addition to the ASCVD risk assessment model. Results: Among all high-risk hypertensive patients, 148 patients experienced MACEs after a mean follow-up of 3.02 years. In both cohorts, after adjusting other confounding risk factors, PAGln remained an independent risk factor the MACEs in hypertensive patients. Patients with plasma PAGln ≥ 1.047 μmol/L have a higher risk of MACEs. PAGln concentration provided incremental predictive value to the ASCVD risk model, with better performance in the discovery cohort. It was most effective in female, patients with a systolic blood pressure (SBP) ≥ 130 mmHg and taking angiotensin-converting enzyme inhibitors (ACEIs). Conclusions: PAGln was associated with an increased risk of MACEs in hypertension, especially in women or in subgroups with SBP ≥ 130 mmHg and taking ACEIs. PAGln should be considered as an independent predictor in risk stratification to improve prognosis. Full article

(This article belongs to the Special Issue Nutrition and Metabolism in Human Diseases 2nd Edition)

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18 pages, 11389 KiB

Open AccessArticle

Artemia Nauplii Enriched with Soybean Lecithin Enhances Growth Performance, Intestine Morphology, and Desiccation Stress Resistance in Yellow Drum (Nibea albiflora) Larvae

by Zhenya Zhou, Pian Zhang, Peng Tan, Ruiyi Chen, Weihua Hu, Ligai Wang, Yuming Zhang and Dongdong Xu

Metabolites 2025, 15(1), 63; https://doi.org/10.3390/metabo15010063 - 17 Jan 2025

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Abstract

The inherent deficiency of phospholipids in Artemia limits its nutritional value as live prey for marine fish larvae. In our previous study, we optimized a phospholipid enrichment method by incubating Artemia nauplii with 10 g of soybean lecithin per m³ of seawater [...] Read more.

The inherent deficiency of phospholipids in Artemia limits its nutritional value as live prey for marine fish larvae. In our previous study, we optimized a phospholipid enrichment method by incubating Artemia nauplii with 10 g of soybean lecithin per m³ of seawater for 12 h, significantly enhancing their phospholipid content. Purpose: The present study evaluated the impact of this enrichment on yellow drum (Nibea albiflora) larvae, focusing on growth performance, intestinal morphology, body composition, weaning success, and desiccation stress resistance. Methods: The larvae (12 days post-hatching, dph) were fed either soybean lecithin-enriched (SL group) or newly hatched (NH group) Artemia nauplii for 10 days. Results: By the end of the experiment, the SL group exhibited a markedly greater body weight and standard length compared to the NH group (p < 0.05). This growth improvement was due to enhanced intestinal morphology, characterized by a significantly higher mucosal fold height, microvillus density, and microvillus length (p < 0.05). Intestinal RNA sequencing identified 160 upregulated and 447 downregulated differentially expressed genes (DEGs) in the SL group compared to the NH group. Soybean lecithin enrichment reduced the expression of lipogenesis-related genes (fasn, scd, elovl1) while upregulating lipid catabolism genes (ppara, cpt1, cpt2), indicating increased lipid breakdown and energy production. After a 5-day weaning period onto a commercial microdiet, the SL group continued to show significantly superior growth performance. In an afterward desiccation stress test, larvae from the SL group demonstrated significantly higher survival rates, potentially due to the decreased expression of intestinal cytokine genes (ccl13, mhc1, mhc2) observed in the RNA-seq analysis. Conclusions: This study highlights that feeding soybean lecithin-enriched Artemia nauplii enhances growth performance and desiccation stress in yellow drum larvae by promoting lipid catabolism, improving intestinal structure, and regulating immune responses. Full article

(This article belongs to the Special Issue Metabolism and Nutrition in Fish)

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21 pages, 3701 KiB

Open AccessArticle

LC-MS-Based Global Metabolic Profiles of Alternative Blood Specimens Collected by Microsampling

by Marlene N. Thaitumu, Daniel Marques De Sá e Silva, Philippine Louail, Johannes Rainer, Glykeria Avgerinou, Anatoli Petridou, Vassilis Mougios, Georgios Theodoridis and Helen Gika

Metabolites 2025, 15(1), 62; https://doi.org/10.3390/metabo15010062 - 16 Jan 2025

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Abstract

Blood microsampling (BμS) has recently emerged as an interesting approach in the analysis of endogenous metabolites but also in metabolomics applications. Their non-invasive way of use and the simplified logistics that they offer renders these technologies highly attractive in large-scale studies, especially the [...] Read more.

Blood microsampling (BμS) has recently emerged as an interesting approach in the analysis of endogenous metabolites but also in metabolomics applications. Their non-invasive way of use and the simplified logistics that they offer renders these technologies highly attractive in large-scale studies, especially the novel quantitative microsampling approaches such as VAMs or qDBS. Objectives: Herein, we investigate the potential of BµS devices compared to the conventional plasma samples used in global untargeted mass spectrometry-based metabolomics of blood. Methods: Two novel quantitative devices, namely, Mitra, Capitainer, and the widely used Whatman cards, were selected for comparison with plasma. Venous blood was collected from 10 healthy, overnight-fasted individuals and loaded on the devices; plasma was also collected from the same venous blood. An extraction solvent optimization study was first performed on the three devices before the main study, which compared the global metabolic profiles of the four extracts (three BµS devices and plasma). Analysis was conducted using reverse phase LC-TOF MS in positive mode. Results: BµS devices, especially Mitra and Capitainer, provided equal or even superior information on the metabolic profiling of human blood based on the number and intensity of features and the precision and stability of some annotated metabolites compared to plasma. Despite their rich metabolic profiles, BµS did not capture metabolites associated with biological differentiation of sexes. Conclusions: Overall, our results suggest that a more in-depth investigation of the acquired information is needed for each specific application, as a metabolite-dependent trend was obvious. Full article

(This article belongs to the Special Issue Metabolomic Fingerprinting: Challenges and Opportunities)

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15 pages, 1179 KiB

Open AccessArticle

A Randomized, Placebo-Controlled, Single-Center, Crossover Study to Evaluate the Effects of Pre-Meal Whey Protein Microgel on Post-Prandial Glucometabolic and Amino Acid Response in People with Type 2 Diabetes and Overweight or Obesity

by Ian J Neeland, Luiz H de Gregório, Roberto Zagury, Bo Ahrén, Joel Neutel, Christian Darimont, John Corthesy, Yohan Grzywinski, Emilie Perrin, Maximilian von Eynatten and Odd Erik Johansen

Metabolites 2025, 15(1), 61; https://doi.org/10.3390/metabo15010061 - 16 Jan 2025

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Abstract

Purpose: Whey protein (WP) consumption prior to a meal curbs appetite and reduces postprandial glucose (PPG) through stimulating endogenous GLP-1 secretion and insulin. Methods: We assessed the metabolic effects of a concentrated WP, using a new micelle-technology (WPM), in people with [...] Read more.

