Metabolites

24 pages, 3424 KiB

Open AccessArticle

Oxidative Stress, Energy Metabolism Disorder, Mitochondrial Damage, and miR-144 Participated in Molecular Mechanisms of 4-Octylphenol-Caused Cardiac Autophagic Damage in Common Carps (Cyprinus carpio L.)

by Minna Qiu, Chunyu Jiang, Jiatian Liang, Qin Zhou, Yuhao Liu, Zhiyu Hao, Yuhang Liu, Xiumei Liu, Xiaohua Teng, Wei Sun and You Tang

Metabolites 2025, 15(6), 391; https://doi.org/10.3390/metabo15060391 (registering DOI) - 11 Jun 2025

Abstract

Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for [...] Read more.

Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for studying the toxic effects of environmental pollutants on fish. Its heart is susceptible to toxicants. However, whether 4-OP has a toxic effect on common carp heart remains unknown. Methods: Here, we conducted a common carp 4-OP exposure experiment (carp treated with 17 μg/L 4-OP for 45 days), aiming to investigate whether 4-OP has a toxic effect on common carp hearts. We observed the microstructure and ultrastructure of carp heart and detected autophagy genes, mitochondrial fission genes, mitochondrial fusion genes, glycolytic enzymes, AMPK, ATPase, and oxidative stress factors, to investigate the molecular mechanism of 4-OP induced damage in common carp hearts. Results: Our results showed that 4-OP exposure caused mitochondrial damage, autophagy, and damage in common carp hearts. 4-OP exposure increased the levels of miR-144, and eight autophagy factors (Beclin1, RB1CC1, ULK1, LC3-I, LC3-II, ATG5, ATG12, and ATG13), and decreased the levels of four autophagy factors (PI3K, AKT, mTOR, and SQSTM1). Furthermore, 4-OP exposure induced the imbalance between mitochondrial fission and fusion and mitochondrial dynamics imbalance, as demonstrated by the increase in three mitochondrial fission factors (Mff, Drp1, and Fis1) and the decrease in three mitochondrial fusion factors (Mfn1, Mfn2, and Opa1). Moreover, excess 4-OP treatment caused energy metabolism disorder, as demonstrated by the reduction in four ATPase (Na⁺K⁺-ATPase, Ca²⁺Mg²⁺-ATPase, Ca²⁺-ATPase, and Mg²⁺-ATPase), elevation in four glycolysis genes (HK1, HK2, LDHA, and PGK1), reduction in glycolysis gen (PGAM2), and the elevation in energy-sensing AMPK. Finally, 4-OP treatment induced the imbalance between antioxidant and oxidant and oxidative stress, as demonstrated by the increase in oxidant H₂O₂, and the decreases in five antioxidant factors (CAT, SOD, T-AOC, Nrf2, and HO-1). Conclusions: miR-144 mediated autophagy by targeting PI3K, mTOR, and SQSTM1, and the miR-144/PI3K-AKT-mTOR/ULK1 pathway was involved in 4-OP-induced autophagy. Mff-Drp1 axis took part in 4-OP-caused mitochondrial dynamics imbalance, and mitochondrial dynamics imbalance mediated autophagy via Mfn2-SQSTM1, Mfn2/Beclin1, and Mff-LC3-II axes. Energy metabolism disorder mediated mitochondrial dynamics imbalance through the AMPK-Mff-Drp1 pathway. Oxidative stress mediated energy metabolism disorder via the H₂O₂-AMPK axis. Taken together, oxidative stress triggered energy metabolism disorder, induced mitochondrial dynamics imbalance, and caused autophagy via the H₂O₂-AMPK-Mff-LC3-II pathway. Our study provided references for the toxic effects of endocrine disruptor on common carp hearts, and provided a basis for assessing environmental pollutant-induced damage in common carp heart. We only studied the toxic effects of 4-OP on common carp, and the toxic effects of 4-OP on other fish species need to be further studied. Full article

(This article belongs to the Section Cell Metabolism)

► Show Figures

Figure 1

15 pages, 1361 KiB

Open AccessReview

Gut Microbiome Dysbiosis and Its Impact on Reproductive Health: Mechanisms and Clinical Applications

by Efthalia Moustakli, Sofoklis Stavros, Periklis Katopodis, Anastasios Potiris, Peter Drakakis, Stefanos Dafopoulos, Athanasios Zachariou, Konstantinos Dafopoulos, Konstantinos Zikopoulos and Athanasios Zikopoulos

Metabolites 2025, 15(6), 390; https://doi.org/10.3390/metabo15060390 - 11 Jun 2025

Abstract

The human gut microbiome is integral to maintaining systemic physiological balance, with accumulating evidence emphasizing its critical role in reproductive health. This review investigates the bidirectional interactions between the gut microbiota and the female reproductive system, mediated by neuroendocrine, immune, and metabolic pathways, [...] Read more.

The human gut microbiome is integral to maintaining systemic physiological balance, with accumulating evidence emphasizing its critical role in reproductive health. This review investigates the bidirectional interactions between the gut microbiota and the female reproductive system, mediated by neuroendocrine, immune, and metabolic pathways, constituting the gut–reproductive axis. Dysbiosis, characterized by microbial imbalance, has been linked to reproductive disorders such as polycystic ovary syndrome (PCOS), endometriosis, infertility, impaired spermatogenesis, and pregnancy complications. These associations can be explained by immunological dysregulation, systemic inflammation, altered sex hormone metabolism, and hypothalamic–pituitary–gonadal (HPG) axis disturbances. This review aims to clarify the molecular and cellular mechanisms underpinning gut–reproductive interactions and to evaluate the feasibility of microbiome-targeted therapies as clinical interventions for improving reproductive outcomes. Full article

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

► Show Figures

Figure 1

23 pages, 972 KiB

Open AccessSystematic Review

Salivaomics: New Frontiers in Studying the Relationship Between Periodontal Disease and Alzheimer’s Disease

by Giuseppina Malcangi, Grazia Marinelli, Alessio Danilo Inchingolo, Irma Trilli, Laura Ferrante, Lucia Casamassima, Paola Nardelli, Francesco Inchingolo, Andrea Palermo, Angelo Michele Inchingolo and Gianna Dipalma

Metabolites 2025, 15(6), 389; https://doi.org/10.3390/metabo15060389 - 10 Jun 2025

Abstract

Background: This study explores the link between oral biofluids, microbial dysbiosis, and Alzheimer’s disease (AD), highlighting saliva and gingival crevicular fluid (GCF) as non-invasive diagnostic sources. AD onset and progression appear to be influenced not only by genetic and environmental factors but also [...] Read more.

Background: This study explores the link between oral biofluids, microbial dysbiosis, and Alzheimer’s disease (AD), highlighting saliva and gingival crevicular fluid (GCF) as non-invasive diagnostic sources. AD onset and progression appear to be influenced not only by genetic and environmental factors but also by changes in the oral microbiome and related inflammatory and metabolic alterations. As global populations age, the incidence of AD is projected to rise significantly. Emerging evidence implicates the oral microbiome and salivary metabolites in neurodegenerative pathways, suggesting that oral health may mirror or influence brain pathology. Materials and Methods: A systematic review of recent multi-omics studies was performed, focusing on salivary and GCF analysis in patients with AD, those with mild cognitive impairment (MCI), and cognitively healthy individuals. Databases searched included PubMed, Web of Science, and Scopus, following PRISMA guidelines. Results: Across the 11 included studies, significant alterations were reported in both the salivary microbiome and metabolome in AD patients. Notable microbial shifts involved increased abundance of Veillonella parvula and Porphyromonas gingivalis, while key metabolites such as L-tyrosine, galactinol, and mannitol were consistently dysregulated. These biomarkers correlated with cognitive performance and systemic inflammation. Conclusions: Oral biofluids represent promising, accessible sources of biomarkers for early AD detection. Multi-omics integration reveals the oral–brain axis as a potential target for diagnosis, monitoring, and therapeutic strategies. Full article

(This article belongs to the Special Issue Advancing Metabolite Biomarkers in Neurodegenerative Disease: Discovery, Integration, and Therapeutic Potential)

25 pages, 4766 KiB

Open AccessArticle

Nitrogen Deprivation Drives Red Motile Cell Formation in Haematococcus pluvialis: Physiological and Transcriptomic Insights

by Hailiang Xing, Na Zhou, Kai Liu, Xiaotian Yan, Wanxia Li, Xue Sun, Liuquan Zhang, Fengjie Liu, Nianjun Xu and Chaoyang Hu

Metabolites 2025, 15(6), 388; https://doi.org/10.3390/metabo15060388 - 10 Jun 2025

Abstract

Background: Natural astaxanthin, a commercially valuable carotenoid, is primarily sourced from Haematococcus pluvialis, a microalga known for its remarkable resilience to environmental stress. Methods: In this study, the physiological and transcriptomic responses of H. pluvialis to ND were investigated at various time [...] Read more.

