Metabolites

19 pages, 586 KiB

Open AccessArticle

In Vitro Antioxidant, Antithrombotic and Anti-Inflammatory Activities of Bioactive Metabolites Extracted from Kiwi and Its By-Products

by Anastasia Maria Moysidou, Konstantina Cheimpeloglou, Spyridoula Ioanna Koutra, Vasileios Manousakis, Anna Ofrydopoulou, Katie Shiels, Sushanta Kumar Saha and Alexandros Tsoupras

Metabolites 2025, 15(6), 400; https://doi.org/10.3390/metabo15060400 - 13 Jun 2025

Abstract

Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and [...] Read more.

Background/Objectives: Growing interest in natural, health-promoting ingredients for functional foods, nutraceuticals, and cosmetics has increased the demand for bioactive compounds from kiwi (Actinidia deliciosa). This study aimed to assess the antioxidant, anti-inflammatory, and antithrombotic properties of amphiphilic bioactives extracted from kiwi fruit and its by-products, including peel, seeds, and pulp. Methods: Bioactive compounds were extracted and analyzed using liquid chromatography–mass spectrometry (LC–MS) and attenuated total reflectance–Fourier transform infrared (ATR–FTIR) spectroscopy. Antioxidant activity was evaluated using DPPH and ABTS radical scavenging assays. Anti-inflammatory and antithrombotic effects were assessed through inhibition of platelet aggregation induced by platelet-activating factor (PAF) and adenosine diphosphate (ADP) in human platelets. Results: All extracts showed significant antioxidant activity. FTIR and LC–MS analyses confirmed the presence of phenolics, flavonoids, carotenoids, and polar lipids. Kiwi peel extract exhibited the strongest inhibition of PAF- and ADP-induced platelet aggregation, attributed to its higher content of phenolics and unsaturated polar lipids. LC–MS data indicated a favorable fatty acid profile with high omega-9 levels and a low omega-6/omega-3 ratio. Polar lipid structural analysis revealed a predominance of phospholipids with unsaturated fatty acids at the sn-2 position. Conclusions: Kiwi by-products are valuable sources of health-promoting bioactives with antioxidant and anti-inflammatory potential. These findings support their incorporation into nutraceutical, nutricosmetic, and cosmeceutical products and lay the groundwork for further studies on safety, efficacy, and practical application. Full article

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

► Show Figures

Figure 1

14 pages, 4541 KiB

Open AccessArticle

A Systems Hypothesis of Lipopolysaccharide-Induced Vitamin Transport Suppression and Metabolic Reprogramming in Autism Spectrum Disorders: An Open Call for Validation and Therapeutic Translation

by Albion Dervishi

Metabolites 2025, 15(6), 399; https://doi.org/10.3390/metabo15060399 - 13 Jun 2025

Abstract

Background: Autism spectrum disorder (ASD) is increasingly linked to systemic metabolic dysfunction, potentially influenced by gut–brain axis dysregulation, but the underlying mechanisms remain unclear. Methods: We developed Personalized Metabolic Margin Mapping (PM³), a computational systems biology framework, to analyze RNA-seq data [...] Read more.

Background: Autism spectrum disorder (ASD) is increasingly linked to systemic metabolic dysfunction, potentially influenced by gut–brain axis dysregulation, but the underlying mechanisms remain unclear. Methods: We developed Personalized Metabolic Margin Mapping (PM³), a computational systems biology framework, to analyze RNA-seq data from 12 ASD and 12 control postmortem brain samples. The model focused on 158 curated metabolic genes selected for their roles in redox balance, mitochondrial function, neurodevelopment, and gut–brain interactions. Results: Using unsupervised machine learning (Isolation Forest) to detect outlier expression patterns, Euclidean distance, and percent expression difference metrics, PM³ revealed a consistent downregulation of glycolysis (e.g., −5.4% in PFKM) and mitochondrial enzymes (e.g., −12% in SUCLA2). By incorporating cofactor dependency and subcellular localization, PM³ identified a coordinated suppression of multivitamin transporters (e.g., −4.5% in SLC5A6, −3.5% in SLC19A2), potentially limiting cofactor availability and compounding energy deficits in ASD brains. Conclusions: These findings suggest a convergent metabolic dysregulation signature in ASD; wherein the subtle suppression of cofactor-dependent pathways may impair energy metabolism and neurodevelopment. We propose that chronic microbial lipopolysaccharide (LPS) exposure in ASD suppresses vitamin transporter function, initiating mitochondrial dysfunction and transcriptomic reprogramming. Validation in LPS-exposed systems using integrated transcriptomic–metabolomic analysis is warranted. Full article