Purpose: Whey protein (WP) consumption prior to a meal curbs appetite and reduces postprandial glucose (PPG) through stimulating endogenous GLP-1 secretion and insulin. Methods: We assessed the metabolic effects of a concentrated WP, using a new micelle-technology (WPM), in people with type 2 diabetes (T2D) and overweight or obesity (NCT04639726). In a randomized-crossover design, participants performed two 240 min lunch meal (622 kcal) tests 7 ± 4 days apart. After an overnight fast and a standardized breakfast, 10 g (125 mL) WPM (40 kcal) or placebo (125 mL water, 0 kcal) was consumed 15 min ahead of the mixed-nutrient meal. Effects on PPG (primary endpoint), insulin, GLP-1, and branched-chain amino acids (BCAAs) were evaluated with frequent blood sampling. Changes in incremental areas under the concentration curve (iAUC) were compared using a mixed model. Results: Twenty-six individuals (14 females, mean ± SD age 62.0 ± 8.3 years, HbA1c 58 ± 12 mmol/mol/7.5 ± 1.1%, BMI 29.2 ± 4.8 kg/m²) completed both tests. WPM significantly reduced PPG iAUC_0–2h by 22% (p = 0.028), and iAUC_0–3h numerically by −18% (p = 0.090) vs. placebo. WPM also increased insulin iAUC_0–1h by 61% (p < 0.001), and iAUC_0–3h by 30% (p = 0.004), respectively. Total GLP-1 iAUC_0–2h was enhanced by 66% (p < 0.001). Postprandial plasma BCAA patterns were characterized by a rapid increase and larger iAUC_0–2h (all p < 0.001) after WPM. No adverse events were ascribed to consuming WPM. Conclusions: A 125 mL pre-meal drink containing just 10 g WPM before a mixed meal reduced PPG and increased insulin, GLP-1, and BCAAs. WPM may therefore serve as a metabolic modulator in people with T2D living with overweight or obesity. Full article

(This article belongs to the Special Issue Metabolic Biomarkers in Type 2 Diabetes: From Discovery to Application)

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14 pages, 5115 KiB

Open AccessArticle

Comparative Study of Lipid Profile for Mice Treated with Cyclophosphamide by HPLC-HRMS and Bioinformatics

by Ekaterina Demicheva, Fernando Jonathan Polanco Espino, Pavel Vedeneev, Vadim Shevyrin, Aleksey Buhler, Elena Mukhlynina, Olga Berdiugina, Alicia del Carmen Mondragon, Alberto Cepeda Sáez, Aroa Lopez-Santamarina, Alejandra Cardelle-Cobas, Olga Solovyova, Irina Danilova, Jose Manuel Miranda and Elena Kovaleva

Metabolites 2025, 15(1), 60; https://doi.org/10.3390/metabo15010060 - 16 Jan 2025

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Abstract

Purpose: Immunodeficiency conditions, which are characterized by reduced immune activity that promotes the development of chronic diseases, are needed for efficient monitoring. A promising area of monitoring and early diagnosis of immunodeficiency diseases is the determination of metabolic biomarkers in the blood. Methods: [...] Read more.

Purpose: Immunodeficiency conditions, which are characterized by reduced immune activity that promotes the development of chronic diseases, are needed for efficient monitoring. A promising area of monitoring and early diagnosis of immunodeficiency diseases is the determination of metabolic biomarkers in the blood. Methods: In this work, we identified a set of lipid biomarkers of immunodeficiency states by performing high-performance liquid chromatography–high-resolution mass spectrometry (HPLC-HRMS) analysis of blood plasma samples from mice and processing them with bioinformatics approaches. Potential biomarkers were selected through statistical analysis and further validated by MS/MS. Conclusions: As a result, 15 lipids were confirmed and selected as potential biomarkers of immunodeficiency states. The selected biomarkers can be further studied and serve as promising targets for the early diagnosis of immunodeficiency diseases. Full article

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

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21 pages, 1534 KiB

Open AccessReview

Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis

by Jiayin Wang, Dandan Jia, Zhiwang Zhang and Dan Wang

Metabolites 2025, 15(1), 59; https://doi.org/10.3390/metabo15010059 - 16 Jan 2025

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Abstract

Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind [...] Read more.

Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind exercise training or physical activity remain poorly understood. The disruption of mitochondrial homeostasis is implicated in the pathogenesis of sarcopenia. Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox. Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia. Methods: In this review, we provide a detailed summary of exercise-induced exerkines and confer their benefit, with particular focus on their impact on mitochondrial homeostasis in the context of sarcopenia. Results: Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function. An expanding body of research highlights that exerkines have the potential to regulate processes such as mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox balance. These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health. Conclusions: Through a comprehensive investigation of the molecular mechanisms within mitochondria, the context reveals new insights into the potential of exerkines as key exercise-protective sensors for combating sarcopenia. Full article

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

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22 pages, 8916 KiB

Open AccessArticle

The Positive Regulatory Effect of DBT on Lipid Metabolism in Postpartum Dairy Cows

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 2025, 15(1), 58; https://doi.org/10.3390/metabo15010058 - 16 Jan 2025

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Abstract

Background/Objectives: The transition from a non-lactating to a lactating state is a critical period for lipid metabolism in dairy cows. Danggui Buxue Tang (DBT), stimulating energy metabolism, ameliorates diseases related to lipid metabolism disorders and is expected to be an effective supplement for [...] Read more.

Background/Objectives: The transition from a non-lactating to a lactating state is a critical period for lipid metabolism in dairy cows. Danggui Buxue Tang (DBT), stimulating energy metabolism, ameliorates diseases related to lipid metabolism disorders and is expected to be an effective supplement for alleviating excessive lipid mobilisation in periparturient dairy cows. This study aimed to investigate the effects of supplemental DBT on serum biochemical indices, faecal microbial communities, and plasma metabolites in dairy cows. Methods: Thirty cows were randomly divided into three groups: H-DBT group, L-DBT group, and control group. DBT administration was started on the day of calving and continued once daily for seven days. Faecal and blood samples were collected on calving day, 7 days after calving, and 14 days after calving. The levels of serum biochemical indices were measured at three time points in the three groups using commercial kits. Cows in the H-DBT group and control group were selected for metabolome and 16S rRNA amplicon sequencing. Results: Our research shows that, in dairy cows 7 days postpartum, DBT significantly reduced serum 3-hydroxybutyric acid (BHB) concentrations and the number of cows with BHB concentrations ≥ 1 mmol/L. Additionally, DBT increased serum total cholesterol contents at both 7 and 14 days postpartum. Analysis of the microbiota community showed that DBT modulated the composition and structure of the hindgut microbiota. Metabolomic analysis revealed decreased plasma acetylcarnitine, 2-hydroxybutyric acid, and BHB levels 7 days postpartum, whereas the TCA cycle was enhanced. At 14 days postpartum, DBT altered the plasma bile acid profile, especially glycine-conjugated bile acids, including GCDCA, GUDCA, and GDCA. Correlation analyses showed that the relative abundances of Bacillus, Solibacillus, Dorea, and Romboutsia were strongly correlated with the differential metabolites, which is crucial for the beneficial effects of DBT. Conclusions: DBT improves energy status and lipid metabolism in postpartum dairy cows by modulating hindgut microbiota and serum lipid metabolites. Full article

(This article belongs to the Special Issue Research on Lipid Metabolism in Animals)

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15 pages, 1672 KiB

Open AccessArticle

Colostrum-Derived Melatonin Plus PEG Microspheres Modulate the Oxidative Metabolism of Human Colostrum Phagocytes

by Caroline G. Silva, Viviane F. Luz, Victor L. Nunes, Ana B. M. Verzoto, Aron C. de M. Cotrim, Wagner B. dos Santos, Eduardo L. França and Adenilda C. Honorio-França

Metabolites 2025, 15(1), 57; https://doi.org/10.3390/metabo15010057 - 16 Jan 2025

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Abstract

Background/Objectives: Exogenous melatonin adsorbed onto PEG microspheres can modulate the functional activity of phagocytes in colostrum, but no data are available on the activity of melatonin found in colostrum. Therefore, the objective of this study was to extract melatonin from human colostrum, develop [...] Read more.

Background/Objectives: Exogenous melatonin adsorbed onto PEG microspheres can modulate the functional activity of phagocytes in colostrum, but no data are available on the activity of melatonin found in colostrum. Therefore, the objective of this study was to extract melatonin from human colostrum, develop and characterize PEG microspheres with the extracted melatonin adsorbed onto them, and evaluate the effects of this system on the oxidative metabolism of colostrum phagocytes. Methods: Thirty colostrum samples were collected; ten were used for melatonin extraction, while twenty were used to obtain phagocytes. Melatonin was extracted from the colostrum supernatant through affinity chromatography and quantified by ELISA. The polyethylene glycol microspheres produced were analyzed using fluorescence microscopy and flow cytometry. Oxidative metabolism was assessed by measuring the release of the superoxide anion and superoxide enzymes. A control was conducted using commercial melatonin. Results: The fluorescence microscopy and flow cytometry analyses demonstrated that PEG microspheres can adsorb melatonin. There was an increase in superoxide release in phagocytes incubated with colostrum-derived or synthetic melatonin. When exposed to bacteria, colostrum phagocytes treated with colostrum melatonin adsorbed to PEG microspheres exhibited increased superoxide, accompanied by a decrease in the release of superoxide dismutase (SOD) and a lower SOD-to-superoxide ratio. In contrast, synthetic melatonin reduced the release of superoxide and increased the release of the enzyme and the SOD-to-superoxide ratio. Conclusions: These data highlight the importance of melatonin on cellular metabolism and suggest that colostrum-derived melatonin may be a more effective option for controlling oxidative metabolism, particularly during infectious processes. Full article

(This article belongs to the Section Cell Metabolism)

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14 pages, 3097 KiB

Open AccessArticle

Role of Carrot (Daucus carota L.) Storage Roots in Drought Stress Adaptation: Hormonal Regulation and Metabolite Accumulation

by Kyoung Rok Geem, Ye-Jin Lee, Jeongmin Lee, Dain Hong, Ga-Eun Kim and Jwakyung Sung

Metabolites 2025, 15(1), 56; https://doi.org/10.3390/metabo15010056 - 16 Jan 2025

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Abstract

Background: Drought stress has become one of the biggest concerns in threating the growth and yield of carrots (Daucus carota L.). Recent studies have shed light on the physiological and molecular metabolisms in response to drought in the carrot plant; however, tissue-specific [...] Read more.

Background: Drought stress has become one of the biggest concerns in threating the growth and yield of carrots (Daucus carota L.). Recent studies have shed light on the physiological and molecular metabolisms in response to drought in the carrot plant; however, tissue-specific responses and regulations are still not fully understood. Methods: To answer this curiosity, this study investigated the interplay among carrot tissues, such as leaves (L); storage roots (SRs); and lateral roots (LRs) under drought conditions. This study revealed that the SRs played a crucial role in an early perception by upregulating key genes, including DcNCED3 (ABA biosynthesis) and DcYUCCA6 (auxin biosynthesis). The abundance of osmolytes (proline; GABA) and carbohydrates (sucrose; glucose; fructose; mannitol; and inositol) was also significantly increased in each tissue. In particular, LRs accumulated high levels of these metabolites and promoted growth under drought conditions. Conclusions: Our findings suggest that the SR acts as a central regulator in the drought response of carrots by synthesizing ABA and auxin, which modulate the accumulation of metabolites and growth of LRs. This study provides new insights into the mechanisms of tissue-specific carrot responses to drought tolerance, emphasizing that the SR plays a key role in improving drought resistance. Full article

(This article belongs to the Special Issue Unlocking Nature's Toolbox: Advances in Plant Metabolites Identification)

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17 pages, 1923 KiB

Open AccessArticle

Unveiling Silent Atherosclerosis in Type 1 Diabetes: The Role of Glycoprotein and Lipoprotein Lipidomics, and Cardiac Autonomic Neuropathy

by Sara de Lope Quiñones, Manuel Luque-Ramírez, Antonio Carlos Michael Fernández, Alejandra Quintero Tobar, Jhonatan Quiñones-Silva, María Ángeles Martínez García, María Insenser Nieto, Beatriz Dorado Avendaño, Héctor F. Escobar-Morreale and Lía Nattero-Chávez

Metabolites 2025, 15(1), 55; https://doi.org/10.3390/metabo15010055 - 16 Jan 2025

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Abstract

Introduction: This study aimed to evaluate whether glycoprotein and lipoprotein lipidomics profiles could enhance a clinical predictive model for carotid subclinical atherosclerosis in patients with type 1 diabetes (T1D). Additionally, we assessed the influence of cardiac autonomic neuropathy (CAN) on these predictive models. [...] Read more.

Introduction: This study aimed to evaluate whether glycoprotein and lipoprotein lipidomics profiles could enhance a clinical predictive model for carotid subclinical atherosclerosis in patients with type 1 diabetes (T1D). Additionally, we assessed the influence of cardiac autonomic neuropathy (CAN) on these predictive models. Methods: We conducted a cross-sectional study including 256 patients with T1D. Serum glycoprotein and lipoprotein lipidomics profiles were determined using ¹H-NMR spectroscopy. Subclinical atherosclerosis was defined as carotid intima-media thickness (cIMT) ≥ 1.5 mm. CAN was identified using the Clarke score. Predictive models were built and their performance evaluated using receiver operating characteristic curves and cross-validation. Results: Subclinical atherosclerosis was detected in 32% of participants. Patients with both CAN and atherosclerosis were older, had a longer duration of diabetes, and were more likely to present with bilateral carotid disease. Clinical predictors such as age, duration of diabetes, and smoking status remained the strongest determinants of subclinical atherosclerosis [AUC = 0.88 (95%CI: 0.84–0.93)]. While glycoprotein and lipoprotein lipidomics profiles were associated with atherosclerosis, their inclusion in the clinical model did not significantly improve its diagnostic performance. Stratification by the presence of CAN revealed no impact on the model’s ability to predict subclinical atherosclerosis, underscoring its robustness across different risk subgroups. Conclusions: In a cohort of patients with T1D, subclinical atherosclerosis was strongly associated with traditional clinical risk factors. Advanced glycoprotein and lipoprotein lipidomics profiling, although associated with atherosclerosis, did not enhance the diagnostic accuracy of predictive models beyond clinical variables. The predictive model remained effective even in the presence of CAN, highlighting its reliability as a screening tool for identifying patients at risk of subclinical atherosclerosis. Full article

(This article belongs to the Special Issue Diabetes and Metabolic Diseases: From Prevention to Clinical Management)

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11 pages, 1553 KiB

Open AccessCommunication

Development of an Alternative Protocol to Study Muscle Fatigue

by Daniela A. Alambarrio, Benjamin K. Morris, R. Benjamin Davis, Emily B. Grabarczyk, Kari K. Turner and John M. Gonzalez

Metabolites 2025, 15(1), 54; https://doi.org/10.3390/metabo15010054 - 16 Jan 2025

Viewed by 437

Abstract

When measuring real-time in vivo muscle fatigue with electromyography (EMG), data collection can be compromised by premature sensor removal or environmental noise; therefore, the objective of this study was to develop a postmortem in vivo methodology to induce muscle fatigue and [...] Read more.

When measuring real-time in vivo muscle fatigue with electromyography (EMG), data collection can be compromised by premature sensor removal or environmental noise; therefore, the objective of this study was to develop a postmortem in vivo methodology to induce muscle fatigue and measure it using EMG. Barrows (N = 20) were stratified by weight and randomly allocated into one of two treatments. The treatments consisted of barrows being subjected to a hog electric stunner super-contraction cycle (ES) or not (CON) postmortem. The right hind limb bicep femoris (BF) and semitendinosus (ST) were selected for ambulatory movement simulation using electronic muscle stimulation (EMS). Muscle workload during EMS was measured with EMG using median power frequency (MdPF) and root mean square (RMS) as indicators of action potential velocity and muscle fiber recruitment. Ambulatory movement was induced and recorded for 20 min with a 4:4 duty cycle at 70 Hz. Muscle biopsies were collected pre- and post-EMS for metabolite analyses to corroborate muscle fatigue onset. There was a TRT × Muscle interaction for normalized RMS percentage (p < 0.01), where BF from CON barrows had greater values (p < 0.01). There were no interactions or TRT main effects for the MdPF normalized value (p ≥ 0.25), but there were Period and muscle effects on MdPF (p < 0.01). Bicep femoris had smaller (p < 0.01) MdPF than ST. The percentage of MdPF decreased (p < 0.01) by Period 5 compared to the other Periods, which did not differ from each other (p ≥ 0.38). There were TRT × Muscle and Muscle × Period interactions for ATP muscle concentration (p ≤ 0.03). The concentration of CON BF ATP was greater (p < 0.01) than that of ES BF and CON and ES ST, which did not differ from each other (p ≥ 0.11), but the APT concentration tended to differ between ES BF and ES ST (p = 0.06). Semitendinosus ATP concentration decreased (p < 0.01) post-EMS compared to ST pre- and BF pre- and post-EMS (p ≥ 0.29), but BF and ST concentration tended to differ pre-EMS (p = 0.07). The data indicated that EMS is a valuable tool for replicating ambulatory movement or physical activity, but super-contraction is not a means to accelerate postmortem muscle fatigue onset. Therefore, further refinement, such as longer EMS stimulation time, should be considered. Full article

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

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28 pages, 10002 KiB

Open AccessArticle

Silymarin as a Therapeutic Agent for Hepatocellular Carcinoma: A Multi-Approach Computational Study

by Ouided Benslama, Sabrina Lekmine, Hamza Moussa, Hichem Tahraoui, Mohammad Shamsul Ola, Jie Zhang and Abdeltif Amrane

Metabolites 2025, 15(1), 53; https://doi.org/10.3390/metabo15010053 - 15 Jan 2025

Viewed by 623

Abstract

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer with limited treatment options. Silymarin, a flavonoid complex derived from milk thistle, has shown promise in liver disease treatment due to its antioxidant, anti-inflammatory, and anticancer properties. This study aims [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer with limited treatment options. Silymarin, a flavonoid complex derived from milk thistle, has shown promise in liver disease treatment due to its antioxidant, anti-inflammatory, and anticancer properties. This study aims to explore the therapeutic potential of silymarin in HCC through a comprehensive in silico approach. Methods: This study employed a network pharmacology approach to identify key molecular targets of silymarin in HCC. The Genecards and Metascape databases were used for target identification and functional annotation. Molecular docking analysis was conducted on the primary silymarin components against VEGFA and SRC proteins, which are critical in HCC progression. MD simulations followed to assess the stability and interactions of the docked complexes. Results: Network pharmacology analysis identified several key molecular targets and pathways implicated in HCC. The molecular docking results revealed strong binding affinities of silymarin components to VEGFA and SRC, with Silybin A and Isosilybin B showing the highest affinities. MD simulations confirmed the stability of these interactions, indicating potential inhibitory effects on HCC progression. Conclusions: This study provides a comprehensive in silico evaluation of silymarin’s therapeutic potential in HCC. The findings suggest that silymarin, particularly its components Silybin A and Isosilybin B, may effectively target VEGFA and SRC proteins, offering a promising avenue for HCC treatment. Further experimental validation is warranted to confirm these findings and facilitate the development of silymarin-based therapeutics for HCC. Full article

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

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16 pages, 5126 KiB

Open AccessArticle

Chemical Diversity of UK-Grown Tea Explored Using Metabolomics and Machine Learning

by Amanda J. Lloyd, Alina Warren-Walker, Jasen Finch, Jo Harper, Kathryn Bennet, Alison Watson, Laura Lyons, Pilar Martinez Martin, Thomas Wilson and Manfred Beckmann

Metabolites 2025, 15(1), 52; https://doi.org/10.3390/metabo15010052 - 15 Jan 2025

Viewed by 562

Abstract

Background/Objectives: Dartmoor Estate Tea plantation in Devon, UK, is renowned for its unique microclimate and varied soil conditions, which contribute to the distinctive flavours and chemical profiles of tea. The chemical diversity of fresh leaf samples from various garden locations was explored within [...] Read more.

Background/Objectives: Dartmoor Estate Tea plantation in Devon, UK, is renowned for its unique microclimate and varied soil conditions, which contribute to the distinctive flavours and chemical profiles of tea. The chemical diversity of fresh leaf samples from various garden locations was explored within the plantation. Methods: Fresh leaf, which differed by location, cultivar, time of day, and variety, was analysed using Flow Infusion Electrospray Ionisation Mass Spectrometry (FIE-MS). Results: Random forest classification revealed no significant differences between Georgian N2 cultivar garden locations. However, a significant degree of variability was observed within four tri-clonal variants (Tocklai Variety) with TV9 exhibiting greater similarity to the Georgian N2 cultivar compared to TV8 and TV11, while TV11 was found to be most like TV1. The intraclass variability in leaf composition was similar between the varieties. We explored the metabolic changes over the day in one variant (Camellia assamica Masters), yielding a model with a significant R² value of 0.617 (p < 0.01, 3000 permutations). Starch and sucrose metabolism was found to be significant where the abundance of these chemical features increased throughout the day and then began to decrease at night. Conclusions: This research highlights the complex interplay of cultivars, geographical location, and temporal factors on the chemical composition of tea. It provides insightful data on the metabolic pathways influencing tea cultivation and production and underscores the importance of these variables in determining the final chemical profile and organoleptic characteristics of tea products. Full article

(This article belongs to the Section Plant Metabolism)

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22 pages, 10819 KiB

Open AccessArticle

MiMeJF: Application of Coupled Matrix and Tensor Factorization (CMTF) for Enhanced Microbiome-Metabolome Multi-Omic Analysis

by Zheyuan Ou, Xi Fu, Dan Norbäck, Ruqin Lin, Jikai Wen and Yu Sun

Metabolites 2025, 15(1), 51; https://doi.org/10.3390/metabo15010051 - 14 Jan 2025

Viewed by 612

Abstract

Background/Objectives: The integration of microbiome and metabolome data could unveil profound insights into biological processes. However, widely used multi-omic data analyses often employ a stepwise mining approach, failing to harness the full potential of multi-omic datasets and leading to reduced detection accuracy. [...] Read more.

Background/Objectives: The integration of microbiome and metabolome data could unveil profound insights into biological processes. However, widely used multi-omic data analyses often employ a stepwise mining approach, failing to harness the full potential of multi-omic datasets and leading to reduced detection accuracy. Synergistic analysis incorporating microbiome/metabolome data are essential for deeper understanding. Method: This study introduces a Coupled Matrix and Tensor Factorization (CMTF) framework for the joint analysis of microbiome and metabolome data, overcoming these limitations. Two CMTF frameworks were developed to factorize microbial taxa, functional pathways, and metabolites into latent factors, facilitating dimension reduction and biomarker identification. Validation was conducted using three diverse microbiome/metabolome datasets, including built environments and human gut samples from inflammatory bowel disease (IBD) and COVID-19 studies. Results: Our results revealed biologically meaningful biomarkers, such as Bacteroides vulgatus and acylcarnitines associated with IBD and pyroglutamic acid and p-cresol associated with COVID-19 outcomes, which provide new avenues for research. The CMTF framework consistently outperformed traditional methods in both dimension reduction and biomarker detection, offering a robust tool for uncovering biologically relevant insights. Conclusions: Despite its stringent data requirements, including the reliance on stratified microbial-based pathway abundances and taxa-level contributions, this approach provides a significant step forward in multi-omics integration and analysis, with potential applications across biomedical, environmental, and agricultural research. Full article

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

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38 pages, 1117 KiB

Open AccessSystematic Review

The Current Applications of Metabolomics in Understanding Endometriosis: A Systematic Review

by Blake Collie, Jacopo Troisi, Martina Lombardi, Steven Symes and Sean Richards

Metabolites 2025, 15(1), 50; https://doi.org/10.3390/metabo15010050 - 14 Jan 2025

Viewed by 574

Abstract

Endometriosis is a common gynecological disease that affects approximately 10–15% of reproductive-aged women worldwide. This debilitating disease has a negative impact on the quality of life of those affected. Despite this condition being very common, the pathogenesis is not well understood. Metabolomics is [...] Read more.

Endometriosis is a common gynecological disease that affects approximately 10–15% of reproductive-aged women worldwide. This debilitating disease has a negative impact on the quality of life of those affected. Despite this condition being very common, the pathogenesis is not well understood. Metabolomics is the study of the array of low-weight metabolites in a given sample. This emerging field of omics-based science has proved to be effective at furthering the understanding of endometriosis. In this systematic review, we seek to provide an overview of the application of metabolomics in endometriosis. We highlight the use of metabolomics in locating biomarkers for identification, understanding treatment mechanisms and symptoms, and relating external factors to endometriosis. The literature search took place in the Web of Science, Pubmed, and Google Scholar based on the keywords “metabolomics” AND “endometriosis” or “metabolome” AND “endometriosis”. We found 58 articles from 2012 to 2024 that met our search criteria. Significant alterations of lipids, amino acids, as well as other compounds were present in human and animal models. Discrepancies among studies of significantly altered metabolites make it difficult to make general conclusions on the metabolic signature of endometriosis. However, several individual metabolites were elevated in multiple studies of women with endometriosis; these include 3-hydroxybutyrate, lactate, phosphatidic acids, succinate, pyruvate, tetradecenoylcarnitine, hypoxanthine, and xanthine. Accordingly, L-isoleucine and citrate were reduced in multiple studies of women with endometriosis. Including larger cohorts, standardizing testing methods, and studying the individual phenotypes of endometriosis may lead to more separable results. Full article

(This article belongs to the Special Issue Towards Clinical Interpretation of Metabolomic Data)

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16 pages, 870 KiB

Open AccessReview

The Use of SGLT-2 Inhibitors and GLP-1RA in Frail Older People with Diabetes: A Personalised Approach Is Required

by Alan J. Sinclair and Ahmed H. Abdelhafiz

Metabolites 2025, 15(1), 49; https://doi.org/10.3390/metabo15010049 - 14 Jan 2025

Viewed by 764

Abstract

Background: Frailty is an increasingly recognised complication of diabetes in older people and should be taken into consideration in management plans, including the use of the new therapies of sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RA). The frailty [...] Read more.

Background: Frailty is an increasingly recognised complication of diabetes in older people and should be taken into consideration in management plans, including the use of the new therapies of sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RA). The frailty syndrome appears to span across a spectrum, from a sarcopenic obese phenotype at one end, characterised by obesity, insulin resistance, and prevalent cardiovascular risk factors, to an anorexic malnourished phenotype at the other end, characterised by significant weight loss, reduced insulin resistance, and less prevalent cardiovascular risk factors. Therefore, the use of the new therapies may not be suitable for every frail older individual with diabetes. Objectives: To review the characteristics and phenotype of frail older people with diabetes who should benefit from the use of SGLT-2 inhibitors or GLP-1RA. Methods: A narrative review of the studies investigating the benefits of SGLT-2 inhibitors and GLP-1RA in frail older people with diabetes. Results: The current evidence is indirect, and the literature suggests that the new therapies are effective in frail older people with diabetes and the benefit appears to be proportional with the severity of frailty. However, frail patients described in the literature who benefited from such therapy appeared to be either overweight or obese, and to have a higher prevalence of unfavourable metabolism and cardiovascular risk factors such as dyslipidaemia, gout, and hypertension compared to non-frail subjects. They also have a higher prevalence of established cardiovascular disease compared with non-frail individuals. In absolute terms, their higher cardiovascular baseline risk meant that they benefited the most from such therapy. The characteristics of this group of frail patients fulfil the criteria of the sarcopenic obese frailty phenotype, which is likely to benefit most from the new therapies due to the unfavourable metabolic profile of this phenotype. There is no current evidence to suggest the benefit of the new therapies in the anorexic malnourished phenotype, which is underrepresented or totally excluded from these studies, such as in patients living in care homes. This phenotype is likely to be intolerant to such therapy due to its associated risk of inducing further weight loss, dehydration, and hypotension. Conclusions: Clinicians should consider the early use of the new therapies in frail older people with diabetes who are either of normal weight, overweight, or obese with prevalent cardiovascular risk factors, and avoid their use in those frail subjects who ae underweight, anorexic, and malnourished. Full article

(This article belongs to the Special Issue Obesity and Metabolic Health)

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13 pages, 1625 KiB

Open AccessArticle

MetaboLabPy—An Open-Source Software Package for Metabolomics NMR Data Processing and Metabolic Tracer Data Analysis

by Christian Ludwig

Metabolites 2025, 15(1), 48; https://doi.org/10.3390/metabo15010048 - 14 Jan 2025

Viewed by 577

Abstract

Introduction: NMR spectroscopy is a powerful technique for studying metabolism, either in metabolomics settings or through tracing with stable isotope-enriched metabolic precursors. MetaboLabPy (version 0.9.66) is a free and open-source software package used to process 1D- and 2D-NMR spectra. The software implements a [...] Read more.

Introduction: NMR spectroscopy is a powerful technique for studying metabolism, either in metabolomics settings or through tracing with stable isotope-enriched metabolic precursors. MetaboLabPy (version 0.9.66) is a free and open-source software package used to process 1D- and 2D-NMR spectra. The software implements a complete workflow for NMR data pre-processing to prepare a series of 1D-NMR spectra for multi-variate statistical data analysis. This includes a choice of algorithms for automated phase correction, segmental alignment, spectral scaling, variance stabilisation, export to various software platforms, and analysis of metabolic tracing data. The software has an integrated help system with tutorials that demonstrate standard workflows and explain the capabilities of MetaboLabPy. Materials and Methods: The software is implemented in Python and uses numerous Python toolboxes, such as numpy, scipy, pandas, etc. The software is implemented in three different packages: metabolabpy, qtmetabolabpy, and metabolabpytools. The metabolabpy package contains classes to handle NMR data and all the numerical routines necessary to process and pre-process 1D NMR data and perform multiplet analysis on 2D-¹H, ¹³C HSQC NMR data. The qtmetabolabpy package contains routines related to the graphical user interface. Results: PySide6 is used to produce a modern and user-friendly graphical user interface. The metabolabpytools package contains routines which are not specific to just handling NMR data, for example, routines to derive isotopomer distributions from the combination of NMR multiplet and GC-MS data. A deep-learning approach for the latter is currently under development. MetaboLabPy is available via the Python Package Index or via GitHub. Full article

(This article belongs to the Special Issue Open-Source Software in Metabolomics)

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18 pages, 4278 KiB

Open AccessArticle

Characterization of Thirty Germplasms of Millet Pepper (Capsicum frutescens L.) in Terms of Fruit Morphology, Capsaicinoids, and Nutritional Components

by Ruihao Zhang, Mengjuan Li, Junheng Lv, Pingping Li, Yunrong Mo, Xiang Zhang, Hong Cheng, Qiaoling Deng, Min Gui and Minghua Deng

Metabolites 2025, 15(1), 47; https://doi.org/10.3390/metabo15010047 - 14 Jan 2025

Viewed by 574

Abstract

Background: Millet peppers have rich and diverse germplasm resources. It is of great significance to characterize their phenotypes and physicochemical indicators. Methods: 30 millet germplasms were selected to measure the fruit length and width, flesh thickness, number of ventricles, fruit stalk length, and [...] Read more.

Background: Millet peppers have rich and diverse germplasm resources. It is of great significance to characterize their phenotypes and physicochemical indicators. Methods: 30 millet germplasms were selected to measure the fruit length and width, flesh thickness, number of ventricles, fruit stalk length, and single fruit weight, and the texture characteristics of fruit such as hardness, cohesiveness, springiness, gumminess, and chewiness were determined by a texture analyzer. At the same time, high-performance liquid chromatography (HPLC) and gas chromatography (GC) were used to determine the fruit of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, fatty acids, vitamin E (VE), total phenol, total sugar, and total dietary fiber. Results: M11 showed outstanding parameters in phenotype and texture. The coefficient of variation (CV) for VE was as high as 94.943% and the highest diversity index (H’) was total soluble solid, at 1.988%. M5 and M18 contained rich and diverse fatty acids. At the same time, the content of capsaicinoids in M18 also ranks among the top, second only to M27 (with a total capsaicin content of 5623.96 μg/g). PCA analysis using phenotypic data and physicochemical data showed that the classification results were different. Further hierarchical group analysis was carried out using all the index data. The results showed that 30 millet pepper germplasms were divided into three new categories: M5, M9, M18, and M24 formed one group (C1), M10, M14, M16, M19, M20, M22, M25, M26, M28, M29, and M30 formed another cluster (C2), and the remaining germplasms formed a third cluster (C3). Among them, the abundance of fatty acids in the C1 germplasm was higher than that in the other two groups. Conclusions: Our study showed that different germplasms had significant differences in morphological traits and nutritional metabolic components and were rich in genetic diversity. This study provides a theoretical basis for the improvement of millet varieties and the development of functional food. Full article

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

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4 pages, 1758 KiB

Open AccessCorrection

Correction: Tai et al. Sea Bass Essence from Lates calcarifer Improves Exercise Performance and Anti-Fatigue in Mice. Metabolites 2022, 12, 531

by Hong-Jun Tai, Mon-Chien Lee, Yi-Ju Hsu, Chun-Yen Kuo, Chi-Chang Huang and Ming-Fu Wang

Metabolites 2025, 15(1), 46; https://doi.org/10.3390/metabo15010046 - 13 Jan 2025

Viewed by 292

Abstract

First, in the original publication [...] Full article

(This article belongs to the Section Animal Metabolism)

16 pages, 4771 KiB

Open AccessArticle

Heterologous and High Production of Ergothioneine in Bacillus licheniformis by Using Genes from Anaerobic Bacteria

by Zhe Liu, Fengxu Xiao, Yupeng Zhang, Jiawei Lu, Youran Li and Guiyang Shi

Metabolites 2025, 15(1), 45; https://doi.org/10.3390/metabo15010045 - 12 Jan 2025

Viewed by 544

Abstract

Purpose: This study aimed to utilize genetically engineered Bacillus licheniformis for the production of ergothioneine (EGT). Given the value of EGT and the application of Bacillus licheniformis in enzyme preparation production, we cloned the key enzymes (EanA and EanB) from Chlorbium limicola. [...] Read more.

Purpose: This study aimed to utilize genetically engineered Bacillus licheniformis for the production of ergothioneine (EGT). Given the value of EGT and the application of Bacillus licheniformis in enzyme preparation production, we cloned the key enzymes (EanA and EanB) from Chlorbium limicola. Through gene alignment, new ergothioneine synthase genes (EanAN and EanBN) were identified and then expressed in Bacillus licheniformis to construct strains. Additionally, we investigated the factors influencing the yield of EGT and made a comparison with Escherichia coli. Methods: The relevant genes were cloned and transferred into Bacillus licheniformis. Fermentation experiments were conducted under different conditions for yield analysis, and the stability of this bacterium was also evaluated simultaneously. Results: The constructed strains were capable of producing EGT. Specifically, the yield of the EanANBN strain reached (643.8 ± 135) mg/L, and its stability was suitable for continuous production. Conclusions: Genetically engineered Bacillus licheniformis demonstrates potential in the industrial-scale production of EGT. Compared with Escherichia coli, it has advantages, thus opening up new possibilities for the application and market supply of EGT. Full article

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

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19 pages, 4057 KiB

Open AccessArticle

A Comprehensive Machine Learning Approach for COVID-19 Target Discovery in the Small-Molecule Metabolome

by Md. Shaheenur Islam Sumon, Md Sakib Abrar Hossain, Haya Al-Sulaiti, Hadi M. Yassine and Muhammad E. H. Chowdhury

Metabolites 2025, 15(1), 44; https://doi.org/10.3390/metabo15010044 - 11 Jan 2025

Viewed by 776

Abstract

Background/Objectives: Respiratory viruses, including Influenza, RSV, and COVID-19, cause various respiratory infections. Distinguishing these viruses relies on diagnostic methods such as PCR testing. Challenges stem from overlapping symptoms and the emergence of new strains. Advanced diagnostics are crucial for accurate detection and effective [...] Read more.

Background/Objectives: Respiratory viruses, including Influenza, RSV, and COVID-19, cause various respiratory infections. Distinguishing these viruses relies on diagnostic methods such as PCR testing. Challenges stem from overlapping symptoms and the emergence of new strains. Advanced diagnostics are crucial for accurate detection and effective management. This study leveraged nasopharyngeal metabolome data to predict respiratory virus scenarios including control vs. RSV, control vs. Influenza A, control vs. COVID-19, control vs. all respiratory viruses, and COVID-19 vs. Influenza A/RSV. Method: We proposed a stacking-based ensemble technique, integrating the top three best-performing ML models from the initial results to enhance prediction accuracy by leveraging the strengths of multiple base learners. Key techniques such as feature ranking, standard scaling, and SMOTE were used to address class imbalances, thus enhancing model robustness. SHAP analysis identified crucial metabolites influencing positive predictions, thereby providing valuable insights into diagnostic markers. Results: Our approach not only outperformed existing methods but also revealed top dominant features for predicting COVID-19, including Lysophosphatidylcholine acyl C18:2, Kynurenine, Phenylalanine, Valine, Tyrosine, and Aspartic Acid (Asp). Conclusions: This study demonstrates the effectiveness of leveraging nasopharyngeal metabolome data and stacking-based ensemble techniques for predicting respiratory virus scenarios. The proposed approach enhances prediction accuracy, provides insights into key diagnostic markers, and offers a robust framework for managing respiratory infections. Full article

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

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28 pages, 2607 KiB

Open AccessReview

Underlying Mechanisms of Chromatographic H/D, H/F, cis/trans and Isomerism Effects in GC-MS

by Dimitrios Tsikas

Metabolites 2025, 15(1), 43; https://doi.org/10.3390/metabo15010043 - 11 Jan 2025

Viewed by 791

Abstract

Charge-free gaseous molecules labeled with deuterium ²H (D) atoms elute earlier than their protium-analogs ¹H (H) from most stationary GC phases. This effect is known as the chromatographic H/D isotope effect (hdIE_C) and can be calculated by [...] Read more.

Charge-free gaseous molecules labeled with deuterium ²H (D) atoms elute earlier than their protium-analogs ¹H (H) from most stationary GC phases. This effect is known as the chromatographic H/D isotope effect (hdIE_C) and can be calculated by dividing the retention times (t_R) of the protiated (t_R(H) ) to those of the deuterated (t_R(D)) analytes: hdIE_C = t_R(H)/t_R(D). Analytes labeled with ¹³C, ¹⁵N or ¹⁸O have almost identical retention times and lack a chromatographic isotope effect. Derivatives of cis- and trans-analytes such as cis- and trans-fatty acids also differ in their retention times. Analytes that contain trans-C=C-double bonds elute earlier in gas chromatography-mass spectrometry (GC-MS) than their cis-C=C-double bonds containing congeners. The chromatographic cis/trans-effect (ctE_C) can be calculated by dividing the retention times of the cis- by those of the trans-analytes: ctE_C = t_R(c)/t_R(t). In the present work, the hdIE_C and ctE_C values of endogenous and exogenous substances were calculated from previously reported GC-MS analyses and found to range each between 1.0009 and 1.0400. The examination suggests that the H/D-isotope effects and the cis/trans-effects observed in GC-MS are based on differences in the inter-molecular interaction strengths of the analyte derivatives with the stationary phase of GC columns. The deuterium atoms, being larger than the H atoms of the analytes, attenuate the interaction of the skeleton of the molecules with the GC stationary phase. The angulation of trans-analytes decreases the interaction of the skeleton of the molecules with the GC stationary phase, as only parts of the molecules are close enough to the GC stationary phase to interact. Other chromatographic effects caused by hydrogen (H) and fluorine (F) atoms and by stereo-isomerism are considered to be based on a similar mechanism due to the different orientation of the side chains. Full article

(This article belongs to the Special Issue Metabolomic Fingerprinting: Challenges and Opportunities)

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14 pages, 701 KiB

Open AccessArticle

A Study of Volatile Organic Compounds in Patients with Obstructive Sleep Apnea

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

Metabolites 2025, 15(1), 42; https://doi.org/10.3390/metabo15010042 - 11 Jan 2025

Viewed by 473

Abstract

Background: Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder characterized by intermittent upper airway obstruction, leading to significant health consequences. Traditional diagnostic methods, such as polysomnography, are time-consuming and resource-intensive. Objectives: This study explores the potential of proton-transfer-reaction mass spectrometry [...] Read more.

Background: Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder characterized by intermittent upper airway obstruction, leading to significant health consequences. Traditional diagnostic methods, such as polysomnography, are time-consuming and resource-intensive. Objectives: This study explores the potential of proton-transfer-reaction mass spectrometry (PTR-MS) in identifying volatile organic compound (VOC) biomarkers for the non-invasive detection of OSA. Methods: Breath samples from 89 participants, including 49 OSA patients and 40 controls, were analyzed using PTR-MS. Significance analysis was performed between OSA patients and controls to identify potential biomarkers for OSA. To as-sess the differences in VOC concentrations between OSA patients and control subjects, the Wilcoxon rank-sum test was employed. partial least squares discriminant analysis (PLS-DA) analysis and heatmap plot was conducted to visualize the differentiation between OSA patients and control subjects based on their VOC profiles.In order to further investigate the correlation between identified biomarkers and the severity of OSA measured by Apnea–Hypopnea Index (AHI), regression analysis was conducted between biomarkers and AHI Index. Results: The results identified specific VOCs, including m045 (acetaldehyde), m095.950, and m097.071, which showed significant differences between OSA patients and controls. Advanced statistical analyses, including PLS-DA and correlation mapping, highlighted the robustness of these biomarkers, with m045 (acetaldehyde) specifically emerging as a potential biomarker associated with the AHI Index. Conclusions: This study underscores the potential of VOCs as biomarkers for identifying patients with severe AHI levels. The analysis of VOCs using PTR-MS presents a rapid, non-invasive, and cost-effective method that could be seamlessly integrated into clinical practice, allowing clinicians to better stratify patients based on their need for polysomnography and prioritize those requiring earlier testing. Future studies are necessary to validate these findings in larger cohorts and to explore the integration of PTR-MS with other diagnostic modalities for improved accuracy and clinical utility. Full article

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

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22 pages, 9142 KiB

Open AccessArticle

Ethyl Acetate Extract of Cichorium glandulosum Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease

by Shuwen Qi, Chunzi Zhang, Junlin Yan, Xiaoyan Ma, Yewei Zhong, Wenhui Hou, Juan Zhang, Tuxia Pang and Xiaoli Ma

Metabolites 2025, 15(1), 41; https://doi.org/10.3390/metabo15010041 - 10 Jan 2025

Viewed by 622

Abstract

Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action [...] Read more.

Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including HMOX1, RSAD2, BCL6, CDKN1A, THBD, SLC2A4, and TGFβ3, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment. Full article

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

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Graphical abstract

21 pages, 3023 KiB

Open AccessArticle

Heat Tolerance Differences Between Hu Sheep and Hu Crossbred Sheep in Microbial Community Structure and Metabolism

by Jing-Da Yuan, Li-Wei Wang, Shao-Yin Fu, Ri-Ge-Li-Tu E, Xiao-Qi Ren, Hua Sun, Fang Liu, Biao Wang, Jiang-Hong An, Meng-Ran Zhao, Jiang-Feng He and Xiao-Long He

Metabolites 2025, 15(1), 40; https://doi.org/10.3390/metabo15010040 - 10 Jan 2025

Viewed by 513

Abstract

Background: The frequent occurrence of extreme temperature events causes significant economic losses to the livestock industry. Therefore, delving into the differences in the physiological and molecular mechanisms of heat stress across different sheep breeds is crucial for developing effective management and breeding strategies. [...] Read more.

Background: The frequent occurrence of extreme temperature events causes significant economic losses to the livestock industry. Therefore, delving into the differences in the physiological and molecular mechanisms of heat stress across different sheep breeds is crucial for developing effective management and breeding strategies. Methods: This study explores the differences in heat tolerance mechanisms between Hu sheep and Xinggao sheep by comparing their growth performance under normal and heat stress conditions, as well as examining the differences in physiological, biochemical, and antioxidant indicators related to heat tolerance, serum metabolomics, and gut microbiomics in a heat stress environment. Results: The results indicate that with changes in the temperature–humidity index (THI), Hu sheep exhibit superior stability in respiratory rate (RR) and rectal temperature (RT) fluctuations compared to Xinggao sheep. In terms of biochemical indicators and antioxidant capacity, the levels of creatinine (Cr) and superoxide dismutase (SOD) in Hu sheep serum are significantly higher than those in Xinggao sheep. In comparison, alkaline phosphatase (ALP) and malondialdehyde (MDA) levels are significantly lower. Metabolomic results showed that, compared to Hu sheep, Xinggao sheep exhibited higher cortisol (COR) and dopamine (DA) levels under heat stress conditions, a stronger lipid mobilization capacity, and elevated levels of tricarboxylic acid (TCA) cycle-related metabolites. Furthermore, gut microbiome analysis results indicate that Hu sheep demonstrate stronger cellulose degradation capabilities, as evidenced by significantly higher abundances of microorganisms such as Ruminococcus, Fibrobacter, and Bacteroidales_RF16_group, compared to Xinggao sheep. Conclusions: In summary, Hu sheep exhibit stronger heat tolerance compared to Xinggao sheep. These findings provide an important theoretical basis for the breeding and selection of heat-tolerant meat sheep varieties and offer strong support for the region’s livestock industry in addressing the challenges posed by global warming. Full article

(This article belongs to the Section Animal Metabolism)

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15 pages, 697 KiB

Open AccessArticle

Pharmacometabolomics Enables Real-World Drug Metabolism Sciences

by Fleur B. Nijdam, Marieke A. J. Hof, Hans Blokzijl, Stephan J. L. Bakker, Eelko Hak, Gérard Hopfgartner, Frank Klont and on behalf of the TransplantLines Investigators

Metabolites 2025, 15(1), 39; https://doi.org/10.3390/metabo15010039 - 10 Jan 2025

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Abstract

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) [...] Read more.

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) “phenoconversion” factors, like drug–drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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13 pages, 2980 KiB

Open AccessArticle

Untargeted Metabolomics Reveals the Metabolic Characteristics and Biomarkers of Antioxidant Properties of Gardeniae Fructus from Different Geographical Origins in China

by Wu Jiang, Lingling Jiang, Xiaoli Yin, Shuhui Zhang, Xiaojing Duan, Jiadong Chen, Yingying Liu, Hong Zheng and Zhengming Tao

Metabolites 2025, 15(1), 38; https://doi.org/10.3390/metabo15010038 - 10 Jan 2025

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Abstract

Background/Objectives: Gardeniae Fructus (GF) has been widely used as both food and medicinal purposes for thousands of years, but their antioxidant properties and potential metabolite biomarkers remain unclear. Methods: The purposes of this study were to examine antioxidant activities of 21 GF [...] Read more.

Background/Objectives: Gardeniae Fructus (GF) has been widely used as both food and medicinal purposes for thousands of years, but their antioxidant properties and potential metabolite biomarkers remain unclear. Methods: The purposes of this study were to examine antioxidant activities of 21 GF varieties from different geographical origins in China and identify potential biomarkers of antioxidant properties using an untargeted LC–MS-based metabolomics approach. Results: The results demonstrate that metabolomics had the ability to trace the geographical origins of GF. We found that antioxidant activities varied with different varieties of GF, which was dependent on their chemical compositions. The key chemical categories were obtained as the primary contributors of the antioxidant activity, including prenol lipids, flavonoids, coumarins and derivatives, as well as steroids and steroid derivatives. In addition, adouetine Y, coagulin R 3-glucoside and epicatechin 3-glucoside were identified as potential biomarkers for the antioxidant activity of GF. Conclusions: Therefore, our study sheds light on the metabolic characteristics and biomarkers of the antioxidant properties of GF, contributing to the selection and cultivation of a high antioxidant variety. Full article

(This article belongs to the Special Issue Analysis of Specialized Metabolites in Natural Products)

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24 pages, 906 KiB

Open AccessReview

Volatile Organic Metabolites as Potential Biomarkers for Genitourinary Cancers: Review of the Applications and Detection Methods

by Kiana L. Holbrook and Wen-Yee Lee

Metabolites 2025, 15(1), 37; https://doi.org/10.3390/metabo15010037 - 10 Jan 2025

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Abstract

Cancer is one of the leading causes of death globally, and is ranked second in the United States. Early detection is crucial for more effective treatment and a higher chance of survival rates, reducing burdens on individuals and societies. Genitourinary cancers, in particular, [...] Read more.

Cancer is one of the leading causes of death globally, and is ranked second in the United States. Early detection is crucial for more effective treatment and a higher chance of survival rates, reducing burdens on individuals and societies. Genitourinary cancers, in particular, face significant challenges in early detection. Finding new and cost-effective diagnostic methods is of clinical need. Metabolomic-based approaches, notably volatile organic compound (VOC) analysis, have shown promise in detecting cancer. VOCs are small organic metabolites involved in biological processes and disease development. They can be detected in urine, breath, and blood samples, making them potential candidates for sensitive and non-invasive alternatives for early cancer detection. However, developing robust VOC detection methods remains a hurdle. This review outlines the current landscape of major genitourinary cancers (kidney, prostate, bladder, and testicular), including epidemiology, risk factors, and current diagnostic tools. Furthermore, it explores the applications of using VOCs as cancer biomarkers, various analytical techniques, and comparisons of extraction and detection methods across different biospecimens. The potential use of VOCs in detection, monitoring disease progression, and treatment responses in the field of genitourinary oncology is examined. Full article

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

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Metabolites, Volume 15, Issue 1 (January 2025) – 66 articles

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