Background: Natural astaxanthin, a commercially valuable carotenoid, is primarily sourced from Haematococcus pluvialis, a microalga known for its remarkable resilience to environmental stress. Methods: In this study, the physiological and transcriptomic responses of H. pluvialis to ND were investigated at various time points under high light conditions. Results: Under high light conditions, nitrogen deprivation (ND) enhances astaxanthin content (33.23 mg g⁻¹) while inhibiting the formation of the secondary cell wall (SCW), increasing astaxanthin content by 29% compared to the nitrogen-replete group (25.64 mg g⁻¹); however, the underlying mechanisms remain unclear. ND reduced chlorophyll fluorescence parameters, elevated reactive oxygen species (ROS) levels, and increased starch and total sugar accumulation while decreasing protein and lipid content. Fatty acid content increased on the first day but had declined by the fifth day. A transcriptomic analysis revealed substantial alterations in gene expression in response to ND. Genes associated with the TCA cycle, glycolysis, astaxanthin biosynthesis, and cell motility were upregulated, while those involved in photosynthesis, lipid synthesis, ribosome biogenesis, amino acid synthesis, and SCW synthesis were downregulated. Additionally, ND modulated the expression of genes involved in ROS scavenging. Conclusions: These findings provide critical insights into the adaptive mechanisms of H. pluvialis in response to ND under high light, contributing to the development of strategies for enhanced production of astaxanthin-rich motile cells. Full article

(This article belongs to the Special Issue New Insights into Microalgae Metabolism)

► Show Figures

Figure 1

12 pages, 2067 KiB

Open AccessArticle

Suppress or Not to Suppress … CRAFT It: A Targeted Metabolomics Case Study Extracting Essential Biomarker Signals Directly from the Full ¹H NMR Spectra of Horse Serum Samples

by James Chen, Ayelet Yablon, Christina Metaxas, Matheus Guedin, Joseph Hu, Kenith Conover, Merrill Simpson, Sarah L. Ralston, Krish Krishnamurthy and István Pelczer

Metabolites 2025, 15(6), 387; https://doi.org/10.3390/metabo15060387 - 10 Jun 2025

Abstract

Background: There are a few very specific inflammation biomarkers in blood, namely lipoprotein NMe⁺ signals of protein clusters (GlycA and GlycB) and a composite resonance of phospholipids (SPC). The relative integrals of these resonances provide clear indication of the unique metabolic [...] Read more.

Background: There are a few very specific inflammation biomarkers in blood, namely lipoprotein NMe⁺ signals of protein clusters (GlycA and GlycB) and a composite resonance of phospholipids (SPC). The relative integrals of these resonances provide clear indication of the unique metabolic changes associated with disease, specifically inflammatory conditions, often related to serious diseases such as cancer or COVID-19 infection. Relatively complicated, yet very efficient experimental methods have been introduced recently (DIRE, JEDI) to suppress the rest of the spectrum, thus allowing measurement of these integrals of interest. Methods: In this study, we introduce a simple alternative processing method using CRAFT (Complete Reduction to Amplitude-Frequency Table), a time-domain (FID) analysis tool which can highlight selected subsets of the spectrum by choice for quantitative analysis. The output of this approach is a direct, spreadsheet-based representation of the required peak amplitude (integral) values, ready for comparative analysis, completely avoiding all the convectional data processing and manipulation steps. The significant advantage of this alternative method is that it only needs a simple water-suppressed 1D spectrum with no further experimental manipulation whatsoever. In addition, there are no pre/post processing steps (such as baseline and/or phase), further minimizing potential dependency on subjective decisions by the user and providing an opportunity to automate the entire process. Results: We applied this methodology to horse serum samples to follow the presence of inflammation for cohorts with or without OCD (Osteochondritis Dissecans) conditions and find diagnostic separation of the of the cohorts through statistical methods. Conclusions: The powerful and simple CRAFT-based approach is suitable to extract selected biomarker information from complex NMR spectra and can be similarly applied to any other biofluid from any source or sample, also retrospectively. There is a potential to extend such a simple analysis to other, previously identified relevant markers as well. Full article

(This article belongs to the Special Issue Nuclear Magnetic Resonance-Powered Metabolomics: Progress and Future Prospects)

► Show Figures

Figure 1

14 pages, 3390 KiB

Open AccessArticle

The Potential of Aloe vera and Opuntia ficus-indica Extracts as Biobased Agents for the Conservation of Cultural Heritage Metals

by Çağdaş Özdemir, Lucia Emanuele, Marta Kotlar, Marina Brailo Šćepanović, Laura Scrano and Sabino Aurelio Bufo

Metabolites 2025, 15(6), 386; https://doi.org/10.3390/metabo15060386 - 10 Jun 2025

Abstract

Background/Objectives: Biocorrosion, driven by microbial colonization and biofilm formation, poses a significant threat to the integrity of metal artifacts, particularly those composed of copper and its alloys. Pseudomonas aeruginosa, a bacterial species that reduces nitrates, plays a key role in this process. [...] Read more.

Background/Objectives: Biocorrosion, driven by microbial colonization and biofilm formation, poses a significant threat to the integrity of metal artifacts, particularly those composed of copper and its alloys. Pseudomonas aeruginosa, a bacterial species that reduces nitrates, plays a key role in this process. This study explores the potential of two metabolite-rich plant extracts, Aloe vera and Opuntia ficus-indica, as sustainable biobased inhibitors of microbial-induced corrosion (MICOR). Methods: The antibacterial and antibiofilm activities of the extracts were evaluated using minimal inhibitory concentration (MIC) assays, time-kill kinetics, and biofilm prevention and removal tests on copper, bronze, and brass samples. Spectrophotometric and microbiological methods were used to quantify bacterial growth and biofilm density. Results: Both extracts exhibited significant antibacterial activity, with MIC values of 8.3% (v/v). A. vera demonstrated superior bactericidal effects, achieving reductions of ≥3 log₁₀ in bacterial counts at lower concentrations. In antibiofilm assays, both extracts effectively prevented biofilm formation and reduced established biofilms, with A. vera exhibiting greater efficacy against them. The active metabolites—anthraquinones, phenolics, flavonoids, and tannins—likely contribute to these effects. Conclusions: These findings highlight the dual role of A. vera and O. ficus-indica extracts as both corrosion and biocorrosion inhibitors. The secondary metabolite profiles of these plants support their application as eco-friendly alternatives in the conservation of metal cultural heritage objects. Full article

(This article belongs to the Special Issue Bioactive Metabolites from Plants)

► Show Figures

Figure 1

15 pages, 2260 KiB

Open AccessReview

Investigating Immune Checkpoint Inhibitor-Induced Pancreatic Injury: When to Discontinue Cancer Therapy

by Enrico Celestino Nista, Sara Sofia De Lucia, Sebastiano Archilei, Jacopo Iaccarino, Giulia Piccirilli, Alberto Nicoletti, Angela Saviano, Antonio Gasbarrini and Veronica Ojetti

Metabolites 2025, 15(6), 385; https://doi.org/10.3390/metabo15060385 - 10 Jun 2025

Abstract

Background/Objectives: The increasing use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to a rise in immune-related adverse events (irAEs), including pancreatic injury. While current guidelines suggest that baseline monitoring of amylase and lipase levels is not necessary, it remains common [...] Read more.

Background/Objectives: The increasing use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to a rise in immune-related adverse events (irAEs), including pancreatic injury. While current guidelines suggest that baseline monitoring of amylase and lipase levels is not necessary, it remains common in clinical settings, leading to confusion regarding their interpretation and management. This practice may lead to confusion, especially when patients exhibit isolated mild elevations of amylase and lipase, which may not always correlate with clinical pancreatitis. In contrast, significant elevations in these enzymes warrant further investigation, including imaging to assess the presence of pancreatitis. Methods: This review aims to provide a clearer framework for clinicians in managing ICI-induced pancreatic injury, promoting consistency in practice, and improving patient outcomes by reducing unnecessary interruptions to ICI therapy. Results: It is critical to distinguish between the severity of pancreatitis to guide management. Conclusions: Considering the expected rise in the use of immune ICIs, it is crucial to increase awareness about the potential for pancreatic injury associated with these treatments. Full article

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

► Show Figures

Figure 1

32 pages, 1153 KiB

Open AccessReview

Unlocking Plant Resilience: Metabolomic Insights into Abiotic Stress Tolerance in Crops

by Agata Głuchowska, Bartłomiej Zieniuk and Magdalena Pawełkowicz

Metabolites 2025, 15(6), 384; https://doi.org/10.3390/metabo15060384 - 9 Jun 2025

Abstract

Background/Objectives: In the context of accelerating climate change and growing food insecurity, improving crop resilience to abiotic stresses such as drought, salinity, heat, and cold is a critical agricultural and scientific challenge. Understanding the biochemical mechanisms that underlie plant stress responses is essential [...] Read more.