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

► Show Figures

Graphical abstract

13 pages, 228 KiB

Open AccessArticle

Outcomes of Different Lifestyle Approaches in a Multicentre, Open-Label, Parallel-Group, Randomised Controlled Trial of the Effectiveness of Integrating a Pragmatic Pathway for Prescribing Liraglutide 3.0 mg in Weight Management Services (STRIVE Study)

by Werd Al-Najim, Babak Dehestani, Ahmed W. Al-Humadi, Danielle H. Bodicoat, Dimitris Papamargaritis, Michael Lean, Barbara McGowan, David R. Webb, John PH Wilding, Melanie J. Davies and Carel W. le Roux

Metabolites 2025, 15(6), 398; https://doi.org/10.3390/metabo15060398 - 13 Jun 2025

Abstract

Background/Objectives: The STRIVE study was a multicentre, open-label, real-world clinical trial evaluating the effectiveness of a targeted prescribing pathway for liraglutide 3.0 mg as an adjunct to standard care versus standard care alone in people with obesity attending Specialist Weight Management Services (SWMS) [...] Read more.

Background/Objectives: The STRIVE study was a multicentre, open-label, real-world clinical trial evaluating the effectiveness of a targeted prescribing pathway for liraglutide 3.0 mg as an adjunct to standard care versus standard care alone in people with obesity attending Specialist Weight Management Services (SWMS) in the UK and Ireland. This post hoc analysis focuses on the standard care arm to explore differences in outcomes between sites, particularly the potential impact of offering meal replacements as part of usual care. Methods: Participants included individuals with a BMI ≥ 35 kg/m² and at least one obesity-related complication who received standard care at five SWMS sites. All sites provided specialist nutrition and exercise counselling; however, only the Dublin site (n = 40) included meal replacements as part of routine care. Baseline characteristics and weight change data were compared between the Dublin and UK cohorts (n = 92) at 52 and 104 weeks. Statistical comparisons were made using appropriate parametric and non-parametric tests. Results: At baseline, the Dublin cohort was significantly older (p < 0.01), had a higher prevalence of hypertension (p < 0.05), and a lower reported incidence of depression/anxiety (p < 0.05) than the UK cohort. At week 52, the Dublin group achieved greater mean weight loss (−6.1%, SD ± 5.7%) compared to the UK cohort (−1.3%, SD ± 6.7%, n = 27, p < 0.01). By week 104, Dublin participants maintained a mean weight loss of −4.4% (SD ± 5.7%) while UK participants had a mean weight gain of 0.37% (SD ± 7.6%) (p < 0.05). Conclusions: The integration of meal replacements as part of usual care may have contributed to the greater and sustained weight loss observed in the Dublin cohort compared to other SWMS in the UK. Full article

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

30 pages, 1219 KiB

Open AccessReview

Gut Microbiota Dysbiosis and Its Impact on Type 2 Diabetes: From Pathogenesis to Therapeutic Strategies

by Yonghua Yu, Yilan Ding, Shuangyuan Wang and Lei Jiang

Metabolites 2025, 15(6), 397; https://doi.org/10.3390/metabo15060397 - 12 Jun 2025

Abstract

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including [...] Read more.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including shifts in the balance between Firmicutes and Bacteroidetes, a reduction in butyrate-producing bacteria, and an increase in opportunistic pathogens. Gut microbiota-derived metabolites—such as short-chain fatty acids, bile acids, and amino acids—have been implicated in the pathogenesis of T2DM, highlighting the critical role of host-microbe interactions. In this overview, we discuss the gut microbiota dysbiosis associated with T2DM and explore the molecular links between microbiota-derived metabolites and the pathogenesis of diseases. Additionally, we explore potential therapeutic strategies, including probiotics and dietary interventions, to modulate the gut microbiota and its metabolites, providing insights for future clinical research and the development of novel treatments for T2DM. Full article

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

► Show Figures

Figure 1

26 pages, 2650 KiB

Open AccessArticle

Combining Metabolomics and Proteomics to Reveal Key Serum Compounds Related to Canine Intervertebral Disc Herniation

by Anita Horvatić, Josipa Kuleš, Andrea Gelemanović, Ozren Smolec, Boris Pirkić, Marko Pećin, Ivana Rubić, Vladimir Mrljak, Marko Samardžija and Marija Lipar

Metabolites 2025, 15(6), 396; https://doi.org/10.3390/metabo15060396 - 12 Jun 2025

Abstract

Background/Objectives: Canine intervertebral disc herniation (IVDH) is an important musculoskeletal pathology. Unlike in humans, IVDH mechanisms in dogs are underinvestigated from a system-level integrative omics point of view. The aim of this study was to identify key serum molecular players in canine [...] Read more.

Background/Objectives: Canine intervertebral disc herniation (IVDH) is an important musculoskeletal pathology. Unlike in humans, IVDH mechanisms in dogs are underinvestigated from a system-level integrative omics point of view. The aim of this study was to identify key serum molecular players in canine IVDH. Methods: An integrative multi-omics approach combining high-resolution LC-MS-based untargeted metabolomics and tandem mass tag (TMT)-based proteomics was applied. Additionally, serum zinc concentration was determined by spectrophotometry. Results: Nineteen serum metabolites were differentially abundant in IVDH dogs. Metabolite analysis highlighted dysregulation in lipoic acid and branched-chain amino acid (BCAA) metabolism, with elevated levels of valine, leucine, and isoleucine in IVDH. These findings suggest disrupted energy, nitrogen, and neurotransmitter metabolism, potentially contributing to the IVDH pathophysiology. Additionally, lower serum uridine, possibly influenced by BCAA accumulation, was observed, indicating altered neuroinflammatory responses. ELISA validation confirmed elevated serum levels of zinc-α2-glycoprotein (ZAG), alpha-1-microglobulin/bikunin precursor (AMBP), and vitronectin (VTN) in IVDH, supporting immune modulation and neuroprotective mechanisms. Serum prekallikrein (KLKB1) and Protein C inhibitor (SERPINA5), involved in fibrin cloth formation, were found to be lowered in IVDH patients. Pathway enrichment revealed disturbances in aromatic amino acid biosynthesis, with elevated phenylalanine, tyrosine, and tryptophan influencing neurotransmission and inflammation. In addition, elevated serum Zn concentration emphasized its antioxidant importance in immune response, wound healing, and neuropathic pain signaling. Conclusions: Integration with our prior CSF multi-omics data reinforced the relevance of identified molecules in IVDH-associated neurodegeneration, inflammation, and repair processes. This study offers insight into potential diagnostic biomarkers and therapeutic targets for canine IVDH through serum-based molecular profiling. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Technology for Metabolic Profiling)

► Show Figures

Graphical abstract

15 pages, 1216 KiB

Open AccessArticle

Blood Metabolic Biomarkers of Diabetes Mellitus Type 2 in Aged Adults Determined by a UPLC-MS Metabolomic Approach

by Alba Simón, Daniel Bordonaba-Bosque, Olimpio Montero, Javier Solano-Castán and Irma Caro

Metabolites 2025, 15(6), 395; https://doi.org/10.3390/metabo15060395 - 12 Jun 2025

Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disease whose importance rises with aging, though it is also looming large in younger populations due to increasing obesity. Its effects may damage renal and heart functioning. Plasma biomarkers of T2DM have been shown [...] Read more.

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a metabolic disease whose importance rises with aging, though it is also looming large in younger populations due to increasing obesity. Its effects may damage renal and heart functioning. Plasma biomarkers of T2DM have been shown through metabolomic studies under different conditions, mainly obesity, but untargeted metabolomic studies on T2DM are lacking for elderly people. Methods: A UPLC-MS-based metabolomic approach was conducted to ascertain potential plasma biomarkers in a cohort older than 65 years. Results: The dipeptide Gly-His, along with diverse lysophosphatidylcholines (LPCs), mainly LPC(14:0) and LPC(20:4), and three gangliosides were found to have different plasma content in T2DM subjects compared to control (non-diabetic) subjects (NT2DM). LPC(20:4) exhibited a gender dependence, with statistically significant differences only in females. Gly-His correlated with MEDAS-14, whereas LPC(14:0) correlated with sugar-rich food consumption. Conclusions: As previously demonstrated for other conditions, mainly obesity, altered lipid metabolism was shown in this study to be a hallmark of T2DM in elderly people also. Full article

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

► Show Figures

Figure 1

20 pages, 4640 KiB

Open AccessArticle

Metabolite Profile and Metabolic Network Analysis of Walnuts (Juglans regia L.) in Response to Chilling Stress

by Kai Liu, Yang Li, Yaxin Sang, Yaru Zhang, Xiuhong An, Hongxia Wang and Ruifen Zhang

Metabolites 2025, 15(6), 394; https://doi.org/10.3390/metabo15060394 - 12 Jun 2025

Abstract

Background: Walnut (Juglans regia L.) is a species of considerable ecological, social, and economic importance. However, comprehensive metabolomic investigations into walnut cultivars under chilling stress remain scarce. Methods: In this study, we utilized LC-MS/MS-based non-targeted metabolomics to analyze differential metabolites in two [...] Read more.

Background: Walnut (Juglans regia L.) is a species of considerable ecological, social, and economic importance. However, comprehensive metabolomic investigations into walnut cultivars under chilling stress remain scarce. Methods: In this study, we utilized LC-MS/MS-based non-targeted metabolomics to analyze differential metabolites in two walnut cultivars exposed to chilling stress at 0.5 °C for 0 and 48 h. Results: A total of 1504 metabolites were identified, including 871 in positive ion mode and 633 in negative ion mode. Specifically, 160 and 287 differential metabolites were detected in ‘Qingxiang’ and ‘Liaoning No.8’, respectively, under positive ion mode. In negative ion mode, 83 and 206 differential metabolites were identified in ‘Qingxiang’ and ‘Liaoning No.8’, respectively. These metabolites were primarily associated with α-linolenic acid metabolism, phenylpropanoid biosynthesis, flavonoid biosynthesis, and phenylalanine metabolism, and multiple candidate genes were obtained that exhibit significant correlations with metabolites, suggesting their critical roles in the walnut’s response to chilling stress. Conclusions: This study proposes a metabolic network for walnut leaves under chilling stress, enriching our understanding of the metabolic adaptation mechanisms of walnuts to low-temperature conditions. It lays a foundation for investigating the regulatory mechanisms of metabolite synthesis under cold stress and provides important theoretical insights for breeding cold-resistant walnut cultivars. Full article

(This article belongs to the Section Plant Metabolism)

► Show Figures

Figure 1

22 pages, 30677 KiB

Open AccessArticle

Mitochondrial Translation Inhibition Uncovers a Critical Metabolic–Epigenetic Interface in Renal Cell Carcinoma

by Kazumi Eckenstein, Beyza Cengiz, Matthew E. K. Chang, Jessie May Cartier, Mark R. Flory and George V. Thomas

Metabolites 2025, 15(6), 393; https://doi.org/10.3390/metabo15060393 - 12 Jun 2025

Abstract

Background/Objectives: Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. Methods: We employed comprehensive metabolomic [...] Read more.

Background/Objectives: Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. Methods: We employed comprehensive metabolomic profiling, subcellular proteomics, and functional assays to characterize the effects of tigecycline on RCC cell lines, patient-derived organoids, and xenograft models. The synergistic potential of tigecycline with the histone deacetylase inhibitor entinostat was evaluated using combination index analysis. Results: Tigecycline selectively inhibited mitochondrial translation in RCC cells, reducing mitochondrially-encoded proteins while sparing nuclear-encoded components, profoundly disrupting mitochondrial bioenergetics and reducing tumor growth in xenograft models. Subcellular proteomic analyses revealed that tigecycline treatment triggered a significant accumulation of multiple histone variants concurrent with cell cycle arrest. Based on this discovery, combined treatment with tigecycline and entinostat demonstrated remarkable synergism across RCC cell lines and patient-derived. Conclusions: Our findings identify a promising therapeutic opportunity by targeting the crosstalk between mitochondrial function and epigenetic homeostasis in RCC, with the potential for rapid clinical translation given the established pharmacological profiles of both agents. Full article

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

► Show Figures

Figure 1

15 pages, 1180 KiB

Open AccessArticle

Differential Expression of Lipid Metabolism Genes, CROT and ABCG1, in Obese Patients with Comorbid Depressive Disorder and Risk of MASLD

by Joanna Michalina Jurek, Elena Cristina Rusu, Javier Camaron, Helena Clavero-Mestres, Carmen Aguilar, David Riesco, Belen Xifré, Javier U. Chicote, Salomé Martinez, Marga Vives, Fàtima Sabench and Teresa Auguet

Metabolites 2025, 15(6), 392; https://doi.org/10.3390/metabo15060392 - 11 Jun 2025

Abstract

Background: There is accumulating evidence supporting a bidirectional relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and depressive disorder (DD), with possible genetic factors related to hepatic lipid metabolism. Our aim was to analyse the prevalence of DD in patients with obesity at [...] Read more.

Background: There is accumulating evidence supporting a bidirectional relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and depressive disorder (DD), with possible genetic factors related to hepatic lipid metabolism. Our aim was to analyse the prevalence of DD in patients with obesity at risk of MASLD, and to evaluate the hepatic expression of genes involved in lipid metabolism, in patients with DD. Methods: In 152 patients with morbid obesity who underwent bariatric surgery, medical data, blood and liver samples were collected. Liver biopsies were scored for MASLD staging were used for gene expression analysis. Results: The DD prevalence in this cohort was 29.6%, and patients with DD had a significantly higher hepatic expression of the CROT and ABCG1 genes. Moreover, patients in the MASLD group showed significantly higher relative hepatic expression of SREBP1 and ABCG1 genes compared to the normal liver group. Some anthropometric and clinical measures (BMI and DBP) were positively correlated with the expression of SREBP2, ABCG1 and CROT genes, while the expression of CPT1α was negatively correlated with age, SBP and DBP. There was a positive relationship between GGT and ALP levels and the relative expression of ABCG1 and ACC1 genes. Conclusions: In this study, individuals with morbid obesity demonstrated an elevated prevalence of DD. Moreover, hepatic genetic dysregulation of lipid metabolism may influence the interplay between MASLD and DD in patients with morbid obesity. Full article

(This article belongs to the Section Lipid Metabolism)

► Show Figures

Figure 1

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 - 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

Elucidation of Mechanisms by Which Microplastics (PET) Facilitates the Rapid Growth of Benthic Cyanobacteria and Toxin Production in Aquatic Ecosystems

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

Journal Description

Metabolites

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI