Metabolites

14 pages, 2123 KiB

Open AccessArticle

Comprehensive Analysis of Small RNA Modifications in Arabidopsis thaliana and Their Dynamics During Seed Germination

by Liu-Cheng Jiang, Meng Men, Xuan-Jun Cui, Ren-Jie Zeng, Shu-Yi Gu, Tian Feng, Chen Zeng, Tiantian Ye, Jun Xiong, Bi-Feng Yuan and Yu-Qi Feng

Metabolites 2025, 15(5), 319; https://doi.org/10.3390/metabo15050319 (registering DOI) - 10 May 2025

Abstract

Background: Small RNA, defined as RNA molecules of less than 200 nucleotides in length, play pivotal regulatory roles in plant growth, development, and environmental stress responses. However, research on modifications in plant small RNA remains limited. Methods: In this study, we [...] Read more.

Background: Small RNA, defined as RNA molecules of less than 200 nucleotides in length, play pivotal regulatory roles in plant growth, development, and environmental stress responses. However, research on modifications in plant small RNA remains limited. Methods: In this study, we developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of 41 RNA modifications, facilitating the systematic qualification and quantification of modifications in plant small RNA. Results: We identified a total of nine modifications, among which N⁶,N⁶-dimethyladenosine (m^6,6A) is a newly identified modification in plant small RNA. Furthermore, we conducted a quantitative analysis of these modifications in Arabidopsis thaliana during the germination process and observed significant dynamic changes in their abundance from 1 to 5 days post-germination. Notably, the trends in the contents of these modifications exhibited a strong correlation with the reported gene expression levels of the relevant modifying enzymes and demodifying enzymes, suggesting that these modifications may play essential roles during seed germination and are tightly regulated by the genes of the corresponding enzymes. Conclusion: The discovery of these modifications in plant small RNA, coupled with the dynamic changes in their levels during germination, holds great promise for a further understanding of the physiological functions of small RNA modifications and their associated regulatory mechanisms in plant seed germination. Full article

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

16 pages, 262 KiB

Open AccessArticle

Fatty Liver and Hyperuricemia in Workers: Combined Effects on Metabolic Dysfunction and the Role of Lifestyle Factors

by Jui-Hua Huang, Ren-Hau Li, Hon-Ke Sia and Feng-Cheng Tang

Metabolites 2025, 15(5), 318; https://doi.org/10.3390/metabo15050318 - 9 May 2025

Abstract

Background/Objectives: Fatty liver and hyperuricemia are growing public health concerns linked to unhealthy lifestyles, yet their combined effects in working populations remain underexplored. This study investigates their associations with metabolic risk factors, inflammation, and liver dysfunction to inform workplace health strategies. Methods [...] Read more.

Background/Objectives: Fatty liver and hyperuricemia are growing public health concerns linked to unhealthy lifestyles, yet their combined effects in working populations remain underexplored. This study investigates their associations with metabolic risk factors, inflammation, and liver dysfunction to inform workplace health strategies. Methods: The participants were employees aged 20 or older from four industrial enterprises located in central Taiwan. A total of 3089 participants (2571 males, 518 females) were analyzed. Lifestyle factors were assessed via a self-administered questionnaire, fatty liver was diagnosed using ultrasound, and serum uric acid levels, metabolic parameters, inflammatory markers, and liver function were measured. Results: The prevalence of fatty liver (43.2%) exceeded that of hyperuricemia (25.5%), with a higher burden among males. Fatty liver was associated with lower physical activity, while alcohol consumption was significantly higher in individuals with both conditions. Both conditions correlated with increased metabolic risk factors, liver dysfunction, and inflammation. Health-related risk factors were compared across four groups, using Group A (no hyperuricemia/no fatty liver, OR = 1.00) as the reference. The risk of metabolic syndrome increased progressively: 2.90 (Group B: hyperuricemia/no fatty liver), 6.15 (Group C: no hyperuricemia/fatty liver), and 11.52 (Group D: hyperuricemia/fatty liver), following the trend A < B < C < D. Notably, Group D had the highest risk, with exacerbated inflammation and liver dysfunction. Conclusions: Fatty liver and hyperuricemia synergistically worsen metabolic disorders, inflammation, and liver dysfunction. Early detection and lifestyle interventions are crucial to mitigating long-term health risks. Full article

(This article belongs to the Special Issue Liver Injury and Regeneration—Metabolic Research)

20 pages, 1481 KiB

Open AccessArticle

A Data-Driven Approach to Link GC-MS and LC-MS with Sensory Attributes of Chicken Bouillon with Added Yeast-Derived Flavor Products in a Combined Prediction Model

by Simon Leygeber, Carmen Diez-Simon, Justus L. Großmann, Anne-Charlotte Dubbelman, Amy C. Harms, Johan A. Westerhuis, Doris M. Jacobs, Peter W. Lindenburg, Margriet M. W. B. Hendriks, Brenda C. H. Ammerlaan, Marco A. van den Berg, Rudi van Doorn, Roland Mumm, Age K. Smilde, Robert D. Hall and Thomas Hankemeier

Metabolites 2025, 15(5), 317; https://doi.org/10.3390/metabo15050317 - 8 May 2025

Abstract

Background: There is a continuous demand to create new, superior sensory food experiences. In the food industry, yeast-derived flavor products (YPs) are often used as ingredients in foods to create new aromas and taste qualities that are appreciated by consumers. Methods: Chicken bouillon [...] Read more.

Background: There is a continuous demand to create new, superior sensory food experiences. In the food industry, yeast-derived flavor products (YPs) are often used as ingredients in foods to create new aromas and taste qualities that are appreciated by consumers. Methods: Chicken bouillon samples containing diverse YPs were chemically and sensorially characterized using statistical multivariate analyses. The sensory evaluation was performed using quantitative descriptive analysis (QDA) by trained panelists. Thirty-four sensory attributes were scored, including odor, flavor, mouthfeel, aftertaste and afterfeel. Untargeted metabolomic profiles were obtained using stir bar sorptive extraction (SBSE) coupled to GC-MS, RPLC-MS and targeted HILIC-MS. Results: In total, 261 volatiles were detected using GC-MS, from chemical groups of predominantly aldehydes, esters, pyrazines and ketones. Random Forest (RF) modeling revealed volatiles associated with roast odor (2-ethyl-5-methyl pyrazine, 2,3,5-trimethyl-6-isopentyl pyrazine) and chicken odor (2,4-nonadienal, 2,4-decadienal, 2-acetyl furan), which could be predicted by our combined model with R² > 0.5. In total, 2305 non-volatiles were detected for RPLC-MS and 34 for targeted HILIC-MS, where fructose-isoleucine and cyclo-leucine-proline were found to correlate with roast flavor and odor. Furthermore, a list of metabolites (glutamate, monophosphates, methionyl-leucine) was linked to umami-related flavor. This study describes a straightforward data-driven approach for studying foods with added YPs to identify flavor-impacting correlations between molecular composition and sensory perception. It also highlights limitations and preconditions for good prediction models. Overall, this study emphasizes a matrix-based approach for the prediction of food taste, which can be used to analyze foods for targeted flavor design or quality control. Full article

(This article belongs to the Section Food Metabolomics)

16 pages, 4798 KiB

Open AccessArticle

Effects of Maillard Reaction Products on Skeletal Muscle Cells: An In Vitro Study Using C2C12 Myotubes

by Marina Miyaki, Yusuke Komiya, Itsuki Sumiya, Rina Yamaguchi, Moeka Kuno, Chika Kojima, Ryosuke Makino, Takahiro Suzuki, Yoshihiro Suzuki, Issei Yokoyama and Keizo Arihara

Metabolites 2025, 15(5), 316; https://doi.org/10.3390/metabo15050316 - 8 May 2025

Abstract

Background: Maillard reaction products (MRPs) are known for their antioxidant properties; however, their effects on muscle cells remain unclear. This study aims to elucidate the effects of MRPs on muscle hypertrophy and atrophy in C2C12 myotubes. Methods: MRPs were prepared by [...] Read more.

Background: Maillard reaction products (MRPs) are known for their antioxidant properties; however, their effects on muscle cells remain unclear. This study aims to elucidate the effects of MRPs on muscle hypertrophy and atrophy in C2C12 myotubes. Methods: MRPs were prepared by heating L-lysine and D-glucose, and their antioxidant activity was assessed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Subsequently, mouse C2C12 myoblasts were cultured with MRPs until myotubes formed, and their diameters were measured to assess hypertrophic and atrophic changes. Akt phosphorylation was evaluated by Western blotting, and gene expression levels were analyzed via quantitative PCR. Results: The prepared MRPs exhibited high antioxidant activity in the DPPH radical scavenging assay. MRP treatment significantly increased the average myotube diameter by approximately 40% and enlarged the largest myotube diameter by up to 80%, potentially mediated by enhanced Akt phosphorylation. Under dexamethasone-induced atrophy, MRPs modestly attenuated the reduction in myotube diameter by approximately 20%, although the effect was not statistically significant, and did not significantly alter the fusion index either. Quantitative PCR analysis revealed that MRP treatment significantly reduced the mRNA expression of Nfe2l2, a key regulator of antioxidant response, whereas it had no notable effects on the expression of genes related to myoblast proliferation (Myod1), differentiation (Myog), hypertrophy (Igf1), atrophy (Foxo1 and Trim63), and oxidative stress (Cat, Gclc, and Nqo1). Conclusions: Our findings suggested that MRPs possess antioxidant activity and promote myotube hypertrophy via Akt signaling. This study highlighted the potential of MRPs as functional ingredients for promoting muscle health, though further in vivo studies are required to validate their physiological relevance. Full article

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

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2 pages, 292 KiB

Open AccessCorrection

Correction: Chen et al. Metabolomics-Based Study on the Anticonvulsant Mechanism of Acorus tatarinowii: GABA Transaminase Inhibition Alleviates PTZ-Induced Epilepsy in Rats. Metabolites 2025, 15, 175

by Liang Chen, Jiaxin Li, Chengwei Fang and Jiepeng Wang

Metabolites 2025, 15(5), 315; https://doi.org/10.3390/metabo15050315 - 8 May 2025

Abstract

Error in Figure [...] Full article

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17 pages, 1679 KiB

Open AccessArticle

Peripheral Antinociception Induced by Carvacrol in the Formalin Test Involves the Opioid Receptor-NO-cGMP-K⁺ Channel Pathway

by Mario I. Ortiz, Raquel Cariño-Cortés, Eduardo Fernández-Martínez, Victor Manuel Muñoz-Pérez, Gilberto Castañeda-Hernández and Martha Patricia González-García

Metabolites 2025, 15(5), 314; https://doi.org/10.3390/metabo15050314 - 7 May 2025

Abstract

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and [...] Read more.

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K⁺ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K⁺ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K⁺ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K⁺ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K⁺ channel blockers), and apamin and charybdotoxin (Ca²⁺-activated K⁺ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K⁺ channel pathway. Full article

(This article belongs to the Special Issue Exploring Innovations in Secondary Metabolites and Their Effects on Pain, Inflammation and Metabolic Syndrome)

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22 pages, 2019 KiB

Open AccessArticle

Metabolic Characteristics of Obese Adolescents with Different Degrees of Weight Loss After Identical Exercise Training Intervention

by Xianyan Xie, Gaoyuan Yang, Yulin Qin, Yu Wang, Zhijun Liu, Zhuofan Zhang, Ziyan Li, Huiguo Wang and Lin Zhu

Metabolites 2025, 15(5), 313; https://doi.org/10.3390/metabo15050313 - 7 May 2025

Abstract

Objectives: This study aims to elucidate the metabolic differences between obese adolescents categorized into low-weight-loss (LWL) and high-weight-loss (HWL) groups. Methods: The objective of this study is to investigate the metabolic characteristics of obese adolescents, with a focus on the statistically significant individual [...] Read more.

Objectives: This study aims to elucidate the metabolic differences between obese adolescents categorized into low-weight-loss (LWL) and high-weight-loss (HWL) groups. Methods: The objective of this study is to investigate the metabolic characteristics of obese adolescents, with a focus on the statistically significant individual differences observed in weight loss outcomes after the same dietary and exercise training intervention. A four-week exercise and dietary intervention was administered to the participants. Obese adolescents were categorized into LWL (with a weight loss percentage of 5–10%) and HWL (with a weight loss percentage of >10%) groups on the basis of their weight loss outcomes. Post-intervention changes in body morphology and body composition between the two groups were compared using Analysis of Covariance (ANCOVA), with gender as a covariate. Additionally, metabolic changes were analyzed in depth; differential metabolites between the groups were identified through ANCOVA adjusted for gender, followed by pathway analysis. Results: After the four-week exercise intervention, the body morphology and composition of the obese adolescents showed significant improvements compared with those before the intervention (p < 0.001). For example, weight decreased from 80.65 kg to 72.35 kg, BMI decreased from 30.57 kg/m² to 27.26 kg/m², waist circumference decreased from 103.64 cm to 94.72 cm, and body fat percentage decreased from 32.68% to 28.54%. Prior to the exercise intervention, no significant differences in body morphology and composition were observed between the HWL and LWL groups (p > 0.05). After the intervention, the HWL group demonstrated significant improvements in weight, body mass index, waist circumference, body fat percentage, fat mass, fat-free mass, body water amount, and skeletal muscle mass compared with the LWL group (p < 0.001). After controlling for the levels of pre-intervention metabolites, 27 differential metabolites were identified between the HWL and LWL groups. These metabolites were categorized into fatty acids, amino acids, organic acids, carnitines, indoles, benzoic acids, and carbohydrates. Notably, they were significantly enriched in the eight metabolic pathways involved in amino acid metabolism, fatty acid biosynthesis, and coenzyme A biosynthesis. Conclusions: A four-week exercise intervention enhanced the body morphology and physical fitness of obese adolescents, although the degree of weight loss varied among individuals. Considerable weight reduction was significantly correlated with metabolites involved in lipid, amino acid, organic acid, carbohydrate, and gut microbiota metabolism and with the enrichment of pathways involved in amino acid metabolism, fatty acid biosynthesis, and coenzyme A biosynthesis. These findings indicate that intrinsic metabolic characteristics considerably influence individual responsiveness to exercise-based weight-loss interventions. Full article

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

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11 pages, 1304 KiB

Open AccessArticle

Determination of Multiple Active Components in Mume Fructus by UPLC-MS/MS

by Nannan Li, Jingyi Yue and Rui Wang

Metabolites 2025, 15(5), 312; https://doi.org/10.3390/metabo15050312 - 6 May 2025

Abstract

Background: This study presents a sensitive method for the simultaneous determination of organic acids, flavonoids, and amino acids in Mume Fructus (MF) using ultra-performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry (UPLC-QTRAP-MS/MS). Methods: Analysis was performed on a UPLC system [...] Read more.

Background: This study presents a sensitive method for the simultaneous determination of organic acids, flavonoids, and amino acids in Mume Fructus (MF) using ultra-performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry (UPLC-QTRAP-MS/MS). Methods: Analysis was performed on a UPLC system (Shimadzu, Kyoto, Japan) equipped with a quaternary pump solvent management system, an online degasser, a triple-quadrupole mass detector, and an autosampler. An Agilent ZORBAX SB-C18 column (3.0 mm × 100 mm, 1.8 µm) was used for chromatographic analyses. The mobile phase was distributed between 0.2% aqueous formic acid (A) and 0.2% formic acid acetonitrile (B) at a velocity of 0.2 mL/min. The gradient evolution protocol was 0–2 min at 90–70% B; 3–7 min at 70–50% B; 7–10 min at 50–20% B; 10–14.5 min at 20–90% B; and 14.5–17 min at 10% B. Results: The method was validated for matrix effects, linearity, limits of detection/quantification, precision, repeatability, stability, and recovery of target components. It effectively determined all target compounds in 12 MF batches from different drying methods. Conclusions: Principal component analysis (PCA) of 47 active components was conducted to evaluate MF quality comprehensively. The proposed method serves as a reliable approach for assessing the consistency of MF’s quality and therapeutic efficacy. Full article

(This article belongs to the Special Issue Advances in Secondary Metabolites: Phytochemical Analysis and Bioactivity Assays)

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19 pages, 1080 KiB

Open AccessArticle

Genistein Reduces Anxiety-like Behavior During Metestrus–Diestrus Phase Without Changing Estradiol or Progesterone Levels in Wistar Rats

by Juan Francisco Rodríguez-Landa, Oscar Jerónimo Olmos-Vázquez, Carlos Fabrizio Quiñonez-Bailón, Gabriel Guillén-Ruiz, Ana Karen Limón-Vázquez, Jonathan Cueto-Escobedo, Eduardo Rivadeneyra-Domínguez and Blandina Bernal-Morales

Metabolites 2025, 15(5), 311; https://doi.org/10.3390/metabo15050311 - 6 May 2025

Abstract

Background: Premenstrual syndrome is characterized by emotional changes, including anxiety and depression symptoms, which may be treated with anxiolytic and antidepressant drugs, as well as estrogen therapy. However, steroidal estrogen therapy is contraindicated for patients with a potential risk of developing estrogen-dependent [...] Read more.

Background: Premenstrual syndrome is characterized by emotional changes, including anxiety and depression symptoms, which may be treated with anxiolytic and antidepressant drugs, as well as estrogen therapy. However, steroidal estrogen therapy is contraindicated for patients with a potential risk of developing estrogen-dependent cancers through interactions with estrogen receptor α (ERα). Alternatively, genistein produces estrogenic effects in animals and humans at dietary dosages that act on the nuclear and membrane ERα, estrogen receptor β (ERβ), and the G-protein-coupled estrogen receptor (GPER). These receptors are likely involved in the anxiety symptoms observed in premenstrual disorders. The objective of this study was to evaluate the effects of genistein and 17β-estradiol on anxiety-like behavior and the plasma concentrations of estradiol and progesterone throughout the ovarian cycle of Wistar rats. Methods: The effect of the administration of 0.09 mg/kg of genistein or 17β-estradiol was evaluated using the elevated plus maze (EPM) test, locomotor activity test (LAT), and light/dark box (LDB) test, as well as by assessing the plasma concentrations of estradiol and progesterone, while considering the ovarian cycle phases. Results: Higher levels of anxiety-like behavior were detected in the metestrus–diestrus phase compared to the proestrus–estrus phase, which was associated with low concentrations of estradiol. Genistein, similarly to 17β-estradiol, significantly reduced anxiety-like behaviors in the EPM and LDB; however, 17β-estradiol, but not genistein, significantly increased the plasma estradiol concentration. No significant changes were found in locomotor activity or the plasma progesterone concentrations due to the treatments. Conclusions: These findings suggest that genistein may be useful in the development of alternative therapies to reduce the anxiety associated with low steroid hormone concentrations, which occur in premenstrual syndrome. Genistein could be an alternative to steroidal estrogen therapy to avoid potential side effects due to estradiol or antidepressant treatments, although it still requires medical care. Full article

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

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14 pages, 2979 KiB

Open AccessArticle

Probiotic Supplementation Improves Hematological Indices and Morphology of Red Blood Cells and Platelets in Obese Women: A Double-Blind, Controlled Pilot Study

by Nina Okuka, Nevena Dj. Ivanovic, Neda Milinkovic, Snezana Polovina, Mirjana Sumarac-Dumanovic, Rajna Minic, Brizita Djordjevic and Ksenija Velickovic

Metabolites 2025, 15(5), 310; https://doi.org/10.3390/metabo15050310 - 6 May 2025

Abstract

Background/Objectives: The prevalence of obesity worldwide has rapidly increased. Numerous studies showed a beneficial effect of probiotics in obese individuals, and changes in hematological parameters are observed in obesity. Therefore, the aim of this study was to investigate the effect of a novel [...] Read more.

Background/Objectives: The prevalence of obesity worldwide has rapidly increased. Numerous studies showed a beneficial effect of probiotics in obese individuals, and changes in hematological parameters are observed in obesity. Therefore, the aim of this study was to investigate the effect of a novel probiotic approach on the red blood cells (RBCs) and platelets. Methods: Twenty-five obese women participated in a randomized, placebo-controlled study and were divided into the experimental group (one capsule daily containing Lactiplantibacillus plantarum 299v (DSM9843), Saccharomyces cerevisiae var. boulardii, and 40 mg octacosanol; n = 13) and the placebo group (n = 12). Blood samples were collected for light microscopic examination, morphometric analysis, and an automated hematology analyzer. A possible relationship between hematological parameters and body mass index (BMI), a common indicator of obesity, was investigated using Spearman correlation. The plasma concentration of soluble P-selectin and fibrinogen were determined using an ELISA assay. All measurements were performed before (T0) and after 12 weeks of supplementation (T1). Results: The three-month supplementation of probiotics improved hemoglobin levels, chromic status, and red blood cell morphology. The mean platelet volume (MPV), a measure of platelet size, was restored to normal levels, platelet morphology was improved, and the number of activated platelets was significantly reduced (p < 0.05). A strong negative correlation (r = −0.5904, p < 0.05) was found between BMI and platelet distribution width (PDW), a measure of variation in platelet size and shape. Conclusions: The results show that the probiotic approach improves morphology and normalizes the values of disturbed hematological parameters of RBCs and platelets in obese women. Full article

(This article belongs to the Special Issue Dysbiosis and Metabolic Disorders of the Microbiota)

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12 pages, 395 KiB

Open AccessArticle

Adapting OptCouple to Identify Strategies with Increased Product Yields in Community Cohorts of E. coli

by Nicole Pearcy and Jamie Twycross

Metabolites 2025, 15(5), 309; https://doi.org/10.3390/metabo15050309 - 6 May 2025

Abstract

Background: Microbesas chemical factories provide an alternative sustainable approach for producing platform chemicals. Until recently, most efforts have involved engineering heterologous pathways into a single microbial chassis to maximise its production of a target chemical. More recently, cohorts of microbes have been used [...] Read more.

Background: Microbesas chemical factories provide an alternative sustainable approach for producing platform chemicals. Until recently, most efforts have involved engineering heterologous pathways into a single microbial chassis to maximise its production of a target chemical. More recently, cohorts of microbes have been used to engineer microbial communities to achieve higher yields than achieved in a single chassis. Full article

(This article belongs to the Special Issue Comprehensive Insights into Metabolic Pathways: Genome-Scale Modeling Techniques)

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14 pages, 1467 KiB

Open AccessArticle

Propionyl Carnitine Metabolic Profile: Optimizing the Newborn Screening Strategy Through Customized Cut-Offs

by Maria Lucia Tommolini, Maria Concetta Cufaro, Silvia Valentinuzzi, Ilaria Cicalini, Mirco Zucchelli, Alberto Frisco, Simonetta Simonetti, Michela Perrone Donnorso, Sara Moccia, Ines Bucci, Maurizio Aricò, Vincenzo De Laurenzi, Luca Federici, Damiana Pieragostino and Claudia Rossi

Metabolites 2025, 15(5), 308; https://doi.org/10.3390/metabo15050308 - 6 May 2025

Abstract

Background: The advent of tandem mass spectrometry (MS/MS) had an essential role in the expansion of newborn screening (NBS) for different inborn errors of metabolism (IEMs). Nowadays, almost 50 IEMs are screened in Italy. The use of second-tier tests (2-TTs) in NBS minimizes [...] Read more.

Background: The advent of tandem mass spectrometry (MS/MS) had an essential role in the expansion of newborn screening (NBS) for different inborn errors of metabolism (IEMs). Nowadays, almost 50 IEMs are screened in Italy. The use of second-tier tests (2-TTs) in NBS minimizes the false positive rate; nevertheless, the metabolic profile is influenced not only by the genome but also by environmental factors and clinical variables. We reviewed the MS/MS NBS data from over 37,000 newborns (of which 8% required 2-TTs) screened in the Italian Abruzzo region to evaluate the impact of neonatal and maternal variables on propionate-related primary biomarker levels. Methods: Expanded NBS and 2-TT analyses were performed using MS/MS and liquid chromatography–MS/MS methods. We set up layered cut-offs dividing all 37,000 newborns into categories. Statistical analysis was used to create alarm thresholds for NBS-positive samples. Statistically significant differences were found in both neonatal and maternal conditions based on the 2-TTs carried out. According to the stratified cut-offs, only 1.47% of the newborns would have required a 2-TT while still retaining the ability to recognize the true-positive case of methylmalonic acidemia with homocystinuria, which has been identified by NBS. To further support the clinical applicability, we performed an external evaluation considering nine positive cases from an extra-regional neonatal population, confirming the potential of our model. Interestingly, the setting of alarm thresholds and their application would allow for establishing the degree of priority/urgency for 2-TTs. Conclusions: Tailoring NBS by customized cut-offs may enhance the application of precision medicine, focusing on true-positive cases and also reducing analysis costs and times. Full article

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

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24 pages, 4582 KiB

Open AccessArticle

Multiple Hits on Cerebral Folate, Tetrahydrobiopterin and Dopamine Metabolism in the Pathophysiology of Parkinson’s Disorder: A Limited Study of Post-Mortem Human Brain Tissues

by Dhruti Balakrishna Doddaballapur, Derren J. Heyes and Jaleel A. Miyan

Metabolites 2025, 15(5), 307; https://doi.org/10.3390/metabo15050307 - 5 May 2025

Abstract

Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is [...] Read more.

Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is an urgent need to investigate upstream metabolic disruptions, including folate and tetrahydrobiopterin (BH4) pathways, in post-mortem CSF and brain tissue to understand their roles in PD pathogenesis. Methods: CSF and brain tissue from 20 PD patients (mean age 84 years; 55% male; disease duration 10–30 years) and 20 controls (mean age 82 years; 50% male) were analysed. Western and Dot Blots measured proteins and metabolites, spectroscopic assays assessed enzyme activities, BH4 and Neopterin levels were measured using ELISA, and levels of hydrogen peroxide, used as a proxy for reactive oxygen species, and calcium were quantified using horseradish peroxidase and flame photometry assays, respectively. ClinVar genetic data were analysed for variants in genes encoding key enzymes. Statistical significance was assessed using unpaired t-tests (p < 0.05). Results: All enzymes were significantly reduced in PD compared to controls (p < 0.01) except for methyltetrahydrofolate reductase (MTHFR), which was elevated (p < 0.0001). Enzymes were functional in control but undetectable in PD CSF except tyrosine hydroxylase (TH). BH4 and Neopterin were elevated in PD CSF (p < 0.0001, p < 0.001) but significantly reduced (p < 0.001) or unchanged in tissue. Peroxide was increased in both PD CSF (p < 0.001) and tissue (p < 0.0001) selectively inhibiting TH. Calcium was 40% higher in PD than controls (p < 0.05). No pathogenic variants in enzyme genes were found in ClinVar data searches, suggesting the observed deficiencies are physiological. Conclusions: We identified significant disruptions in folate and BH4 pathways in PD, with enzyme deficiencies, oxidative stress and calcium dysregulation pointing to choroid plexus dysfunction. These findings highlight the choroid plexus and CSF as key players in cerebral metabolism and promote further exploration of these as therapeutic targets to address dopaminergic dysfunction and ventricular enlargement in PD. Full article

(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases, 2nd Edition)

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14 pages, 1355 KiB

Open AccessArticle

Exploring the Medicinal Potential of Taraxacum Kok-Saghyz (TKS) Using Widely Targeted Metabolomics

by Michele Tan, Jeffrey Shih-Chieh Chu and Daniel Robin Swiger

Metabolites 2025, 15(5), 306; https://doi.org/10.3390/metabo15050306 - 3 May 2025

Abstract

Background/Objectives: Plant-derived secondary metabolites have long contributed to the discovery of novel therapeutic agents, especially in the treatment of parasitic and infectious diseases in developing countries. Metabolomics provides a systems-level approach to understanding plant biochemistry, enabling the discovery of secondary metabolites with [...] Read more.

Background/Objectives: Plant-derived secondary metabolites have long contributed to the discovery of novel therapeutic agents, especially in the treatment of parasitic and infectious diseases in developing countries. Metabolomics provides a systems-level approach to understanding plant biochemistry, enabling the discovery of secondary metabolites with pharmacological relevance. Taraxacum kok-saghyz (TKS), widely known for its rubber-producing capabilities, remains underexplored as a medicinal plant. Given the well-established therapeutic properties of Taraxacum officinale and the emerging pharmacological profiles of related species, this study investigates the metabolic composition of TKS roots and leaves to uncover bioactive compounds with antioxidant, anti-inflammatory, or hepatoprotective potential. Methods: Widely targeted metabolomics was conducted on 10-month-old field-grown Kultevar™ TKS plants using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Samples were hand-harvested and preserved on dry ice to maintain biochemical integrity. Metabolite identification and classification were performed using the MWDB and KEGG databases. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to evaluate metabolic variation between tissues. Results: A total of 1813 metabolites were identified, including flavonoids, alkaloids, lipids, amino acids, and phenolic compounds. Differential analysis revealed 964 significantly altered metabolites—609 downregulated and 355 upregulated in roots relative to leaves. Multivariate analysis confirmed clear tissue-specific metabolic profiles. KEGG pathway enrichment highlighted the involvement of flavonoid biosynthesis, amino acid metabolism, and lipid metabolism pathways, suggesting bioactive potential. This study presents the first comprehensive metabolic profile of TKS, highlighting its potential value beyond rubber production. The detection of numerous therapeutic secondary metabolites supports its promise as a pharmaceutical and nutraceutical resource. Further functional validation of identified compounds is warranted. Full article

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

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18 pages, 1862 KiB

Open AccessReview

SMARCB1 Deficiency as a Driver of the Hallmarks of Cancer in Rhabdoid Tumours: Novel Insights into Dysregulated Energy Metabolism, Emerging Targets, and Ongoing Clinical Trials

by Abdul L. Shakerdi and Graham P. Pidgeon

Metabolites 2025, 15(5), 304; https://doi.org/10.3390/metabo15050304 - 3 May 2025

Abstract

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review [...] Read more.

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review explores the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate the translational potential of targeted therapies in SMARCB1-deficient rhabdoid tumours. Results: Loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune-evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Conclusions: SMARCB1 loss is a central driver of cancer hallmarks in RTs, enabling proliferation, immune evasion, metabolic reprogramming, and epigenetic dysregulation. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation. Full article

(This article belongs to the Special Issue Cancer Metabolomics 2024)

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16 pages, 2864 KiB

Open AccessArticle

Brown Algae from San Andres Island, Southwest Caribbean: A Nuclear Magnetic Resonance Spectroscopy–Metabolomic Study

by Felipe de la Roche, Sara P. Abril, Lady J. Sepulveda, Anderson Piza, Leonardo Castellanos, Natalia Rincón, Mónica Puyana and Freddy A. Ramos

Metabolites 2025, 15(5), 305; https://doi.org/10.3390/metabo15050305 - 2 May 2025

Abstract

Background: Brown algae from the order Dictyotales are known to produce specialized metabolites with a wide array of biological activities. Studying these compounds is important for understanding their ecological roles, exploring biomedical potential and developing biotechnological applications. Methods: To evaluate the metabolic diversity [...] Read more.

Background: Brown algae from the order Dictyotales are known to produce specialized metabolites with a wide array of biological activities. Studying these compounds is important for understanding their ecological roles, exploring biomedical potential and developing biotechnological applications. Methods: To evaluate the metabolic diversity of brown algae from the shallow habitats of the northern region of San Andrés Island (Colombia, SW Caribbean), a metabolic profiling approach was employed, based on ¹H-NMR spectra taken from organic extracts. Four sampling expeditions were conducted to collect the most abundant species, taking into account the taxonomic identity, growth substrate and collection date. Results: Five species were found and identified as Canistrocarpus crispatus, Stypopodium zonale, Dictyopteris delicatula, Padina gymnospora and Dictyota spp. Multivariate analyses applied to these spectra revealed that S. zonale and C. crispatus differentiated from the other samples mainly due to the signals for meroditerpenes and diterpenes, respectively. S. zonale had differential metabolic production observed when comparing algae collected in rocky bottoms with thalli growing on dead coral. This difference was attributed to changes in concentrations of the meroditerpene atomaric acid (1). Meanwhile, the major metabolite found in C. crispatus samples was dictyol B acetate (2). Conclusions: NMR metabolomics of San Andrés brown algae differentiated species based on lipid content and metabolic complexity. Notably, prenylated-guaiane diterpenes characterized C. crispatus, and meroditerpenoid concentrations varied in S. zonale. Temporal lipid variations were observed in P. gymnospora, while juvenile Dictyota spp. presented a less complex metabolic signature. Full article

(This article belongs to the Section Environmental Metabolomics)

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29 pages, 2365 KiB

Open AccessReview

Caloric Restriction and Sirtuins as New Players to Reshape Male Fertility

by Diana C. A. André, Pedro F. Oliveira, Marco G. Alves and Ana D. Martins

Metabolites 2025, 15(5), 303; https://doi.org/10.3390/metabo15050303 - 2 May 2025

Abstract

Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown [...] Read more.

Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown to be a promising contributor towards longevity and delaying the onset of age-related diseases. This diet consists of a reduction in caloric intake while maintaining essential energy and nutritional requirements to achieve optimal health while avoiding malnutrition. However, the effects of this nutritional regimen on male reproductive health have not yet been comprehensively studied. Nevertheless, such a complex process will certainly be regulated by a variety of metabolic sensors, likely sirtuins. Evidence has been gathered regarding this group of enzymes, and their ability to regulate processes such as chromatin condensation, the cell cycle, insulin signaling, and glucose and lipid metabolism, among many others. Concerning testicular function and male fertility, sirtuins can modulate certain metabolic processes through their interaction with the hypothalamic–pituitary–gonadal axis and mitochondrial dynamics, among many others, which remain largely unexplored. This review explores the impact of caloric restriction on male fertility, highlighting the emerging role of sirtuins as key regulators of male reproductive health through their influence on cellular metabolism. Full article

(This article belongs to the Special Issue The Impact of Environmental Contaminants on Neurodevelopment and Human Metabolism)

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28 pages, 1315 KiB

Open AccessArticle

Early Gestational Hepatic Lipidomic Profiles Are Modulated by One-Carbon Metabolite Supplementation and Nutrient Restriction in Beef Heifers and Fetuses

by Kazi Sarjana Safain, Matthew S. Crouse, Jessica G. Syring, Yssi L. Entzie, Layla E. King, Alison K. Ward, Lawrence P. Reynolds, Pawel P. Borowicz, Carl R. Dahlen, Kendall C. Swanson and Joel S. Caton

Metabolites 2025, 15(5), 302; https://doi.org/10.3390/metabo15050302 - 1 May 2025

Abstract

Background: Maternal nutrition during early gestation induces metabolic adaptations that support maternal health and fetal development. This study evaluated the effects of maternal one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B₁₂) supplementation and restricted rates of maternal gain on the [...] Read more.

Background: Maternal nutrition during early gestation induces metabolic adaptations that support maternal health and fetal development. This study evaluated the effects of maternal one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B₁₂) supplementation and restricted rates of maternal gain on the hepatic lipid profiles of dams and fetuses at day 63 of gestation. Methods: Thirty-one crossbred Angus heifers were inseminated and assigned to a 2 × 2 factorial design with two factors: maternal dietary intake (control [CON]; 0.60 kg/day average daily gain [ADG] vs. restricted [RES]; −0.23 kg/day ADG) and OCM supplementation (supplemented [+OCM] vs. not supplemented [−OCM]). The four resulting groups (CON − OCM, CON + OCM, RES − OCM, RES + OCM) were maintained for 63 days post-breeding. Maternal and fetal liver samples were collected, and lipidomic profiling was performed using ultra-performance liquid chromatography–tandem mass-spectrometry. Results: In maternal liver, 485 lipid metabolites were detected, with 243 differing significantly in maternal gain. RES heifers showed increased levels (p ≤ 0.05) of acylcarnitines, plasmalogens, lysoplasmalogens, glycosphingolipids, and sphingomyelins. Additionally, RES combined with OCM supplementation led to the accumulation of secondary bile acids and a depletion of monoacylglycerols (p ≤ 0.05) in maternal liver. In fetal liver, 487 lipid metabolites were detected, but treatment effects were minimal. Conclusions: Maternal rate of gain significantly influenced hepatic lipid metabolism in the maternal liver, while fetal liver lipid profiles remained relatively unaffected. These findings underscore the significant role of dietary intake/rate of gain compared with OCM supplementation in modulating hepatic lipid metabolism and highlight the maternal liver’s metabolic adaptations during early pregnancy. Full article

(This article belongs to the Special Issue One-Carbon Metabolism in Pregnant Women, Fetuses, and Infants)

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23 pages, 1326 KiB

Open AccessReview

Gut Microbiota Modulation in Osteoporosis: Probiotics, Prebiotics, and Natural Compounds

by Xufeng Chu, Hailin Xing, Minghao Chao, Panpan Xie and Lili Jiang

Metabolites 2025, 15(5), 301; https://doi.org/10.3390/metabo15050301 - 30 Apr 2025

Abstract

Osteoporosis is a multifactorial bone metabolic disorder characterized by the deterioration of bone mass and microarchitecture, leading to increased fragility and fracture risk. Recent advances have revealed the critical role of the gut microbiota in the pathogenesis of osteoporosis, primarily mediated by metabolite-driven [...] Read more.

Osteoporosis is a multifactorial bone metabolic disorder characterized by the deterioration of bone mass and microarchitecture, leading to increased fragility and fracture risk. Recent advances have revealed the critical role of the gut microbiota in the pathogenesis of osteoporosis, primarily mediated by metabolite-driven and immune-mediated interactions along the gut–bone axis. Dysbiosis, or microbial imbalance, can influence bone health by modulating host metabolism, immune function, and endocrine responses. While growing evidence suggests that gut microbiota modulation holds therapeutic potential for osteoporosis, the underlying mechanisms remain poorly understood. This review examines the latest findings on the role of prebiotics, probiotics, and natural bioactive substances in modulating the gut microbiota to improve bone health. We discuss how these interventions may restore microbial balance, enhance gut barrier function, and reduce systemic inflammation, thereby influencing bone metabolism. A deeper understanding of the gut–bone axis will pave the way for more targeted, effective, and personalized therapeutic strategies for osteoporosis prevention and treatment. Full article

(This article belongs to the Special Issue Effects of Environmental Exposure on Host and Microbial Metabolism)

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