Background/Objectives: In the context of accelerating climate change and growing food insecurity, improving crop resilience to abiotic stresses such as drought, salinity, heat, and cold is a critical agricultural and scientific challenge. Understanding the biochemical mechanisms that underlie plant stress responses is essential for developing resilient crop varieties This review aims to provide an integrative overview of how metabolomics can elucidate biochemical mechanisms underlying stress tolerance and guide the development of stress-resilient crops. Methods: We reviewed the recent literature on metabolomic studies addressing abiotic stress responses in various crop species, focusing on both targeted and untargeted approaches using platforms such as nuclear magnetic resonance (NMR), liquid chromatography–mass spectrometry (LC-MS), and gas chromatography–mass spectrometry (GC-MS). We also included emerging techniques such as capillary electrophoresis–mass spectrometry (CE-MS), ion mobility spectrometry (IMS-MS), Fourier transform infrared spectroscopy (FT-IR), and data-independent acquisition (DIA). Additionally, we discuss the integration of metabolomics with transcriptomics and physiological data to support system-level insights. Results: The reviewed studies identify common stress-responsive metabolites, including osmoprotectants, antioxidants, and signaling compounds, which are consistently linked to enhanced tolerance. Novel metabolic biomarkers and putative regulatory hubs are highlighted as potential targets for molecular breeding and bioengineering. We also address ongoing challenges related to data standardization and reproducibility across analytical platforms. Conclusions: Metabolomics is a valuable tool for advancing our understanding of plant abiotic stress responses. Its integration with other omics approaches and phenotypic analyses offers promising avenues for improving crop resilience and developing climate-adaptive agricultural strategies. Full article

(This article belongs to the Special Issue Climate Change-Related Stresses and Plant Metabolism)

► Show Figures

Figure 1

29 pages, 2155 KiB

Open AccessReview

Molecular Mechanisms by Which Polyethylene Terephthalate (PET) Microplastic and PET Leachate Promote the Growth of Benthic Cyanobacteria

by Rashid Mir, Shrooq Albarqi, Wed Albalawi, Ghaida Alanazi, Shouq S. Alsubaie, Razan I. Alghaban, Hanadi Saud Alanazi, Nora Taleb Alsharif, Manal M. Aljammaz, Nouf Faisal Alghabban, Wafaa Seluman Alhwiti, Alaa Albogmi and Faras Falah Alblwi

Metabolites 2025, 15(6), 383; https://doi.org/10.3390/metabo15060383 - 9 Jun 2025

Abstract

Polyethylene terephthalate (PET) is one of the most frequently used synthetic polymers and it plays a major role in plastic pollution in aquatic environments. As PET undergoes environmental degradation, it sheds microplastics and chemical leachates, which have an effect on microbial communities, including [...] Read more.

Polyethylene terephthalate (PET) is one of the most frequently used synthetic polymers and it plays a major role in plastic pollution in aquatic environments. As PET undergoes environmental degradation, it sheds microplastics and chemical leachates, which have an effect on microbial communities, including benthic cyanobacteria. This review focuses on the molecular processes by which PET microplastics and their associated leachate affect the growth, physiological performance, and ecological performance of benthic cyanobacteria. We explore how PET-derived compounds serve as carbon and energy sources or signaling molecules, possibly affecting photosynthesis, nitrogen fixation, or stress response pathways through changes in gene expression. Moreover, the function of PET leachates as environmental modulators of microbial community structure, generators of reactive oxygen species (ROS), and disruptors of hormonal and quorum sensing networks are also outlined. Knowledge of these interactions is essential for the evaluation of the wider ecological risks resulting from plastic pollution and the likelihood of cyanobacterial blooms in PET-polluted environments. This review synthesizes evidence on how PET microplastics and leachates act as carbon sources and stressors, modulating gene expression to promote benthic cyanobacterial growth and toxin production, potentially exacerbating ecological risks in polluted aquatic systems. Full article

(This article belongs to the Section Environmental Metabolomics)

► Show Figures

Figure 1

18 pages, 2481 KiB

Open AccessArticle

Alteration of Metabolic Profile in Patients with Narcolepsy Type 1

by Md Abdul Hakim, Waziha Purba, Akeem Sanni, Md Mostofa Al Amin Bhuiyan, Farid Talih, Giuseppe Lanza, Firas Kobeissy, Giuseppe Plazzi, Fabio Pizza, Raffaele Ferri and Yehia Mechref

Metabolites 2025, 15(6), 382; https://doi.org/10.3390/metabo15060382 - 9 Jun 2025

Abstract

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive [...] Read more.

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive and not always feasible in clinical practice, there is a critical need for less invasive biomarkers to improve diagnostic accuracy and accessibility. Very few studies have explored serum-based biomolecules that could serve as biomarkers for NT1. Methods: This study examines the differential abundance of serum metabolites in patients with NT1 using an LC-MS/MS-based comprehensive metabolomics approach. Results: An untargeted analysis identified a total of 1491 metabolites, 453 of which were differentially abundant compared to the control cohort. Ingenuity pathway analysis revealed that key pathways, such as the inflammatory response (p-value of 0.01, activation z-score of 0.5), generation and synthesis of reactive oxygen species (p-value of 0.0008, z-score of 1.3), and neuronal cell death (p-value of 0.04, z-score of 0.4), are predicted to be activated in NT1. A targeted analysis using parallel reaction monitoring validated 49 metabolites, including important downregulated metabolites such as uridine (fold change (FC) of 0.004), epinephrine (FC of 0.05), colchicine (FC of 0.2), corticosterone (FC of 0.3), and arginine (FC of 0.6), as well as upregulated metabolites such as p-cresol sulfate (FC of 2601.7), taurine (FC of 1315.4), inosine (FC of 429.7), and malic acid (FC of 7.9). Conclusions: Understanding the pathways identified in this study and further investigating the differentially abundant metabolites associated with them may pave the way for gaining insight into disease pathogenesis and developing novel therapeutic interventions. Full article

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

► Show Figures

Figure 1

20 pages, 746 KiB

Open AccessReview

The Effect of Frailty on Body Composition and Its Impact on the Use of SGLT-2 Inhibitors and GLP-1RA in Older Persons with Diabetes

by Alan Sinclair, Izel Siqueira and Ahmed Abdelhafiz

Metabolites 2025, 15(6), 381; https://doi.org/10.3390/metabo15060381 - 9 Jun 2025

Abstract

The association of frailty with body composition is complex. Frailty can be associated with significant anorexia and weight loss or overweight and obesity. In addition, the development of frailty leads to changes in muscle mass, muscle fibre type, and visceral fat. In older [...] Read more.

The association of frailty with body composition is complex. Frailty can be associated with significant anorexia and weight loss or overweight and obesity. In addition, the development of frailty leads to changes in muscle mass, muscle fibre type, and visceral fat. In older people with diabetes, frailty-induced body composition changes are clinically relevant as they may affect the metabolic profile of the frail person. The determinants of insulin resistance in frail older persons with diabetes include factors such as total body weight and the ratio of lean muscle mass to visceral fat mass. The predominant loss of insulin-resistant skeletal muscle fibres type II, in comparison to insulin-sensitive type I fibres, is another factor that modifies the overall insulin resistance of the individual. As a result, frailty appears to be a heterogeneous condition with variable insulin resistance across a metabolic spectrum. The spectrum spans from a sarcopenic obese frail phenotype at one end to an anorexic malnourished frail phenotype at the other end. The introduction of SGLT-2 inhibitors and GLP-1RA with novel anti-metabolic syndrome properties, not just glucose-lowering effect, should influence clinicians’ choice in frail older persons with diabetes. These agents are likely to be beneficial in patients at the sarcopenic obese end of the frailty spectrum, who should benefit most due to their high baseline risk of progression of metabolic syndrome, high insulin resistance, and the increased prevalence of cardiovascular risk factors. On the other hand, patients at the anorexic malnourished end of the frailty spectrum are likely not suitable for such therapy due to the regression of metabolic syndrome in this group of patients and the increased risk of further weight loss, dehydration, and hypotension. Full article

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

► Show Figures

Figure 1

13 pages, 648 KiB

Open AccessArticle

New Players in Metabolic Syndrome

by Iveta Nedeva, Yavor Assyov, Vera Karamfilova, Zdravko Kamenov, Pavel Dobrev, Tsvetelina Velikova and Vlayko Vodenicharov

Metabolites 2025, 15(6), 380; https://doi.org/10.3390/metabo15060380 - 9 Jun 2025

Abstract

Background/Objectives: Metabolic syndrome (MetS) is a complex, multifaceted disorder with significant socioeconomic and public health consequences, increasingly acknowledged as a global epidemic. Fibroblast growth factor 21 (FGF-21) is known to play a vital role in metabolic regulation; however, the precise roles and [...] Read more.

Background/Objectives: Metabolic syndrome (MetS) is a complex, multifaceted disorder with significant socioeconomic and public health consequences, increasingly acknowledged as a global epidemic. Fibroblast growth factor 21 (FGF-21) is known to play a vital role in metabolic regulation; however, the precise roles and interactions of free fatty acids (FFAs) and insulin in influencing FGF-21 activity under both normal and pathological conditions are not yet fully understood. Meteorin-like protein (Metrnl) is a newly identified adipokine that appears to have the potential to regulate metabolic inflammation, which is a critical pathological factor in obesity and insulin resistance. Additionally, nesfatin-1, which is widely expressed in both central and peripheral tissues, is thought to be involved in various physiological functions beyond appetite control, such as glucose homeostasis, stress response, and cardiovascular health. Recent studies have indicated that sortilin may play a role in the pathophysiology of several metabolic disorders, including type 2 diabetes mellitus. Methods: This investigation was a cross-sectional study involving 200 individuals with obesity, which included both metabolically healthy obese participants and those experiencing obesity along with glycemic disorders. Serum levels of FGF-21, sortilin, Metrnl, and nesfatin-1 were measured using standardized enzyme-linked immunosorbent assay (ELISA) techniques. Results: The results indicated that FGF-21 levels were significantly elevated in patients with metabolic syndrome (p < 0.001), as well as those with insulin resistance (p = 0.009) and dyslipidemia (p = 0.03). Serum Metrnl levels were notably elevated in individuals meeting the criteria for insulin resistance, with a statistical significance of p < 0.001. Additionally, patients experiencing carbohydrate metabolism disorders exhibited significantly higher serum sortilin levels compared to those with normal blood glucose levels, with a p-value of 0.003. Conclusions: This research highlights FGF-21, Metrnl, nesfatin-1, and sortilin as potential biomarkers involved in the development of critical aspects of metabolic syndrome. Full article

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

► Show Figures

Graphical abstract

19 pages, 1080 KiB

Open AccessReview

Dietary and Lifestyle Interventions to Mitigate Oxidative Stress in Male and Female Fertility: Practical Insights for Infertility Management—A Narrative Review

by Efthalia Moustakli, Athanasios Zikopoulos, Periklis Katopodis, Stefanos Dafopoulos, Vasilis Sebastian Paraschos, Athanasios Zachariou and Konstantinos Dafopoulos

Metabolites 2025, 15(6), 379; https://doi.org/10.3390/metabo15060379 - 8 Jun 2025

Abstract

Background/Objectives: Infertility in both men and women can be significantly influenced by oxidative stress (OS), which occurs due to an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. In women, OS disrupts oocyte maturation, implantation, and the viability of the [...] Read more.

Background/Objectives: Infertility in both men and women can be significantly influenced by oxidative stress (OS), which occurs due to an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses. In women, OS disrupts oocyte maturation, implantation, and the viability of the embryo; in men, it impairs sperm quality, reduces motility, and damages DNA integrity. This review explores existing research on how dietary and lifestyle interventions can reduce OS and enhance reproductive health outcomes. Methods: We conducted a comprehensive review of clinical, translational, and molecular studies exploring the mechanisms by which OS affects fertility, as well as the efficacy of nutritional and behavioral strategies. The interventions evaluated include weight management, regular exercise, micronutrient supplementation, antioxidant-rich diets, smoking and alcohol cessation, and stress-reduction techniques. Results: Specific dietary components such as zinc, selenium, vitamins C and E, and polyphenols have been found to neutralize reactive oxygen species (ROS) and enhance gamete function. OS is additionally reduced through lifestyle modifications, including minimizing harmful exposures, managing stress, and participating in moderate physical activity. Biomarkers such as ROS levels, total antioxidant capacity, 8-OHdG, and DNA fragmentation index are essential for assessing the effectiveness of interventions. Conclusions: Fertility in both sexes can be improved, and oxidative stress significantly reduced, through a multimodal approach incorporating dietary and lifestyle changes. There are encouraging opportunities to improve reproductive health through customized approaches that are informed by biomarker profiles. To incorporate these treatments into regular fertility care, future studies should concentrate on standardized procedures and long-term results. Full article

(This article belongs to the Special Issue Interactions of Diet, Exercise, and Metabolism)

► Show Figures

Figure 1

14 pages, 238 KiB

Open AccessArticle

Comparative Assessment of Immune Cell Subset Ratios (NKT/NK, Th/Tc, B1/B2) in Gestational Diabetes and Healthy Pregnancy: Links to Biochemical and Immunochemical Profiles

by Jelena Omazić, Andrijana Muller, Mirta Kadivnik, Blaženka Dobrošević, Barbara Vuković, Mirela Florijančić and Jasenka Wagner

Metabolites 2025, 15(6), 378; https://doi.org/10.3390/metabo15060378 - 8 Jun 2025

Viewed by 31

Abstract

Introduction: Gestational diabetes (GD) is a common pregnancy metabolic disorder involving immune alterations. While there is a link between immune cells and GD, the specific roles of NKT/NK, helper/cytotoxic T, and B1/B2 lymphocyte ratios in complicated/uncomplicated pregnancies with and without GD are underexplored. [...] Read more.

Introduction: Gestational diabetes (GD) is a common pregnancy metabolic disorder involving immune alterations. While there is a link between immune cells and GD, the specific roles of NKT/NK, helper/cytotoxic T, and B1/B2 lymphocyte ratios in complicated/uncomplicated pregnancies with and without GD are underexplored. This cross-sectional study hypothesized that specific imbalances in these lymphocyte ratios would be present in GD, and that these ratios would correlate with key metabolic parameters in pregnancy. Methods: We compared these lymphocyte ratios in 162 third-trimester pregnant women across four groups: healthy uncomplicated (n = 40), healthy complicated (n = 40), GD uncomplicated (n = 42), and GD complicated (n = 40), using flow cytometry and by measuring biochemical parameters. Results: No significant differences in lymphocyte ratios were found between GD and healthy pregnancies. Novel correlations emerged: in the entire cohort, the NKT/NK ratio positively correlated with C-peptide and triglycerides, and negatively with HDL cholesterol. The helper/cytotoxic ratio negatively correlated with insulin and C-peptide. In the GD group, NKT/NK correlated positively with C-peptide, and helper/cytotoxic negatively with insulin. Conclusion: These findings suggest a subtle yet significant link between immune cell subsets and metabolic status in pregnancy and GD, warranting further investigation. Full article

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

15 pages, 542 KiB

Open AccessReview

The Association Between Psoriasis and Metabolic Syndrome in Children: A Narrative Review

by Mateusz Matwiejuk, Hanna Myśliwiec, Agnieszka Mikłosz, Adrian Chabowski and Iwona Flisiak

Metabolites 2025, 15(6), 377; https://doi.org/10.3390/metabo15060377 - 6 Jun 2025

Viewed by 204

Abstract

Psoriasis is a common inflammatory skin disease with a complex pathogenesis consisting of genetic factors, immune dysfunction and environmental background. In adults, psoriasis is strongly associated with a higher risk of developing metabolic abnormalities; however, data in children are inconclusive. Metabolic syndrome (MetS) [...] Read more.

Psoriasis is a common inflammatory skin disease with a complex pathogenesis consisting of genetic factors, immune dysfunction and environmental background. In adults, psoriasis is strongly associated with a higher risk of developing metabolic abnormalities; however, data in children are inconclusive. Metabolic syndrome (MetS) is a group of conditions that include central and abdominal obesity, hypertension, dyslipidemia and hyperglycemia. Potential pathogenic mechanisms linking psoriasis with metabolic syndrome include releasing large amounts of proinflammatory cytokines such as interleukins (IL-17, IL-23) and tumor necrosis factor alpha (TNF-α). These abnormalities promote excessive keratinocyte proliferation and impaired differentiation, which leads to typical psoriatic skin lesions. This paper aims to assess the potential link between psoriasis and each component of metabolic syndrome in children. It is speculated that the same proinflammatory cytokines produced by Th17 cells are also implicated in the development and progression of various metabolic disorders in patients with a severe course of the disease. Psoriatic patients are at higher risk for development metabolic diseases such as diabetes mellitus and cardiovascular disease. Full article

(This article belongs to the Special Issue Psoriasis and Metabolic Syndrome)

► Show Figures

Graphical abstract

15 pages, 2681 KiB

Open AccessArticle

Metabolomic Profiling and Bioanalysis of Chronic Myeloid Leukemia: Identifying Biomarkers for Treatment Response and Disease Monitoring

by Selim Sayın, Murat Yıldırım, Batuhan Erdoğdu, Ozan Kaplan, Emine Koç, Tuba Bulduk, Melda Cömert, Mustafa Güney, Mustafa Çelebier and Meltem Aylı

Metabolites 2025, 15(6), 376; https://doi.org/10.3390/metabo15060376 - 6 Jun 2025

Viewed by 154

Abstract

Background: Including Chronic Myeloid Leukemia (CML) patients with deep molecular responses (MR4.5) and those with suboptimal responses provides valuable insights into treatment-associated metabolic changes. This study aimed to characterize the metabolomic alterations associated with CML and identify potential biomarkers for treatment response, particularly [...] Read more.

Background: Including Chronic Myeloid Leukemia (CML) patients with deep molecular responses (MR4.5) and those with suboptimal responses provides valuable insights into treatment-associated metabolic changes. This study aimed to characterize the metabolomic alterations associated with CML and identify potential biomarkers for treatment response, particularly in patients achieving a deeper molecular response versus those with poorer responses. Methods: Plasma samples were collected from 51 chronic-phase CML patients and 24 healthy controls. CML patients were classified into two groups based on molecular responses: T1 (BCR-ABL1 IS ≤ 0.0032%) and T2 (BCR-ABL1 IS > 0.0032%, <1%). Metabolomic profiling was conducted using quadrupole time-of-flight liquid chromatography/mass spectrometry. The data analysis involved a partial least squares discriminant analysis, variable importance in projection (VIP) scores, and a pathway enrichment analysis. Significant metabolites were identified. Results: The PLS-DA revealed distinct metabolomic profiles between CML patients and healthy controls as well as between the T1 and T2 groups. Key differentiating metabolites with VIP scores > 1.5 included glutamate, hypoxanthine, and D-galactonic acid. In the T2 group, significant increases in malate and 5-aminoimidazole-4-carboxamide ribonucleotide were observed, reflecting disruptions in purine metabolism, the tricarboxylic acid cycle, and amino acid metabolism. The pathway enrichment analysis highlighted significant alterations in CML energy metabolism, nucleotide synthesis, and amino acid biosynthesis. Conclusions: CML patients exhibit pronounced metabolic changes, particularly in energy and nucleotide metabolism, which are linked to treatment response. These findings provide novel insights into CML biology and suggest potential biomarkers for monitoring treatment efficacy and predicting outcomes and therapeutic targets for improving treatment outcomes and overcoming tyrosine kinase inhibitor resistance. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

► Show Figures

Figure 1

12 pages, 1185 KiB

Open AccessArticle

High-Calorie Diet Consumption Induces Lac-Phe Changes in the Brain in a Time-of-Day Manner Independent of Exercise

by Jarne Jermei, Han Jiao, Ayano Shiba, Julia C. Goedhart, Roberta Tandari, Andries Kalsbeek, Eduard A. Struys and Chun-Xia Yi

Metabolites 2025, 15(6), 375; https://doi.org/10.3390/metabo15060375 - 6 Jun 2025

Viewed by 163

Abstract

Background/Objectives: N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite, has been shown to reduce food intake, decrease body weight and adiposity, and improve glucose homeostasis without affecting energy expenditure. Until now, Lac-Phe has mainly been investigated in blood plasma, showing its appetite-suppressing effects. Interestingly, these beneficial [...] Read more.

Background/Objectives: N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite, has been shown to reduce food intake, decrease body weight and adiposity, and improve glucose homeostasis without affecting energy expenditure. Until now, Lac-Phe has mainly been investigated in blood plasma, showing its appetite-suppressing effects. Interestingly, these beneficial effects were caused by a temporary increase in Lac-Phe levels after exercise. Second, despite the central role of the central nervous system in the homeostatic control of energy metabolism, little is known about the presence and function of Lac-Phe in the brain. The goal of this study is to investigate how Lac-Phe concentrations in the brain change during the 24 h light/dark cycle. Methods: We conducted an experiment in rats in which time-restricted running was combined with time-restricted feeding (TRF) of a high-calorie diet, after which Lac-Phe levels were measured in the hypothalamus and cortex using stable isotope dilution LC-MS/MS. Microglia were isolated from rat brains to study Lac-Phe-related gene expression. Results: We found that Lac-Phe levels changed over time within the 24 h light/dark cycle in the hypothalamus and/or cortex, even without exercise. Our study indicates that brain Lac-Phe is not only induced by exercise but also by high-calorie diet intake independent of exercise. Finally, we showed that microglial cells are cytosolic nonspecific dipeptidase 2 (CNDP2) positive and therefore able to produce Lac-Phe. Hereby, we identified SLC16A1 in microglia as a possible key mediator of Lac-Phe production. Conclusions: We conclude that high-calorie diet consumption induces Lac-Phe changes in the brain in a time-of-day manner independent of exercise. This study provides new knowledge on the presence and production of Lac-Phe in the brain. Further research is needed to elucidate the potential mechanism by which Lac-Phe reduces food intake and body weight by targeting appetite-suppressing neurons. Full article

(This article belongs to the Section Bioinformatics and Data Analysis)

► Show Figures

Figure 1

13 pages, 574 KiB

Open AccessArticle

Application of Craniosacral Therapy Versus Blood Levels of Corticoliberin and Oxytocin in Male Firefighters Exposed to Occupational Stress—A Randomised Control Trial

by Małgorzata Wójcik and Idzi Siatkowski

Metabolites 2025, 15(6), 374; https://doi.org/10.3390/metabo15060374 - 6 Jun 2025

Viewed by 176

Abstract

Background: Firefighters’ work exposes them to high levels of stress. Oxytocin (OXT) and corticotrophin-releasing hormone (CRH) are hormones released in response to stress. Prolonged exposure to stress can have negative effects, such as increased blood pressure and glucose levels, and a weakened [...] Read more.

Background: Firefighters’ work exposes them to high levels of stress. Oxytocin (OXT) and corticotrophin-releasing hormone (CRH) are hormones released in response to stress. Prolonged exposure to stress can have negative effects, such as increased blood pressure and glucose levels, and a weakened immune system. Methods: This study involved 57 fire department cadets, randomly divided into craniosacral therapy (CS) and contralateral therapy (CO) groups. This study aimed to check whether 5-week craniosacral therapy affects CRH and OXT levels, determined from blood. Results: For the CS group, CRH_1 and CRH_2 showed slight increases in median values, 1.73 vs. 2.16, and OXT_1 and OXT_2 showed significant increases in median values, 54.71 vs. 57.77. Spearman’s correlation coefficient for CRH_1 vs. OXT_1 was r = 0.26, p = 0.124; similarly, for CRH_2 vs. OXT_2 was r = −0.02, p = 0.920; for CRH_ 1 vs. CRH_2 was r = 0.25, p = 0.173; and for OXT_1 vs. OXT_2 was r = 0.77, p < 0.00001. The values of the point statistics for CRH were similar in CO_1 and CS_1. After the end of therapy, in the CS_2 group, the values of the point statistics were greater than those for the CO_2 group. The median values for oxytocin in the CO_1 group were greater than those in the CS_1 group. After the end of therapy, in the CO_2 group, the values of the scoring statistics were smaller than those for the CS_2 group. The effect of the intervention in the CS group and the CO group showed a significance of p = 0.0003 and p = 0.023. Conclusions: After the end of therapy, a significant increase in OXT levels was observed, as well as a slight increase in CRH levels. Full article

(This article belongs to the Special Issue Stress and Inflammation: Drivers, Biomarkers and Physiological Effects)

► Show Figures

Figure 1

14 pages, 1761 KiB

Open AccessArticle

Ergosterol Protects Canine MDCK Cells from Gentamicin-Induced Damage by Modulating Autophagy and Apoptosis

by Zhipeng Qin, Liuwei Xie, Yao Wang, Na Zhang, Hailong Bi, Mingqiang Song and Chao Xu

Metabolites 2025, 15(6), 373; https://doi.org/10.3390/metabo15060373 - 5 Jun 2025

Viewed by 147

Abstract

Background: Renal injury is a critical health issue in pet dogs, often exacerbated by drug-induced nephrotoxicity such as gentamicin (GM). This study investigated the protective effects of ergosterol (Erg), a natural compound from edible mushrooms, against GM-induced damage in Madin–Darby canine kidney (MDCK) [...] Read more.

Background: Renal injury is a critical health issue in pet dogs, often exacerbated by drug-induced nephrotoxicity such as gentamicin (GM). This study investigated the protective effects of ergosterol (Erg), a natural compound from edible mushrooms, against GM-induced damage in Madin–Darby canine kidney (MDCK) cells. Methods: MDCK cells were treated with GM (0.5–3 mmol/L) for 12 h to establish injury. Erg (1 to 32 μg/mL) was pretreated for 12 h before GM exposure (2 mmol/L). Cell viability, nitric oxide (NO), lactate dehydrogenase (LDH), oxidative stress markers (SOD, GSH, CAT, MDA), inflammatory cytokines (IL-1β, IL-6, TNF-α), renal function indicators (Scr, BUN), and autophagy/apoptosis-related proteins (ATG5, Beclin1, P62, BAX, BCL-2) were assessed via CCK-8, ELISA, fluorescence staining, and Western blot. Statistical significance (p < 0.05) was determined by ANOVA and LSD post hoc tests. Results: GM (2 mmol/L) significantly reduced cell viability (p < 0.01) and elevated NO and LDH levels (p < 0.01). Erg pretreatment (4–8 μg/mL) restored cell viability (p < 0.01), suppressed NO (p < 0.01) and LDH release (p < 0.01), and enhanced antioxidant enzyme activities (SOD, GSH, CAT; p < 0.01). Erg attenuated GM-induced reactive oxygen species (ROS) overproduction (p < 0.01) and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α; p < 0.01). Renal markers Scr and BUN were reduced (p < 0.01). Mechanistically, Erg upregulated autophagy proteins ATG5 and Beclin1 (p < 0.01), reduced P62 accumulation (p < 0.01), and lowered the BAX/BCL-2 ratio (p < 0.01). Conclusions: Erg protects MDCK cells from GM-induced nephrotoxicity by restoring autophagy flux, suppressing mitochondrial apoptosis, and mitigating oxidative stress and inflammation. These findings highlight Erg’s potential as a natural therapeutic agent for canine renal injury. Further in vivo studies are needed to validate its clinical efficacy. Full article

(This article belongs to the Special Issue Effects of Nutrition Intake on Pet Metabolism)

► Show Figures

Figure 1

29 pages, 1977 KiB

Open AccessReview

Capsaicin as a Microbiome Modulator: Metabolic Interactions and Implications for Host Health

by Iván Artemio Corral-Guerrero, Angela Elena Martínez-Medina, Litzy Yazmin Alvarado-Mata, Ana Cristina Figueroa Chávez, Roberto Muñoz-García, Miriam Paulina Luévanos-Escareño, Jazel Doménica Sosa-Martínez, María José Castro-Alonso, Padma Nimmakayala, Umesh K. Reddy and Nagamani Balagurusamy

Metabolites 2025, 15(6), 372; https://doi.org/10.3390/metabo15060372 - 5 Jun 2025

Viewed by 587

Abstract

Background/Objectives: Capsaicin is the principal pungent compound in chili peppers and is increasingly recognized as a multifunctional phytochemical with systemic effects beyond its sensory properties. It has been linked to metabolic regulation, neuroprotection, inflammation control, and cancer modulation. This review aims to provide [...] Read more.

Background/Objectives: Capsaicin is the principal pungent compound in chili peppers and is increasingly recognized as a multifunctional phytochemical with systemic effects beyond its sensory properties. It has been linked to metabolic regulation, neuroprotection, inflammation control, and cancer modulation. This review aims to provide an integrative synthesis of capsaicin’s metabolism, its interaction with the gut microbiome, and its physiological implications across organ systems. Methods: We conducted a critical literature review of recent in vivo and in vitro studies exploring capsaicin’s metabolic fate, biotransformation by host enzymes and gut microbes, tissue distribution, and molecular pathways. The literature was analyzed thematically to cover gastrointestinal absorption, hepatic metabolism, microbiota interactions, and systemic cellular responses. Results: Capsaicin undergoes extensive hepatic metabolism, producing hydroxylated and dehydrogenated metabolites that differ in transient receptor potential vanilloid type 1 (TRPV1) receptor affinity and tissue-specific bioactivity. It crosses the blood–brain barrier, alters neurotransmitter levels, and accumulates in brain regions involved in cognition. In addition to its systemic effects, capsaicin appears to undergo microbial transformation and influences gut microbial composition, favoring short-chain fatty acid producers and suppressing pro-inflammatory taxa. These changes contribute to anti-obesity, anti-inflammatory, and potentially anticancer effects. Dose-dependent adverse outcomes, such as epithelial damage or tumor promotion, have also been observed. Conclusions: Capsaicin represents a diet-derived bioactive molecule whose systemic impact is shaped by dynamic interactions between host metabolism and the gut microbiota. Clarifying its biotransformation pathways and context-specific effects is essential for its safe and effective use in metabolic and neurological health strategies. Full article

(This article belongs to the Special Issue Nutritional Metabolism in Model Organisms: Phytochemicals and Genetic Responses)

► Show Figures

Figure 1

15 pages, 1279 KiB

Open AccessFeature PaperArticle

Comparison of the Metabolic Profiles Associated with Protonitazene and Protonitazepyne in Two Severe Poisonings

by Romain Magny, Thomas Schiestel, Aymen M’Rad, Bertrand Lefrère, Jean-Herlé Raphalen, Stanislas Ledochowski, Laurence Labat, Bruno Mégarbane and Pascal Houzé

Metabolites 2025, 15(6), 371; https://doi.org/10.3390/metabo15060371 - 5 Jun 2025

Viewed by 142

Abstract

Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. Background: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood [...] Read more.

Nitazenes represent an emerging class of new synthetic opioids characterized by a high-potency μ-opioid receptor (MOR) agonist activity. Background: We report two 20-year-old males who presented with severe neurorespiratory depression with typical opioid syndrome, but no opioid identification based on routine blood and urine screening tests. The first patient recovered with supportive care, mechanical ventilation, and naloxone infusion, whereas the second patient developed post-anoxic cardiac arrest and died from brain death. Methods: A complementary comprehensive toxicological screening using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) was performed, and data were processed using a dedicated molecular network strategy to profile the metabolites. Results: Protonitazene and protonitazepyne, two nitazenes differing in their ethylamine moieties (i.e., a diethyl versus a pyrrolidine substitution, respectively), were identified. We found an extensive metabolism of protonitazene, leading to the identification of multiple phase I (resulting from hydroxylation, N-desethylation, and O-despropylation) and phase II (resulting from glucuronidation) metabolites. By contrast, protonitazepyne metabolism appeared limited, with one metabolite annotated confidently, protonitazepyne acid, which resulted from the oxidative pyrrolidine ring cleavage. Concusions: To conclude, nitazene detection is highly challenging due to its extensive structural and metabolic diversity. Our findings highlight the contribution of the untargeted LC-HRMS screening approach and suggest that diagnostic product ions can serve as robust markers for nitazene identification. Full article

(This article belongs to the Special Issue Metabolite Profiling of Novel Psychoactive Substances)

► Show Figures

Figure 1

10 pages, 290 KiB

Open AccessArticle

The Associations of Serum Folate Forms with Metabolic Dysfunction-Associated Fatty Liver Disease and Liver Fibrosis: A Nationwide Cross-Sectional Study

by Hai Zhao, Wei Fan, Yan Yan, Yuxing Liu and Xuejun Kang

Metabolites 2025, 15(6), 370; https://doi.org/10.3390/metabo15060370 - 5 Jun 2025

Viewed by 180

Abstract

Background: Accumulating evidence indicates a link between folate and metabolic dysfunction-associated fatty liver disease (MAFLD). Objectives: The aim of this study was to ascertain whether different serum folate forms are associated with newly defined MAFLD as well as liver fibrosis in [...] Read more.

Background: Accumulating evidence indicates a link between folate and metabolic dysfunction-associated fatty liver disease (MAFLD). Objectives: The aim of this study was to ascertain whether different serum folate forms are associated with newly defined MAFLD as well as liver fibrosis in the US general population. Methods: This cross-sectional study used data from the 2017–2020 (March) cycle and 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES) in the US. Hepatic steatosis and fibrosis were evaluated by transient elastography, which employed controlled attenuation parameters and liver stiffness measurements as assessment indicators. Results: 7447 eligible individuals were included. The estimated prevalence of MAFLD and liver fibrosis was 51.6% (95% confidence interval [CI]: 50.4–52.7%) and 10.0% (95% CI: 9.3–10.7%). After adjusting for confounding factors, for every 1 nmol/L increase in serum 5-methyltetrahydrofolate (5-mTHF), the risk of developing liver fibrosis decreased by 1% (95% CI: 1–2%, p < 0.001), and the risk of developing MAFLD decreased by 1% (95% CI: 0–2%, p = 0.005). There were also significant differences in indicators such as alanine aminotransferase (ALT), gamma-glutamyl transaminase (GGT), and C-reactive protein (CRP) between the MAFLD group and the non-MAFLD group (all p values < 0.001). Conclusions: This study suggests the prevalence of MAFLD and liver fibrosis decreased significantly with the increase in serum 5-mTHF concentration. Full article

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

► Show Figures

Figure 1

25 pages, 4964 KiB

Open AccessArticle

Optimization of Tunisian Myrtus communis L. Essential Oil Extraction by Complete Factorial Experimental Design

by Rania Zayani, Eya BenSalem, Mariem Khouja, Amani Bouhjar, Mohamed Boussaid and Chokri Messaoud

Metabolites 2025, 15(6), 369; https://doi.org/10.3390/metabo15060369 - 3 Jun 2025

Viewed by 271

Abstract

Background: Myrtus communis L. is a typical aromatic species of the Mediterranean basin, whose leaves are rich in essential oil known for its biological properties. Methods: The essential oil of Tunisian Myrtus communis L. leaves was extracted via hydrodistillation using a Clevenger-type [...] Read more.

Background: Myrtus communis L. is a typical aromatic species of the Mediterranean basin, whose leaves are rich in essential oil known for its biological properties. Methods: The essential oil of Tunisian Myrtus communis L. leaves was extracted via hydrodistillation using a Clevenger-type apparatus and optimized using a complete factorial design including three factors with two different modalities and one factor with three modalities, hence the total number of experiments N_total = 2³ × 3¹. This optimization concerns the yield, the terpene composition by GC-MS and the antioxidant activity by the two radical scavenging assays, DPPH and ABTS. Four factors were retained, namely, the type of leaf used (dry or fresh sample), the leaf granulometry (whole or ground), the extraction time (1 h 30 min, 2 h 30 min and 3 h 30 min) and the water volume/plant material ratio (1/4 and 1/10). Results: The dry and whole leaves, duration 3 h 30 min, and V/M 1/10 modalities gave the best yield of essential oil (0.77%). The optimal contents of the majority of the terpene compounds, 1,8-cineole (37.23%), α-pinene (54.79%), myrtenyl acetate (23.43%) and limonene (17.77%), were recorded using the modalities dry and whole leaves, duration 2 h 30 min, V/M 1/10; dry and ground leaves, duration 1 h 30 min, V/M 1/4; fresh and whole leaves, duration 3 h 30 min, V/M 1/4; and fresh and whole leaves, duration 3 h 30 min, V/M 1/4, respectively. The antioxidant activity of the essential oil of myrtle leaves was optimized for the two DPPH (7.477 mg TE/g EO) with the GDL, duration 3 h 30 min, V/M 1/4 and ABTS assays (14.053 mg TE/g EO) with WDL terms, duration 3 h 30 min, V/M 1/10. Conclusions: Optimizing essential oil extraction is of significant interest to the cosmetic, perfumery, and pharmaceutical industries, which are constantly seeking optimal conditions to enhance essential oil yield and to ensure a high concentration of terpenic compounds, valued for their aromatic qualities and diverse biological activities. Full article

(This article belongs to the Special Issue Identification of Plant Metabolites: Characterization and Biological Activities, 2nd Edition)

► Show Figures

Figure 1

14 pages, 543 KiB

Open AccessArticle

Analysis of the Acute Cytokine Dynamics Induced in Professional Padel According to the Playing Side of the Court and Sex-Related Differences

by María Pía Cádiz-Gallardo, Francisco Pradas, Pamela Patanè, Alejandro García-Giménez, Miguel Lecina and Luis Carrasco

Metabolites 2025, 15(6), 368; https://doi.org/10.3390/metabo15060368 - 3 Jun 2025

Viewed by 246

Abstract

Background/Objectives: Moderate-intensity physical exercise induces an anti-inflammatory state that may help prevent or manage various diseases. In contrast, high-intensity exercise is closely associated with systemic inflammation, which can lead to immunosuppression, especially when recovery periods are too short, reduced sports performance and potential [...] Read more.

Background/Objectives: Moderate-intensity physical exercise induces an anti-inflammatory state that may help prevent or manage various diseases. In contrast, high-intensity exercise is closely associated with systemic inflammation, which can lead to immunosuppression, especially when recovery periods are too short, reduced sports performance and potential health risks for the athlete. This study aimed to analyze the acute cytokine dynamics in professional padel players, focusing on differences related to the side of play on the court (forehand or backhand) and sex. Methods: A total of 21 elite padel players (11 females and 10 males; age: 27.7 ± 6.3 y) voluntarily participated in the study. Pro-inflammatory cytokines (interleukin (IL)-1ß, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, tumor necrosis factor alpha and interferon gamma) and anti-inflammatory cytokines (IL-5, IL-6, IL-10, IL-13) were analyzed before and after a padel match. Results: The results showed significant changes in pro- and anti-inflammatory, including a decrease in IL-7 (p = 0.02), an increase in IL-8 (p ≤ 0.001) and an increase in IL-10 (p = 0.001). No significant differences were observed based on the side of play on the court, suggesting that this variable does not influence the immune response. Conclusions: Competitive padel at an elite level elicits an anti-inflammatory response, characterized by an increase in IL-10 and a reduction in pro-inflammatory cytokines. This response highlights the potential health benefits of padel as a moderate-intensity sport, particularly in managing systemic inflammation. Full article

(This article belongs to the Special Issue Sex Differences in Physical Exercise and Dietary Habits Effects on Metabolic Health)

► Show Figures

Figure 1

19 pages, 1772 KiB

Open AccessSystematic Review

Circulating MicroRNAs Associated with Changes in the Placenta and Their Possible Role in the Fetus During Gestational Diabetes Mellitus: A Review

by Ninna Leslie Trejo-Gonzalez, Martin Palomar-Morales, Luis Arturo Baiza-Gutman, Guadalupe Diaz-Rosas, Clara Ortega-Camarillo and Alejandra Contreras-Ramos

Metabolites 2025, 15(6), 367; https://doi.org/10.3390/metabo15060367 - 3 Jun 2025

Viewed by 289

Abstract

MicroRNAs (miRs) are epigenetic regulators of several metabolic diseases, including gestational diabetes mellitus (GDM). Objectives: Following a systematic review, we propose a pattern of key circulating miRs associated with placental changes and their potential role in the fetus. Methods: A systematic investigation of [...] Read more.

MicroRNAs (miRs) are epigenetic regulators of several metabolic diseases, including gestational diabetes mellitus (GDM). Objectives: Following a systematic review, we propose a pattern of key circulating miRs associated with placental changes and their potential role in the fetus. Methods: A systematic investigation of studies published between January 2011 and July 2024 was conducted in the PubMed, ScienceDirect, Trip Database, and Wiley databases. A total of 90 articles were analyzed. Results: Two hundred twenty-six circulating microRNAs were identified in women with GDM, and fifty miRs were validated by PCR, with miRs-16-5p, -29a-5p, and -195-5p being the most frequently reported. Interestingly, miR-16-5p was also expressed in the placenta but not in umbilical cord blood or amniotic fluid. Conversely, miR-126-3p was expressed in circulation, the placenta, umbilical cord blood, and amniotic fluid. Several reports describe high expression levels of miR-518d in maternal circulation, umbilical cord blood, and placenta. Controversial results regarding the expression of miR-29a-3p, -137, and -148a-3p were identified when comparing umbilical cord blood and the placenta. Conclusions: In silico analyses suggest that the miR-29 family, as well as miRs-16-5p, -126-3p, -195-5p, and -518b, may be involved in alterations in the heart, brain, and kidneys in the embryo when exposed to a hyperglycemic environment. Full article

(This article belongs to the Special Issue Adipose Tissue, Reproduction and Metabolic Health in Women)

► Show Figures

Figure 1

17 pages, 4737 KiB

Open AccessArticle

Soluble Siglec-9 Improves Intestinal Barrier Function in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis

by Hisanori Muto, Fumitaka Mizuno, Takashi Honda, Shinya Yokoyama, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Norihiro Imai, Yoji Ishizu, Kiyoshi Sakai, Hideharu Hibi, Masatoshi Ishigami and Hiroki Kawashima

Metabolites 2025, 15(6), 366; https://doi.org/10.3390/metabo15060366 - 30 May 2025

Viewed by 267

Abstract

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous [...] Read more.

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM) exerted therapeutic effects in a MASH mouse model. The gut–liver axis is thought to be associated with liver disease progression, and soluble Siglec-9 (sSiglec-9), an immunoinhibitory receptor, is a key protein in SHED-CM that induces anti-inflammatory macrophages and has intestinal epithelial protective effects. Therefore, we evaluated sSiglec-9’s role in intestinal barrier protection in MASH mice. Methods: We evaluated sSiglec-9 effects on intestinal barrier function using in vitro Caco-2 cell monolayers injured by TNF-α and IFN-γ. For the MASH mouse model, male C57BL/6J mice were given a Western diet and high-sugar solution orally; to induce liver injury, CCl4 was intraperitoneally administered for 12 weeks. Mice were treated weekly with 10 ng/g sSiglec-9 or vehicle. Intestinal permeability was assessed by blood 4 kDa FITC-dextran concentration, and intestinal transcriptomes and liver histology were analyzed. Results: sSiglec-9 decreased intestinal permeability and liver inflammation in MASH mice. sSiglec-9 and SHED-CM reduced 4 kDa FITC-dextran permeability in injured Caco-2 cells, and sSiglec-9 significantly reduced intestinal permeability and modulated expression of 34 intestinal genes. The NAFLD Activity Score indicated significantly reduced inflammation following sSiglec-9 treatment. Conclusions: sSiglec-9 may protect intestinal barrier function by mitigating mucosal inflammation. sSiglec-9 treatment may represent a novel therapeutic approach for MASH via gut–liver axis modulation. Full article

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

► Show Figures

Figure 1

15 pages, 539 KiB

Open AccessReview

Secreted Phosphoprotein 1 in Lung Diseases

by Hongli Liu, Cristian Coarfa, Arzoo N. Charania, Jennifer L. Larson-Casey, Ivan O. Rosas and Chao He

Metabolites 2025, 15(6), 365; https://doi.org/10.3390/metabo15060365 - 30 May 2025

Viewed by 259

Abstract

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN) or early T lymphocyte activation protein 1 (ETA-1), is a multifunctional protein involved in numerous biological processes, including immune modulation, stress response, and tissue remodeling. The role of SPP1 in interstitial lung diseases (ILDs) [...] Read more.

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN) or early T lymphocyte activation protein 1 (ETA-1), is a multifunctional protein involved in numerous biological processes, including immune modulation, stress response, and tissue remodeling. The role of SPP1 in interstitial lung diseases (ILDs) has become an area of increasing interest, given its elevated expression in various ILDs such as idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), and pneumoconiosis, especially with recent data derived from single-cell RNA sequencing. In addition to ILDs, SPP1 has been implicated in infectious granulomatous lung diseases, lung and pleural malignancies, airway diseases, and COVID-19. In most cases, higher SPP1 levels in serum, bronchoalveolar lavage fluid, or lung tissue carry a poor prognosis. SPP1 is expressed in multiple cells critical for fibrogenesis, including macrophages, epithelial cells, and fibroblasts, and SPP1 has emerged as a potential target for therapeutic interventions. Here, we review the proposed mechanisms by which SPP1 contributes to the development of lung disease, with an emphasis on ILD. Full article

(This article belongs to the Special Issue Immunometabolism and Lung Fibrosis)

► Show Figures

Figure 1

17 pages, 1787 KiB

Open AccessArticle

Plasma TMAO Concentrations and Gut Microbiota Composition in Subjects with and Without Metabolic Syndrome: Results from Pilot Study

by Mohammed E. Hefni, Cornelia M. Witthöft, Patrik Hellström, Ingegerd Johansson and Anders Esberg

Metabolites 2025, 15(6), 364; https://doi.org/10.3390/metabo15060364 - 30 May 2025

Viewed by 254

Abstract

Background/Objectives: Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite considered as a risk metabolite for various non-communicable diseases. This study aims to identify differences in the gut microbiota composition and concentrations of TMAO and related metabolites in subjects with and without metabolic [...] Read more.

Background/Objectives: Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite considered as a risk metabolite for various non-communicable diseases. This study aims to identify differences in the gut microbiota composition and concentrations of TMAO and related metabolites in subjects with and without metabolic syndrome (MetS). Methods: Plasma samples were collected following an overnight fast on two occasions from subjects with (n = 12) and without (n = 21) MetS. Feces samples were collected on the day before the first blood sampling. The gut microbiota was profiled using 16S rRNA full-gene amplification sequencing. TMAO and related methylamines were quantified using UPLC-MSMS. The fasted plasma glucose, plasma lipid profile, and HbA1c were determined, and blood pressure, circumference, height, and weight were measured. Results: A divergent gut microbiota composition was observed in feces samples from both groups. In contrast to subjects without MetS, subjects with MetS had a reduced microbial diversity, with lower Blautia glucerasea and higher Ruminococcus torques—a pattern associated with (increased) inflammation. Trimethylamine (TMA)-producing bacteria were low in abundance across both groups. While plasma TMAO and related methylamines displayed no significant differences between both groups, L-carnitine was elevated (p = 0.0191) in subjects with MetS. A strong positive correlation was detected between TMAO and TMA (r = 0.439, p = 0.003), with a tendency to correlate with carnitine (r = 0.212, p = 0.087). Conclusions: Subjects with MetS were characterized by gut microbiota favoring inflammation-associated species but not TMA producers. This suggests that TMAO may not play a role in MetS subjects without overt comorbidities, e.g., CVD or T2D. The influence of the gut microbiota on early MetS is likely mediated through inflammatory mechanisms driven by specific bacterial shifts rather than TMAO production. Full article

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

► Show Figures

Graphical abstract

18 pages, 5983 KiB

Open AccessArticle

Plasma and Fecal Metabolites Combined with Gut Microbiome Reveal Systemic Metabolic Shifts in ⁶⁰Co Gamma-Irradiated Rats

by Jie Zong, Haiyang Wu, Xuan Hu, Ami Yao, Wenhua Zhu, Guifang Dou, Shuchen Liu, Xiaoxia Zhu, Ruolan Gu, Yunbo Sun, Zhuona Wu, Shanshan Wang and Hui Gan

Metabolites 2025, 15(6), 363; https://doi.org/10.3390/metabo15060363 - 29 May 2025

Viewed by 288

Abstract

Background: High-dose γ-ray exposure (≥7 Gy) in nuclear emergencies induces life-threatening acute radiation syndrome, characterized by rapid hematopoietic collapse (leukocytes <0.5 × 10⁹/L) and gastrointestinal barrier failure. While clinical biomarkers like leukocyte depletion guide current therapies targeting myelosuppression, the concomitant metabolic disturbances [...] Read more.

Background: High-dose γ-ray exposure (≥7 Gy) in nuclear emergencies induces life-threatening acute radiation syndrome, characterized by rapid hematopoietic collapse (leukocytes <0.5 × 10⁹/L) and gastrointestinal barrier failure. While clinical biomarkers like leukocyte depletion guide current therapies targeting myelosuppression, the concomitant metabolic disturbances and gut microbiota dysbiosis—critical determinants of delayed mortality—remain insufficiently profiled across the 28-day injury-recovery continuum. Methods: This study investigates the effects of ⁶⁰Co γ-ray irradiation on metabolic characteristics and gut microbiota in Sprague Dawley rats using untargeted metabolomics and 16S rRNA sequencing. Meanwhile, body weight and complete blood counts were measured. Results: Body weight exhibited significant fluctuations, with the most pronounced deviation observed at 14 days. Blood counts revealed a rapid decline in white blood cells, red blood cells, and platelets post-irradiation, reaching nadirs at 7–14 days, followed by gradual recovery to near-normal levels by 28 days. Untargeted metabolomics identified 32 upregulated and 33 downregulated plasma metabolites at 14 days post-irradiation, while fecal metabolites showed 47 upregulated and 18 downregulated species at 3 days. Key metabolic pathways impacted included Glycerophospholipid metabolism, alpha-linolenic acid metabolism, and biosynthesis of unsaturated fatty acids. Gut microbiota analysis demonstrated no significant change in α-diversity but significant β-diversity shifts (p < 0.05), indicating a marked alteration in the compositional structure of the intestinal microbial community following radiation exposure. Principal coordinate analysis confirmed distinct clustering between control and irradiated groups, with increased abundance of Bacteroidota and decreased Firmicutes in irradiated rats. These findings highlight dynamic metabolic and microbial disruptions post-irradiation, with recovery patterns suggesting a 28-day restoration cycle. Spearman’s rank correlation analysis explored associations between the top 20 fecal metabolites and 50 abundant bacterial taxa. Norank_f_Muribaculaceae, Prevotellaceae_UCG-001, and Bacteroides showed significant correlations with various radiation-altered metabolites, highlighting metabolite–microbiota relationships post-radiation. Conclusions: This study provides insights into potential biomarkers for radiation-induced physiological damage and underscores the interplay between systemic metabolism and gut microbiota in radiation response. Full article

(This article belongs to the Section Advances in Metabolomics)

► Show Figures

Figure 1

29 pages, 2657 KiB

Open AccessReview

Bridging Ethnobotanical Knowledge and Multi-Omics Approaches for Plant-Derived Natural Product Discovery

by Kekeletso H. Chele, Lizelle A. Piater, Justin J. J. van der Hooft and Fidele Tugizimana

Metabolites 2025, 15(6), 362; https://doi.org/10.3390/metabo15060362 - 29 May 2025

Viewed by 317

Abstract

For centuries, plant-derived natural products (NPs) have been fundamental to traditional medicine, providing essential therapeutic compounds. Ethnobotanical knowledge has historically guided NP discovery, leading to the identification of key pharmaceuticals such as aspirin, morphine, and artemisinin. However, conventional bioactivity-guided fractionation methods for NP [...] Read more.

For centuries, plant-derived natural products (NPs) have been fundamental to traditional medicine, providing essential therapeutic compounds. Ethnobotanical knowledge has historically guided NP discovery, leading to the identification of key pharmaceuticals such as aspirin, morphine, and artemisinin. However, conventional bioactivity-guided fractionation methods for NP isolation are labour-intensive and can result in the loss of bioactive properties due to the focus on a single compound. Advances in omics sciences—genomics, transcriptomics, proteomics, metabolomics, and phenomics—coupled with computational tools have altogether revolutionised NP research by enabling high-throughput screening and more precise compound identification. This review explores how integrating traditional medicinal knowledge with multi-omics strategies enhances NP discovery. We highlight emerging bioinformatics tools, mass spectrometry techniques, and metabologenomics approaches that accelerate the identification, annotation, and functional characterisation of plant-derived metabolites. Additionally, we discuss challenges in omics data integration and propose strategies to harness ethnobotanical knowledge for targeted NP discovery and drug development. By combining traditional wisdom with modern scientific advancements, this integrated approach paves the way for novel therapeutic discoveries and the sustainable utilisation of medicinal plants. Full article

(This article belongs to the Section Plant Metabolism)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Metabolites, Volume 15, Issue 6 (June 2025) – 47 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI