Metabolites

13 pages, 1248 KiB

Open AccessArticle

Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization

by Natalia V. Beloborodova and Nadezhda I. Fedotcheva

Metabolites 2024, 14(12), 703; https://doi.org/10.3390/metabo14120703 - 13 Dec 2024

Abstract

Background. Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate [...] Read more.

Background. Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied. Methods. In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods. Results. It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5–1 mM decreased the respiratory control and the swelling rate by 20–30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor. Conclusions. The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions. Full article

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4 pages, 183 KiB

Open AccessEditorial

COVIDomics: Metabolomic Views on COVID-19

by Armando Cevenini, Lucia Santorelli and Michele Costanzo

Metabolites 2024, 14(12), 702; https://doi.org/10.3390/metabo14120702 - 12 Dec 2024

Abstract

During the COVID-19 pandemic, omics-based methodologies were extensively used to study the pathological mechanisms of SARS-CoV-2 infection and replication in human cells at a large scale [...] Full article

(This article belongs to the Special Issue COVIDomics: Metabolomic Views on COVID-19 and Related Diseases)

26 pages, 10465 KiB

Open AccessArticle

Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress

by Aishwarya Rajakumar, Sarah Nguyen, Nicole Ford, Gbenga Ogundipe, Ethan Lopez-Nowak, Olena Kondrachuk and Manish K Gupta

Metabolites 2024, 14(12), 701; https://doi.org/10.3390/metabo14120701 - 12 Dec 2024

Abstract

Background: Cardiac diseases remain one of the leading causes of death globally, often linked to ischemic conditions that can affect cellular homeostasis and metabolism, which can lead to the development of cardiovascular dysfunction. Considering the effect of ischemic cardiomyopathy on the global population, [...] Read more.

Background: Cardiac diseases remain one of the leading causes of death globally, often linked to ischemic conditions that can affect cellular homeostasis and metabolism, which can lead to the development of cardiovascular dysfunction. Considering the effect of ischemic cardiomyopathy on the global population, it is vital to understand the impact of ischemia on cardiac cells and how ischemic conditions change different cellular functions through post-translational modification of cellular proteins. Methods: To understand the cellular function and fine-tuning during stress, we established an ischemia model using neonatal rat ventricular cardiomyocytes. Further, the level of cellular acetylation was determined by Western blotting and affinity chromatography coupled with liquid chromatography–mass spectroscopy. Results: Our study found that the level of cellular acetylation significantly reduced during ischemic conditions compared to normoxic conditions. Further, in mass spectroscopy data, 179 acetylation sites were identified in the proteins in ischemic cardiomyocytes. Among them, acetylation at 121 proteins was downregulated, and 26 proteins were upregulated compared to the control groups. Differentially, acetylated proteins are mainly involved in cellular metabolism, sarcomere structure, and motor activity. Additionally, a protein enrichment study identified that the ischemic condition impacted two major biological pathways: the acetyl-CoA biosynthesis process from pyruvate and the tricarboxylic acid cycle by deacetylation of the associated proteins. Moreover, most differential acetylation was found in the protein pyruvate dehydrogenase complex. Conclusions: Understanding the differential acetylation of cellular protein during ischemia may help to protect against the harmful effect of ischemia on cellular metabolism and cytoskeleton organization. Additionally, our study can help to understand the fine-tuning of proteins at different sites during ischemia. Full article

(This article belongs to the Section Cell Metabolism)

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14 pages, 3544 KiB

Open AccessArticle

Enhanced Synthesis of Volatile Compounds by UV-B Irradiation in Artemisia argyi Leaves

by Haike Gu, Zhuangju Peng, Xiuwen Kuang, Li Hou, Xinyuan Peng, Meifang Song and Junfeng Liu

Metabolites 2024, 14(12), 700; https://doi.org/10.3390/metabo14120700 - 11 Dec 2024

Abstract

Background: Volatile compounds have a deep influence on the quality and application of the medicinal herb Artemisia argyi; however, little is known about the effect of UV-B radiation on volatile metabolites. Methods: We herein investigated the effects of UV-B exposure on the [...] Read more.

Background: Volatile compounds have a deep influence on the quality and application of the medicinal herb Artemisia argyi; however, little is known about the effect of UV-B radiation on volatile metabolites. Methods: We herein investigated the effects of UV-B exposure on the volatile compounds and transcriptome of A. argyi to assess the potential for improving its quality and medicinal characteristics. Results: Out of 733 volatiles obtained, a total of 133 differentially expressed metabolites (DEMs) were identified by metabolome analysis. These were classified into 16 categories, primarily consisting of terpenoids, esters, heterocyclic compounds, alcohols, and ketones. Sensory odor analysis indicated that green was the odor with the highest number of annotations. Among the 544 differentially expressed genes (DEGs) identified by transcriptome analysis, most DEGs were linked to “metabolic pathways” and “biosynthesis of secondary metabolites”. Integrated analysis revealed that volatiles were mainly synthesized through the shikimate pathway and the MEP pathway. RNA-seq and qPCR results indicated that transcription factors HY5, bHLH25, bHLH18, bHLH148, MYB114, MYB12, and MYB111 were upregulated significantly after UV-B radiation, and were therefore considered key regulatory factors for volatiles synthesis under UV-B radiation. Conclusions: These findings not only provide new insights into UV-induced changes in volatile compounds, but also provide an exciting opportunity to enhance medicinal herbs’ value, facilitating the development of products with higher levels of essential oils, flavor, and bioactivity. Full article

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12 pages, 4972 KiB

Open AccessArticle

Effects of Acute Stress on Metabolic Interactions Related to the Tricarboxylic Acid (TCA) Cycle in the Left Hippocampus of Mice

by Chang-Soo Yun, Yoon Ho Hwang, Jehyeong Yeon, Hyeon-Man Baek, Dong Youn Kim and Bong Soo Han

Metabolites 2024, 14(12), 699; https://doi.org/10.3390/metabo14120699 - 11 Dec 2024

Abstract

Background/objectives: The acute stress response affects brain metabolites closely linked to the tricarboxylic acid (TCA) cycle. This response involves time-dependent changes in hormones and neurotransmitters, which contribute to resilience and the ability to adapt to acute stress while maintaining homeostasis. This physiological mechanism [...] Read more.

Background/objectives: The acute stress response affects brain metabolites closely linked to the tricarboxylic acid (TCA) cycle. This response involves time-dependent changes in hormones and neurotransmitters, which contribute to resilience and the ability to adapt to acute stress while maintaining homeostasis. This physiological mechanism of metabolic dynamics, combined with time-series analysis, has prompted the development of new methods to observe the relationship between TCA cycle-related brain metabolites. This study aimed to observe the acute stress response through metabolic interactions using time-series proton magnetic resonance spectroscopy (1H-MRS) in the left hippocampus of mice. Methods: In this study, 4-week-old male C57BL/6N mice (n = 24) were divided into control (n = 12) and acute stress groups (n = 12). Acute stress was induced through a 2 h restraint protocol. Time-series 1H-MRS data were obtained on the left hippocampus of both groups using a 9.4 T 1H-MRS scanner. Time-series MRS data were quantified using LCModel, and significant metabolic interactions were identified through Spearman correlation analysis, a one-tailed sign test, and false discovery rate correction. Results: No significant metabolic correlation coefficient was observed in the control group. However, in the acute stress group, glutathione (GSH) and N-acetyl aspartate (NAA) showed a significant positive correlation over time, with a high correlation coefficient exceeding 0.5. Conclusions: Temporal measurement of GSH and NAA, combined with correlation analysis, offers a comprehensive understanding for the metabolic dynamics during acute stress. This approach emphasizes their distinct roles and interdependence in the progression of oxidative stress, mitochondrial function, and the maintenance of physiological homeostasis. Full article

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

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15 pages, 1109 KiB

Open AccessArticle

Using Serum Metabolomic Signatures to Investigate Effects of Acupuncture on Pain-Fatigue-Sleep Disturbance in Breast Cancer Survivors

by Hongjin Li, Ardith Z. Doorenbos, Yinglin Xia, Jun Sun, Hannah Choi, Richard E. Harris, Shuang Gao, Katy Sullivan and Judith M. Schlaeger

Metabolites 2024, 14(12), 698; https://doi.org/10.3390/metabo14120698 - 10 Dec 2024

Abstract

Background/Objectives: Acupuncture is an efficacious integrative therapy for treating pain, fatigue, and sleep disturbance (the psychoneurological symptom cluster) in breast cancer survivors. However, the mechanisms underlying its effects remain unclear, and related metabolomics studies are limited. This study aimed to examine serum metabolite [...] Read more.

Background/Objectives: Acupuncture is an efficacious integrative therapy for treating pain, fatigue, and sleep disturbance (the psychoneurological symptom cluster) in breast cancer survivors. However, the mechanisms underlying its effects remain unclear, and related metabolomics studies are limited. This study aimed to examine serum metabolite changes after acupuncture and their relationships to symptom improvement. Methods: Forty-two breast cancer survivors experiencing pain, fatigue, and sleep disturbance participated in a single-arm acupuncture trial. They received a 10-session acupuncture intervention over 5 weeks. Fasting blood samples and symptom surveys were collected before and after the acupuncture intervention, and untargeted metabolomics profiling was conducted on serum samples. Mixed-effects models adjusting for covariates (age, race, body mass index, and antidepressant use) were applied for analysis. Results: After acupuncture, there was a significant reduction in the psychoneurological symptom cluster (mean reduction = −6.2, p < 0.001).Bonferroni correction was applied to 40 independent metabolite clusters (α = 0.00125); cysteine-glutathione disulfide (p = 0.0006) significantly increased, and retinal (p = 0.0002) and cis-urocanate (p = 0.0005) were significantly decreased. Dimethyl sulfone (p = 0.00139) showed a trend towards reduction after acupuncture and its change (p = 0.04, β =1.97) was positively associated with reduction in the psychoneurological symptom cluster. Also, increased lauroylcarnitine (p = 0.0009) and decreased cytosine (p = 0.0008) can modulate the therapeutic effects of acupuncture. Conclusions: Acupuncture demonstrates beneficial effects on the psychoneurological symptom cluster in breast cancer survivors. Dimethyl sulfone may be a promising mediator in the relationship between acupuncture and psychoneurological symptoms, while acylcarnitine metabolism may modulate the therapeutic effect of acupuncture. Full article

(This article belongs to the Special Issue Investigation of the Metabolic Mechanisms Underlying Breast Cancer: Navigating from Diagnosis to Survivorship)

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22 pages, 984 KiB

Open AccessReview

Molecular Mechanism of Indoor Exposure to Airborne Halogenated Flame Retardants TCIPP (Tris(1,3-Dichloro-2-Propyl) Phosphate) and TCEP Tris(2-chloroethyl) Phosphate and Their Hazardous Effects on Biological Systems

by Albatul Alharbi and Muhanad Alhujaily

Metabolites 2024, 14(12), 697; https://doi.org/10.3390/metabo14120697 - 10 Dec 2024

Abstract

TCIPP (tris(1,3-dichloro-2-propyl) phosphate) and TCEP (tris(2-chloroethyl) phosphate) are organophosphate ester flame retardants found in various consumer products, posing significant health and environmental risks through inhalation, ingestion, and dermal exposure. Research reveals these compounds cause oxidative stress, inflammation, endocrine disruption, genotoxicity, neurotoxicity, and potentially [...] Read more.

TCIPP (tris(1,3-dichloro-2-propyl) phosphate) and TCEP (tris(2-chloroethyl) phosphate) are organophosphate ester flame retardants found in various consumer products, posing significant health and environmental risks through inhalation, ingestion, and dermal exposure. Research reveals these compounds cause oxidative stress, inflammation, endocrine disruption, genotoxicity, neurotoxicity, and potentially hepatotoxicity, nephrotoxicity, cardiotoxicity, developmental, reproductive, and immunotoxicity. This review summarizes the current knowledge on the toxicological mechanisms of TCIPP and TCEP and presents the latest data on their toxicological effects obtained in vitro and in vivo, using omic systems, and on the basis of computational modelling. It also elaborates on the scope of further toxicities and highlights the necessity of ongoing mechanistic research, integration of new technologies, and successful transfer of the acquired knowledge into risk evaluation, policies and regulations, and the creation of safer products. Since flame retardants are already present in homes, schools, offices, and daycare centres, efforts to scale back the exposure to these chemicals, most especially the hazardous ones, must be made to protect human health and the environment. Therefore, effective and timely prevention, based upon a deep knowledge of the entire toxicological profile of these substances, is the only way to face this difficult toxicological issue and provide for a healthy and safe future. Full article

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

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16 pages, 2114 KiB

Open AccessArticle

Untargeted Metabolomics Reveals Dysregulation of Glycine- and Serine-Coupled Metabolic Pathways in an ALDH1L1-Dependent Manner In Vivo

by Grace Fu, Sabrina Molina, Sergey A. Krupenko, Susan Sumner and Blake R. Rushing

Metabolites 2024, 14(12), 696; https://doi.org/10.3390/metabo14120696 - 10 Dec 2024

Abstract

Background: ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 [...] Read more.

Background: ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂ in a NADP⁺-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, Aldh1l1 knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine. Serine and glycine play crucial roles in pathways linked to cancer initiation and progression, including one-carbon metabolism. Objective/Methods: To further investigate the metabolic role of ALDH1L1, an untargeted metabolomic analysis was conducted on the liver and plasma of both KO and wild-type (WT) male and female mice. Since ALDH1L1 affects glycine- and serine-coupled metabolites and metabolic pathways, correlation analyses between liver glycine and serine with other liver or plasma metabolites were performed for both WT and KO mice. Significantly correlated metabolites were input into MetaboAnalyst 5.0 for pathway analysis to uncover metabolic pathways coupled with serine and glycine in the presence or absence of ALDH1L1 expression. Results: This analysis showed substantial alterations in pathways associated with glycine and serine following ALDH1L1 loss, including the amino acid metabolism, antioxidant pathways, fatty acid oxidation, and vitamin B5 metabolism. These results indicate the glycine- and serine-linked metabolic reprogramming following ALDH1L1 loss to support macromolecule biosynthesis and antioxidant defense. Additional research is required to further explore the correlation between specific alterations in these pathways and tumor growth, as well as to identify potential dietary interventions to mitigate the detrimental effects of ALDH1L1 loss. Full article

(This article belongs to the Special Issue Metabolomics Techniques in Nutrition and Pharmacy Research)

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17 pages, 3163 KiB

Open AccessArticle

Intracellular and Extracellular Metabolic Response of the Lactic Acid Bacterium Weissella confusa Under Salt Stress

by Ali Wang, Qinqin Du, Xiaomin Li, Yimin Cui, Jiahua Luo, Cairong Li, Chong Peng, Xianfeng Zhong and Guidong Huang

Metabolites 2024, 14(12), 695; https://doi.org/10.3390/metabo14120695 - 10 Dec 2024

Abstract

Background: Weissella confusa is a member of the lactic acid bacterium group commonly found in many salt-fermented foods. Strains of W. confusa isolated from high-salinity environments have been shown to tolerate salt stress to some extent. However, the specific responses and mechanisms of [...] Read more.

Background: Weissella confusa is a member of the lactic acid bacterium group commonly found in many salt-fermented foods. Strains of W. confusa isolated from high-salinity environments have been shown to tolerate salt stress to some extent. However, the specific responses and mechanisms of W. confusa under salt stress are not fully understood. Methods: To study the effect of NaCl stress on W. confusa, growth performance and metabolite profiles of the strains were compared between a NaCl-free group and a 35% NaCl-treated group. Growth performance was assessed by measuring viable cell counts and examining the cells using scanning electron microscopy (SEM). Intracellular and extracellular metabolites were analyzed by non-targeted metabolomics based on liquid chromatography-mass spectrometry (LC-MS). Results: It was found that the viable cell count of W. confusa decreased with increasing salinity, and cells could survive even in saturated saline (35%) medium for 24 h. When exposed to 35% NaCl, W. confusa cells exhibited surface pores and protein leakage. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, 42 different metabolites were identified in the cells and 18 different metabolites in the culture medium. These different metabolites were mainly involved in amino acid metabolism, carbohydrate metabolism, and nucleotide metabolism. In addition, salt-exposed cells exhibited higher levels of intracellular ectoine and lactose, whose precursors, such as aspartate, L-2,4-diaminobutanoate, and galactinol, were reduced in the culture medium. Conclusions: This study provides insight into the metabolic responses of W. confusa under salt stress, revealing its ability to maintain viability and alter metabolism in response to high NaCl concentrations. Key metabolites such as ectoine and lactose, as well as changes in amino acid and nucleotide metabolism, may contribute to its tolerance to salt. These findings may improve our understanding of the bacterium’s survival mechanisms and have potential applications in food fermentation and biotechnology. Full article

(This article belongs to the Section Plant Metabolism)

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14 pages, 7233 KiB

Open AccessArticle

Non-Targeted Metabolomics Analysis Reveals Metabolite Profiles Change During Whey Fermentation with Kluyveromyces marxianus

by Yansong Gao, Lei Gao, You Kang, Ge Yang, Zijian Zhao, Yujuan Zhao and Shengyu Li

Metabolites 2024, 14(12), 694; https://doi.org/10.3390/metabo14120694 - 9 Dec 2024

Abstract

Background: Whey fermentation could produce bioactive substances with immunomodulatory effects, metabolic syndrome modulation, and antioxidant properties, thereby imparting functional characteristics to products and facilitating the development of novel foods with health-promoting potential. Methods: A non-targeted metabolomics approach using liquid chromatography–mass spectrometry (LC-MS) was [...] Read more.

Background: Whey fermentation could produce bioactive substances with immunomodulatory effects, metabolic syndrome modulation, and antioxidant properties, thereby imparting functional characteristics to products and facilitating the development of novel foods with health-promoting potential. Methods: A non-targeted metabolomics approach using liquid chromatography–mass spectrometry (LC-MS) was employed to investigate changes in the metabolite profiles of whey fermented by Kluyveromyces marxianus strain KM812 over varying fermentation durations. Results: The findings demonstrated a progressive enrichment of metabolites over time. A total of 151 differential metabolites were identified and categorized primarily into amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, as well as benzoic acids and derivatives. The highest relative content of whey metabolites was observed at 48 h of fermentation, with a cumulative increase of 1.45-fold, 1.49-fold, 3.39-fold, and 1.24-fold for peptides and amino acids, peptides, and analogues, fatty acids and conjugates, and carbohydrates and conjugates, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed associations with 23 specific metabolites and delineated 9 metabolic pathways, predominantly involved in amino acid and lipid metabolism. Conclusions: Based on the above, KM812 could effectively degrade macromolecular substances in whey into small molecules such as L-isoleucine, ornithine, betaine, α-linolenic acid, and palmitoleic acid, thereby influencing the nutritional and functional properties of whey. In-depth analysis of the metabolic products in KM812-fermented whey could provide a theoretical basis for the development of functional foods derived from small molecules in the future. Full article

(This article belongs to the Section Food Metabolomics)

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15 pages, 2093 KiB

Open AccessArticle

Exploring the In Vitro Effects of Zingerone on Differentiation and Signalling Pathways in Bone Cell Lines

by Brunhildé De Vos, Abe E. Kasonga, Anna M. Joubert and Trevor T. Nyakudya

Metabolites 2024, 14(12), 693; https://doi.org/10.3390/metabo14120693 - 9 Dec 2024

Abstract

Objective: Ensuring adequate bone health is crucial for preventing conditions such as osteoporosis and fractures. Zingerone, a phytonutrient isolated from cooked ginger, has gained attention for its potential benefits in bone health. This study evaluated the osteoprotective potential of zingerone and its effects [...] Read more.

Objective: Ensuring adequate bone health is crucial for preventing conditions such as osteoporosis and fractures. Zingerone, a phytonutrient isolated from cooked ginger, has gained attention for its potential benefits in bone health. This study evaluated the osteoprotective potential of zingerone and its effects on differentiation and signalling pathways in vitro using SAOS-2 osteosarcoma and RAW264.7 macrophage cell lines, aiming to elucidate its mechanism of action in bone remodelling. Methods: SAOS-2 osteosarcoma and RAW264.7 macrophage cells were treated with zingerone at concentrations of 200 µM. Osteoblast differentiation was assessed by alkaline phosphatase (ALP) activity, bone mineralisation via Alizarin Red S stain, and gene expression markers (ALP, runt-related transcription factor 2 (Runx2), and osteocalcin) via quantitative polymerase chain reaction (q-PCR). Osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining, TRAP activity, and mitogen-activated protein kinase (MAPK) pathways. Results: Treatment with zingerone was non-toxic at 200 µM. Zingerone (200 µM) significantly stimulated the gene expression of ALP and Runx2 in SAOS-2 cells (p < 0.05) without statistically significantly enhancing SAOS-2 mineralisation via calcium deposits. Moreover, zingerone significantly inhibited osteoclast differentiation in RAW264.7 cells as evidenced by reduced TRAP staining and activity (p < 0.05). Conclusions: Zingerone shows promise in reducing osteoclast activity and supporting early osteoblast differentiation, suggesting its potential as a dietary supplement for bone health. Further in vivo and clinical studies are needed to confirm its role in managing osteoporosis. Full article

(This article belongs to the Special Issue Advances in Phytomedicine Intervention on Metabolic Disorders)

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17 pages, 3918 KiB

Open AccessArticle

Long-Term Aerobic Exercise Enhances Hepatoprotection in MAFLD by Modulating Exosomal miR-324 via ROCK1

by Yang Zhang, Qiangman Wei, Xue Geng and Guoliang Fang

Metabolites 2024, 14(12), 692; https://doi.org/10.3390/metabo14120692 - 9 Dec 2024

Abstract

Background: Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms—particularly those involving exosomal pathways—are not fully elucidated. Method: Exosomes were isolated from 15 MAFLD patients’ [...] Read more.

Background: Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms—particularly those involving exosomal pathways—are not fully elucidated. Method: Exosomes were isolated from 15 MAFLD patients’ plasma following the final session of a 12-week aerobic exercise intervention. Liver fat content was measured using MRI-PDFF, and metabolic parameters were assessed via OGTT, HOMA-IR, QUICKI, and VO₂ max. Co-culture experiments evaluated the effects of exercise-derived exosomes on IR signaling pathways. miRNA microarray analysis identified miR-324, which was quantified in high-fat diet (HFD) mice with and without exercise and compared between athletes and sedentary controls. Functional assays assessed miR-324’s role in glucose and lipid metabolism, while luciferase reporter and Western blot assays confirmed ROCK1 as its direct target. Result: Aerobic exercise significantly reduced liver fat and improved insulin sensitivity in both MAFLD patients and HFD mice. Notably, exosomal miR-324 levels were lower in athletes than sedentary controls, indicating an inverse association with insulin sensitivity. Post-exercise, precursor and mature miR-324 increased in adipose tissue and decreased in muscle, suggesting its adipose origin and inverse regulation. Functional assays demonstrated that miR-324 modulates insulin resistance by targeting ROCK1. Conclusion: Exercise-induced exosomal miR-324 from adipose tissue targets ROCK1, revealing a novel mechanism by which aerobic exercise confers hepatoprotection against insulin resistance in MAFLD. These findings enhance our understanding of how exercise influences metabolic health and may inform future therapeutic strategies for managing MAFLD and related conditions. Full article

(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome)

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12 pages, 863 KiB

Open AccessArticle

A Ketogenic Diet Followed by Gradual Carbohydrate Reintroduction Restores Menstrual Cycles in Women with Polycystic Ovary Syndrome with Oligomenorrhea Independent of Body Weight Loss: Results from a Single-Center, One-Arm, Pilot Study

by Rebecca Rossetti, Vittoria Strinati, Alessandra Caputi, Renata Risi, Maria Letizia Spizzichini, Alessandro Mondo, Lorenzo Spiniello, Carla Lubrano, Antonella Giancotti, Dario Tuccinardi, Lucio Gnessi and Mikiko Watanabe

Metabolites 2024, 14(12), 691; https://doi.org/10.3390/metabo14120691 - 8 Dec 2024

Abstract

Background/Objectives: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of fertile age. Some studies suggest that a ketogenic diet (KD) may have a role in treating PCOS. We aimed to demonstrate the long-term effectiveness of a KD in PCOS. [...] Read more.

Background/Objectives: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of fertile age. Some studies suggest that a ketogenic diet (KD) may have a role in treating PCOS. We aimed to demonstrate the long-term effectiveness of a KD in PCOS. Methods: Eighteen patients with PCOS phenotype A were enrolled: 28% were of normal weight, 28% were overweight, and 44% had obesity. All participants followed a KD without meal replacements for 45 days. After this period, patients underwent gradual carbohydrate reintroduction over 45 days, and thereafter healthy eating indications were given. Twelve patients completed the study. The patients were assessed at baseline and after 6 months. Anthropometric data, body composition, pelvic ultrasound, blood chemistry, hirsutism, and menstrual cycles frequency were recorded; Results: Besides improvement in anthropometric parameters, menstrual cycles (p 0.012), ovarian volume (p 0.029), FSH (p 0.05), LH (p 0.037), and progesterone (p 0.017) improved independently of weight or fat loss. However, testosterone and hirsutism improvements were influenced by weight and fat mass reduction. Conclusions: Our study showed that a KD followed by gradual carbohydrate reintroduction in PCOS has beneficial effects medium term, mostly independent of body weight loss, even in normal-weight women, suggesting that nutritional ketosis exerts beneficial effects per se. Full article

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

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11 pages, 544 KiB

Open AccessArticle

Protective Effects of a Brassica nigra Sprout Hydroalcoholic Extract on Lipid Homeostasis, Hepatotoxicity, and Nephrotoxicity in Cyclophosphamide-Induced Toxicity in Rats

by Hassan Barakat, Thamer Aljutaily, Raghad I. Alkhurayji, Huda Aljumayi, Khalid S. Alhejji and Sami O. Almutairi

Metabolites 2024, 14(12), 690; https://doi.org/10.3390/metabo14120690 - 8 Dec 2024

Abstract

Background: Brassica nigra possesses a significant concentration of bioactive compounds and has been demonstrated to have a variety of pharmacological properties, although its sprout has not been extensively studied. Thus, the protective effects of Brassica nigra sprout hydroalcoholic extract (BNSE) on lipid [...] Read more.

Background: Brassica nigra possesses a significant concentration of bioactive compounds and has been demonstrated to have a variety of pharmacological properties, although its sprout has not been extensively studied. Thus, the protective effects of Brassica nigra sprout hydroalcoholic extract (BNSE) on lipid homeostasis, hepatotoxicity, and nephrotoxicity in cyclophosphamide (CYP)-induced toxicity in rats were examined in this study. Methods: Four experimental rat groups (n = 8 for each group) were examined as follows: NR, normal rats that received normal saline by oral gavage daily; CYP, injected with a single dose of CYP at 250 mg kg⁻¹ intraperitoneally (i.p.) and did not receive any treatment, receiving only normal saline by oral gavage daily; CYP + BNSE250, injected with a single dose of CYP at 250 mg kg⁻¹ i.p. and treated with BNSE at 250 mg kg⁻¹ by oral gavage daily for three weeks; and CYP + BNSE500, injected with a single dose of CYP at 250 mg kg⁻¹ i.p. and treated with BNSE at 500 mg kg⁻¹ by oral gavage daily for three weeks. Results: The results indicated a significant increase (p < 0.05) in triglyceride (TG), cholesterol (CHO), low-density lipoprotein cholesterol (LDL-c), and very low-density lipoprotein cholesterol (VLDL-c) levels in CYP-induced toxicity rats. The administration of BNSE at 250 and 500 mg kg⁻¹ significantly (p < 0.05) attenuated TG, CHO, LDL-c, and VLDL-c at values comparable with the NR group. The most efficient treatment for improving the lipid profile and atherogenicity complication was BNSE at 500 mg kg⁻¹, performing even better than 250 mg kg⁻¹. Administrating BNSE at 250 or 500 mg kg⁻¹ improved the liver’s function in a dose-dependent manner. Comparing the lower dose of 250 mg kg⁻¹ of BNSE with 500 mg kg⁻¹ showed that administrating 250 mg kg⁻¹ attenuated alanine transaminase (ALT) by 28.92%, against 33.36% when 500 mg kg⁻¹ was given. A similar trend was observed in aspartate aminotransferase (AST), where 19.44% was recorded for BNSE at 250 mg kg⁻¹ and 34.93% for BNSE at 500 mg kg⁻¹. Higher efficiency was noticed for BNSE at 250 and 500 mg kg⁻¹ regarding alkaline phosphatase (ALP). An improvement of 38.73% for BNSE at 500 mg kg⁻¹ was shown. The best treatment was BNSE at 500 mg kg⁻¹, as it markedly improved liver function, such as total bilirubin (T.B.), in a dose-dependent manner. The administration of BNSE attenuated the total protein (T.P.), albumin, and globulin levels to be close to or higher than the typical values in NR rats. Conclusions: BNSE might be used for its promising hypolipidemic, hepatoprotective, and nephroprotective potential and to prevent diseases related to oxidative stress. Further research on its application in humans is highly recommended. Full article

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

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15 pages, 3781 KiB

Open AccessArticle

Metabolic Alterations of Short-Chain Organic Acids in the Elderly Link Antibiotic Exposure with the Risk for Depression

by Shujing Sun, Li Kong, Fangting Hu, Sheng Wang, Menglong Geng, Hongjuan Cao, Xingyong Tao, Fangbiao Tao and Kaiyong Liu

Metabolites 2024, 14(12), 689; https://doi.org/10.3390/metabo14120689 - 7 Dec 2024

Abstract

Background: Our previous study showed that antibiotic exposure was linked to depressive symptomatology in community-dwelling older adults in China. Our current study aims to explore the underlying mechanisms by assessing the intermediated effects of circulating short-chain organic acids (SCOAs) on this association. Methods: [...] Read more.

Background: Our previous study showed that antibiotic exposure was linked to depressive symptomatology in community-dwelling older adults in China. Our current study aims to explore the underlying mechanisms by assessing the intermediated effects of circulating short-chain organic acids (SCOAs) on this association. Methods: Depressive symptoms were screened by the 30-item Geriatric Depression Scale (GDS-30). Urinary concentrations of antibiotics and serum SCOAs were measured using a liquid chromatography–mass spectrometry method. Results: Increased exposure to sulfadiazine, azithromycin, tetracyclines, or veterinary antibiotics (VAs) was positively associated with GDS-30 scores. Tetracycline reduced levels of caproic acid, iso-butyric acid, and iso-caproic acid (iso-CA), with iso-CA concentration inversely correlating with GDS-30 scores, while β-hydroxybutyric acids showed a positive correlation. The mediating effect of serum iso-CA on the association between depression and ofloxacin, with a mediating effect of 25.3%, and the association between depression and tetracycline, with a mediating effect of 46.3%, were both statistically significant, indicating partial mediation. Conclusions: Antibiotics may affect the levels of SCOAs in older adults and could potentially contribute to depressive symptoms by influencing alterations in serum iso-CA levels. Full article

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

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14 pages, 8565 KiB

Open AccessArticle

Role of Milk Intake in Modulating Serum Lipid Profiles and Gut Metabolites

by Ting Xu, Chang Zhang, Yufeng Yang, Liang Huang, Qingyou Liu, Ling Li, Qingkun Zeng and Zhipeng Li

Metabolites 2024, 14(12), 688; https://doi.org/10.3390/metabo14120688 - 7 Dec 2024

Abstract

Background/Objectives: Milk is one of the main sources of nutrition in people’s daily diet, but the fat in milk raises health concerns in consumers. Here, we aimed to elucidate the impact of Buffalo milk and Holstein cow milk consumption on blood lipid health [...] Read more.

Background/Objectives: Milk is one of the main sources of nutrition in people’s daily diet, but the fat in milk raises health concerns in consumers. Here, we aimed to elucidate the impact of Buffalo milk and Holstein cow milk consumption on blood lipid health through metabolomics analysis. Methods: Golden hamsters were administered Murrah Buffalo milk (BM) or Holstein cow milk (HM), and the body weight and serum lipid indicators were tested and recorded. The hamsters receiving equal amounts of physiological saline were used as the negative control (NC). Serum and fecal samples were collected, and LC-MS was used to identify the metabolites in the samples. Results: The results showed that both the BM and HM groups exhibited a significant reduction in body weight compared to that of the NC group from day 9, and the serum TG, TC, and LDL-C levels were significantly lower than those of the NC group. Further analysis identified 564 and 567 metabolites in the serum and fecal samples shared in the BM and HM groups and significantly different from those in the NC group, which were mainly enriched in the pathways related to lipid metabolism, such as fatty acid biosynthesis, arachidonic acid metabolism, and primary bile acid biosynthesis. Correlation analysis further suggested that milk intake can increase the levels of Muramic Acid, Oleoyl Ethanolamide, Seratrodast, Chenodeoxycholic Acid, Docosahexaenoic Acid Ethyl Ester, and Deoxycholic Acid in the serum and gut microbiota, which may affect TG, TC, HDL-C, and LDL-C in the serum, and thereby benefit the body’s lipid health. Conclusions: The results further confirmed that milk intake has a beneficial effect on blood lipid health by altering multiple metabolites in the serum and the gut. This study provides novel evidence that milk consumption is beneficial to health and is a reference for guiding people to a healthy diet. Full article

(This article belongs to the Special Issue Nutritional and Metabolic Influences on Animal Growth and Reproduction)

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15 pages, 3309 KiB

Open AccessArticle

Multi-Omics Analysis Provides Insights into Green Soybean in Response to Cold Stress

by Yanhui Lin, Guangping Cao, Jing Xu, Honglin Zhu and Liqiong Tang

Metabolites 2024, 14(12), 687; https://doi.org/10.3390/metabo14120687 - 7 Dec 2024

Abstract

Green soybean (Glycine max (L.) Merrill) is a highly nutritious food that is a good source of protein and fiber. However, it is sensitive to low temperatures during the growing season, and enhancing cold tolerance has become a research hotspot for breeding [...] Read more.

Green soybean (Glycine max (L.) Merrill) is a highly nutritious food that is a good source of protein and fiber. However, it is sensitive to low temperatures during the growing season, and enhancing cold tolerance has become a research hotspot for breeding improvement. Background/Objectives: The underlying molecular mechanisms of cold tolerance in green soybean are not well understood. Methods: Here, a comprehensive analysis of transcriptome and metabolome was performed on a cold-tolerant cultivar treated at 10 °C for 24 h. Results: Compared to control groups, we identified 17,011 differentially expressed genes (DEGs) and 129 differentially expressed metabolites (DEMs). The DEGs and DEMs were further subjected to KEGG functional analysis. Finally, 11 metabolites (such as sucrose, lactose, melibiose, and dehydroascorbate) and 17 genes (such as GOLS, GLA, UGDH, and ALDH) were selected as candidates associated with cold tolerance. Notably, the identified metabolites and genes were enriched in two common pathways: ‘galactose metabolism’ and ‘ascorbate and aldarate metabolism’. Conclusions: The findings suggest that green soybean modulates the galactose metabolism and ascorbate and aldarate metabolism pathways to cope with cold stress. This study contributes to a deeper understanding of the complex molecular mechanisms enabling green soybeans to better avoid low-temperature damage. Full article

(This article belongs to the Special Issue Metabolic Responses to Abiotic Stress in Plants: Latest Advances and Prospects)

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9 pages, 912 KiB

Open AccessCommunication

Calcitriol Concentration in the Early Phase of Myocardial Infarction and Its Relation to Left Ventricular Ejection Fraction

by Szymon Olędzki, Aldona Siennicka, Dominika Maciejewska-Markiewicz, Ewa Stachowska, Natalia Jakubiak, Radosław Kiedrowicz, Karolina Jakubczyk, Karolina Skonieczna-Żydecka, Izabela Gutowska and Jarosław Kaźmierczak

Metabolites 2024, 14(12), 686; https://doi.org/10.3390/metabo14120686 - 6 Dec 2024

Abstract

Vitamin D deficiency is one of the most common metabolic disorders in the European population. A low level of 25-OH vitamin D3 is related to an elevated risk of myocardial infarction (MI). The aim of our study was to examine the relationship between [...] Read more.

Vitamin D deficiency is one of the most common metabolic disorders in the European population. A low level of 25-OH vitamin D3 is related to an elevated risk of myocardial infarction (MI). The aim of our study was to examine the relationship between calcidiol and calcitriol serum concentration and left ventricular ejection fraction early after interventional treatment for acute coronary syndrome. A total of 80 patients diagnosed with MI, who underwent primary percutaneous coronary intervention, were included in the study. Blood samples for calcidiol, calcitriol, and vitamin D-binding protein were obtained 24 h after primary PCI and were measured using an enzyme-linked immunosorbent assay. Only 9% of patients had a proper level of 25-OHD3 in the serum (30–80 ng/mL). A total of 16% of patients revealed a suboptimal concentration of 25-OHD3 (20–30 ng/mL), and in 75% of patients, the concentration of 25-OHD3 was lower than 20 ng/mL. Moreover, patients with left ventricle ejection fraction of <40% had significantly lower concentrations of calcidiol and calcitriol. A low calcitriol serum concentration affects post-MI left ventricle ejection fraction early after myocardial infarction onset. It seems that 1.25(OH)D3 may contribute to acute myocardial infarction; however, there are insufficient clinical trials related to this topic, and the available evidence is mainly from in vitro studies. We hope these preliminary reports will provide a better understanding of post-MI. Full article

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

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14 pages, 5767 KiB

Open AccessArticle

Early Diagnosis of Bloodstream Infections Using Serum Metabolomic Analysis

by Shuang Han, Ruihua Li, Hao Wang, Lin Wang, Yiming Gao, Yaolin Wen, Tianyang Gong, Shiyu Ruan, Hui Li and Peng Gao

Metabolites 2024, 14(12), 685; https://doi.org/10.3390/metabo14120685 - 6 Dec 2024

Abstract

Background: Bloodstream infections (BSIs) pose a great challenge to treating patients, especially those with underlying diseases, such as immunodeficiency diseases. Early diagnosis helps to direct precise empirical antibiotic administration and proper clinical management. This study carried out a serum metabolomic analysis using blood [...] Read more.

Background: Bloodstream infections (BSIs) pose a great challenge to treating patients, especially those with underlying diseases, such as immunodeficiency diseases. Early diagnosis helps to direct precise empirical antibiotic administration and proper clinical management. This study carried out a serum metabolomic analysis using blood specimens sampled from patients with a suspected infection whose routine culture results were later demonstrated to be positive. Methods: A liquid chromatograph-mass spectrometry-based metabolomic analysis was carried out to profile the BSI serum samples. The serum metabolomics data could be used to successfully differentiate BSIs from non-BSIs. Results: The major classes of the isolated pathogens (e.g., Gram-positive and Gram-negative bacteria) could be differentiated using our optimized statistical algorithms. In addition, by using different machine-learning algorithms, the isolated pathogens could also be classified at the species levels (e.g., Escherichia coli and Klebsiella pneumoniae) or according to their specific antibiotic-resistant phenotypes (e.g., extended-spectrum β-lactamase-producing and non-producing phenotypes) if needed. Conclusions: This study provides an early diagnosis method that could be an alternative to the traditional time-consuming culture process to identify BSIs. Moreover, this metabolomics strategy was less affected by several risk factors (e.g., antibiotics administration) that could produce false culture results. Full article

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

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