Metabolites

29 pages, 3281 KB

Open AccessReview

Ganoderma lucidum as a Functional Bioactive Candidate for Glycemic Regulation: Mechanisms, Preclinical Evidence, and Clinical Translation

by Bogdan Florea, Doru Morar, Corina Marina Kracunovic, Simina Velescu, Vlad Iorgoni, Paula Nistor, Janos Degi, Ionica Iancu, Maria-Larisa Ardelean (Rusu), Romeo Teodor Cristina, Alexandra Pocinoc and Eugenia Dumitrescu

Metabolites 2026, 16(5), 334; https://doi.org/10.3390/metabo16050334 - 15 May 2026

Abstract

Type 2 diabetes mellitus (T2DM) is a major global health challenge that has intensified interest in multi-target nutraceuticals with potential adjunctive benefits. Ganoderma lucidum (Lingzhi/Reishi) is a medicinal mushroom traditionally used in East Asia and is increasingly investigated for its role in glycemic [...] Read more.

Type 2 diabetes mellitus (T2DM) is a major global health challenge that has intensified interest in multi-target nutraceuticals with potential adjunctive benefits. Ganoderma lucidum (Lingzhi/Reishi) is a medicinal mushroom traditionally used in East Asia and is increasingly investigated for its role in glycemic regulation and metabolic disturbances. This review critically synthesizes current evidence on its hypoglycemic effects, focusing on bioactive compounds, molecular mechanisms, and translational limitations. Unlike broader reviews on Ganoderma bioactivity and health-related benefits, this review specifically evaluates the alignment between taxonomic authentication, chemical standardization, preclinical mechanisms, and human clinical evidence in the context of glycemic regulation. This narrative review was based on a targeted literature search conducted in PubMed/MEDLINE, Web of Science, and Scopus for studies published up to October 2025, supplemented by Google Scholar. The included studies comprised in vitro experiments, in vivo animal models, and human clinical trials evaluating glycemic and metabolic outcomes of Ganoderma preparations. In vitro and animal studies indicate that polysaccharides, including β-(1→3)/(1→6)-glucans and proteoglycans such as FYGL, may improve insulin sensitivity via AMPK (AMP-activated protein kinase) and PI3K/Akt pathways, promote GLUT4 (glucose transporter type 4) translocation, suppress hepatic gluconeogenesis, protect pancreatic β-cells, and modulate gut microbiota. In enzyme assays and preclinical models, lanostane-type triterpenoids act primarily by inhibiting α-glucosidase and α-amylase, thereby potentially reducing postprandial glucose excursions. Despite consistent preclinical evidence, clinical findings remain heterogeneous, with the largest randomized controlled trial reporting no significant glycemic benefit. Overall, Ganoderma lucidum shows strong mechanistic plausibility but insufficient clinical evidence for antidiabetic efficacy. Future research should prioritize species authentication, chemical standardization, and adequately powered clinical trials. Full article

(This article belongs to the Special Issue Functional Foods and Natural Bioactive Compounds: Strategies to Face Metabolic Syndrome and Related Non-Communicable Diseases—2nd Edition)

► Show Figures

Figure 1

27 pages, 4164 KB

Open AccessArticle

A Multi-Omics Approach Uncovers Divergent Mechanisms of Asthma in Normal Weight and Obese Children

by Ilhame Diboun, Harshita Shailesh, Shana Jacob, Mohamed A. Elrayess, Stefan Worgall, Younes Mokrab and Ibrahim Janahi

Metabolites 2026, 16(5), 333; https://doi.org/10.3390/metabo16050333 - 15 May 2026

Abstract

Background: Children with obesity-related asthma exhibit poorer symptom control and more frequent exacerbations than their normal-weight peers, but the underlying metabolic mechanisms are unclear. This study aimed to identify drivers of obesity-related asthma through untargeted plasma metabolomic and lipidomic profiling. Methods: [...] Read more.

Background: Children with obesity-related asthma exhibit poorer symptom control and more frequent exacerbations than their normal-weight peers, but the underlying metabolic mechanisms are unclear. This study aimed to identify drivers of obesity-related asthma through untargeted plasma metabolomic and lipidomic profiling. Methods: Plasma was obtained from normal weight (NW) asthmatic (n = 95) and non-asthmatic (n = 67) and overweight/obese (OO) asthmatic (n = 99) and non-asthmatic (n = 100) children (6–17 years). We assessed metabolic and lipidomic differences between asthmatics and controls within each BMI group using orthogonal partial least squares discriminant analysis (OPLS-DA), examined overlap with the adult Qatar Biobank cohort, and mapped metabolic–clinical interactions using Gaussian Graphical Models. Results: In the fitted OPLS-DA models, separation between asthmatic and control groups was stronger in the NW group (R²Y = 0.72/0.52) than in OO (R²Y = 0.65/0.63) children. Asthma was associated with altered tricarboxylic acid (TCA) intermediates, ether-linked phosphatidylethanolamines, and sphingomyelins (SM) in NW, and with phosphatidylcholines, lysophosphatidylcholines, and phosphatidylethanolamines in OO. Integrating metabolomic, lipidomic, and clinical data revealed connections between altered SMs and interleukins, and TCA intermediates and electrolytes, all associated with elevated leptin in NW. An increased residual volume to total lung capacity ratio in OO was associated with phospholipid shifts. The overall dynamics in lipid metabolism with asthma, conditioned on BMI, was also observed in the adult Qatar Biobank cohort. Conclusions: Among NW children with asthma, we found enhanced TCA cycle activity and inflammation linked to altered SM metabolism, whereas in OO, the findings suggest oxidative stress arising from chronic obesity-related inflammation. These data reveal BMI-specific metabolic mechanisms of pediatric asthma that might inform precision approaches to disease management. Full article

(This article belongs to the Special Issue Metabolic Signatures of Pediatric Endocrine and Metabolic Disorders)

► Show Figures

Graphical abstract

22 pages, 4418 KB

Open AccessArticle

Mechanistic Investigation of Vitexin in Ameliorating Ovarian Fibrosis in PCOS Mice via the NR4A1/NLRP3 Signaling Pathway

by Haoran Sun, Jiejing Xu, Chengxue Pan, Jia-Le Song and Yanyuan Zhou

Metabolites 2026, 16(5), 332; https://doi.org/10.3390/metabo16050332 - 15 May 2026

Abstract

Objective: In this study, Dehydroepiandrosterone (DHEA-induced Polycystic Ovary Syndrome (PCOS) mice were used as models to evaluate the improvement effect of Vitexin (Vit) on ovarian fibrosis and explore the mechanism of action of the NR4A1/NLRP3 signaling pathway. Method: Sixty 4-week-old female ICR mice [...] Read more.

Objective: In this study, Dehydroepiandrosterone (DHEA-induced Polycystic Ovary Syndrome (PCOS) mice were used as models to evaluate the improvement effect of Vitexin (Vit) on ovarian fibrosis and explore the mechanism of action of the NR4A1/NLRP3 signaling pathway. Method: Sixty 4-week-old female ICR mice of the same batch number were selected and their systems were divided into 6 groups (n = 10): normal (Control, Ctrl) group, model (Polycystic Ovary Syndrome, PCOS) group, treatment (Vitexin, The Vit group, normal NR4A1 gene silencing group (Ctrl NR4A1^-/-), NR4A1 gene silencing model group (PCOS NR4A1^-/-), and NR4A1 gene silencing treatment group (Vit NR4A1^-/-). Silencing gene modeling was performed by tail vein injection of adeno-associated virus (serotype AAV-8), and the mouse genotypes were detected by qRT-PCR technology 14 days after injection. After the genotype was determined, the PCOS group and the PCOS NR4A1^-/- group were administered dehydroepandrosterone (6 mg/100 g/d) by gavage for 28 consecutive days for modeling, while the Vit group and the Vit NR4A1^-/- group were treated with dehydroepandrosterone + vitexin (10 mg/kg/d) by gavage for 28 consecutive days. All mice were raised with pure water and regular maintenance food. After 4 weeks of drug intervention, the mice were euthanized and samples were collected. The pathological changes in ovarian tissue were observed by H&E staining, and the degree of ovarian tissue fibrosis was observed by Masson staining. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in mouse serum were detected by biochemical kits. The levels of inflammatory factors (IL-1β, IL-6, IL-18, TNF-α) in mouse serum were determined by enzyme-linked immunosorbent assay. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect oxidative kinase (Gsta4, Prdx3, Mgst1, Gpx3, Gsr), inflammatory factors (Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tnf-α) and fibrotic pathway-related genes (Tgf-β1, Smad3, Collagen1, CTGF, α-SMA, Mmp-13, and β-catenin) in ovarian tissues. The levels of inflammatory factors (NLRP3, Caspase-1, ASC, IL-1β, IL-18, TNF-α, IκBα) and fibrosis in mice were determined by Western blot method, and statistical description and analysis were performed using SPSS software. Result: In the wild-type genotype group, compared with the PCOS group, Vit treatment could effectively regulate the metabolic abnormalities of PCOS mice, including inhibiting excessive weight gain, restoring normal glucose tolerance, and reducing body fat content. After Vit treatment, the levels of MDA, TC, TG, LDL, IL-1β, IL-6, IL-18 and TNF-α in the serum of PCOS mice were significantly reduced, while the levels of SOD and HDL in the serum of PCOS mice were increased. The staining results indicated that Vit treatment could significantly inhibit the process of ovarian fibrosis in PCOS mice. The results of WB and PCR demonstrated that after Vit gavage treatment in mice, inflammatory and fibrotic factors such as Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tgf-β1, Smad3, Collagen1, CTGF, and α-SMA in ovarian tissues could be significantly down-regulated, and the fibrotic level of ovarian tissues could be reduced. Among the same measurement indicators, the silenced NR4A1 group showed a certain degree of increase compared with the wild genotype group, but there was no significant difference. Conclusions: Vit intervention can restore the sex hormone levels and follicular development in ovarian tissues of PCOS mice, regulate reproductive endocrine disorders and abnormal lipid metabolism levels, and regulate the expression of Collagen I, a-SMA and CTGF in the ovaries by inhibiting the NR4A1/NLRP3 signaling pathway, thereby improving the ovarian fibrosis level of PCOS mice. It is suggested that it may play a key role in the treatment of PCOS and the prevention and delay of its long-term complications. Full article

(This article belongs to the Section Plant Metabolism)

► Show Figures

Figure 1

17 pages, 6697 KB

Open AccessArticle

Annexin A2 Is Associated with Dietary Cholesterol-Induced Metabolic Dysregulation and the Progression of Hepatic Fibrosis

by Jiayang Liu, Ling Ou, Haiyan Tai, Yinghan Chai, Lirong Tan, Jie Lin, Bing Li, Ying Cao and Tingting Zhu

Metabolites 2026, 16(5), 331; https://doi.org/10.3390/metabo16050331 - 15 May 2026

Abstract

Background/Objectives: Dietary cholesterol intake significantly influences liver health, yet the specific molecular mechanisms by which it accelerates fibrogenesis remain incompletely defined. This study aimed to characterize the dose-dependent effects of dietary cholesterol on hepatic injury and fibrogenesis, identify cholesterol-responsive gene networks through [...] Read more.

Background/Objectives: Dietary cholesterol intake significantly influences liver health, yet the specific molecular mechanisms by which it accelerates fibrogenesis remain incompletely defined. This study aimed to characterize the dose-dependent effects of dietary cholesterol on hepatic injury and fibrogenesis, identify cholesterol-responsive gene networks through transcriptomic analysis, and investigate Annexin A2 (ANXA2) as a candidate molecular mediator linking dietary cholesterol to hepatic fibrosis progression. Methods: A CCl₄-induced liver fibrosis mouse model was established and supplemented with dietary cholesterol (1–2%). Liver injury and fibrosis were assessed by liver-to-body weight ratios, serum biochemical markers, histological analysis, and fibrogenic gene expression. RNA sequencing combined with multiple hepatic fibrosis database analyses was performed to identify potential molecular mediators. Results: Dietary cholesterol supplementation aggravated CCl₄-induced hepatic fibrosis in mice, with dose-dependent increases in liver-to-body weight ratios and serum AST and ALT levels. Histological analysis showed enhanced collagen deposition and upregulation of fibrogenic genes. By integrating RNA-sequencing with multiple hepatic fibrosis database analysis and correlation analysis, we identified Annexin A2 (ANXA2) as a cholesterol-responsive gene associated with fibrosis. Conclusions: Dietary cholesterol promotes liver fibrosis progression, and ANXA2 may act as a potential mediator linking cholesterol metabolism to hepatic fibrogenesis. Full article

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

► Show Figures

Figure 1

19 pages, 8640 KB

Open AccessSystematic Review

Lipidomic Signatures in Feline Disease: A PRISMA-Guided Systematic Review

by Ana Carolina Fontes, Carolina Santos Silva, Ana Carolina Matos, Isabel Ribeiro Dias, Francisco Peixoto, Maria Manuel Oliveira, Maria Rosario Domingues and Carlos Antunes Viegas

Metabolites 2026, 16(5), 330; https://doi.org/10.3390/metabo16050330 - 15 May 2026

Abstract

Background/Objectives: Lipidomics has become a key component of systems biology, enabling comprehensive characterisation of lipid species and their roles in health and disease. As regulators of membrane architecture, energy balance, inflammation, and cellular signalling, lipids offer a powerful framework for understanding metabolic [...] Read more.

Background/Objectives: Lipidomics has become a key component of systems biology, enabling comprehensive characterisation of lipid species and their roles in health and disease. As regulators of membrane architecture, energy balance, inflammation, and cellular signalling, lipids offer a powerful framework for understanding metabolic dysfunction. In veterinary medicine, however, lipidomics remains comparatively underdeveloped. In cats, lipid metabolism is central to disorders such as hepatic lipidosis, cystitis, obesity, diabetes mellitus, and chronic inflammatory enteropathies, yet available data remain limited. This systematic review synthesised current evidence on lipidomics and lipid-focused profiling in feline disease and identified lipid alterations with potential clinical relevance. Methods: Following PRISMA 2020 guidelines, PubMed, ScienceDirect, and Scopus were searched for original studies (1994–2026) evaluating lipidomics or lipid-focused profiling in cats. Eligible studies assessed lipid species, fatty acids, lipid mediators, or lipoproteins in disease or physiological states. Owing to methodological heterogeneity, findings were synthesised narratively. Results: Seventeen studies met inclusion criteria, covering hepatic, urinary, gastrointestinal, renal, neurological, oncological, metabolic, and pharmacologically modulated conditions. Recurring alterations involved lipoproteins, triglycerides, phospholipids, sphingolipids, fatty acids, and oxylipins. More consistent patterns emerged in hepatic lipidosis, where lipoprotein disturbances may aid diagnosis; in lower urinary tract disease, where PUFA-derived oxylipins differentiated bacterial from idiopathic cystitis; and in obesity, where phospholipid and triglyceride shifts reflected metabolic risk. Fatty acid remodelling in chronic enteropathies aligned with mucosal inflammation, while sphingolipid changes in neurological disease correlated with severity. Heterogeneity in analytical platforms, dietary control, and study design limited comparability. Conclusions: Feline lipidomics reveals biologically meaningful alterations with emerging diagnostic and prognostic value. Although still developing, lipid-focused approaches may enhance disease characterisation and support translational research. Larger, standardised studies and robust reference datasets are needed to validate lipid signatures for clinical implementation. Full article

(This article belongs to the Topic New Perspectives on Metabolism and Metabolic Disease in Wildlife, Domestic, and Exotic Pets and Livestock)

► Show Figures

Figure 1

18 pages, 28651 KB

Open AccessArticle

Regulation of Mitophagy by Low-Intensity Pulsed Ultrasound Attenuates Endothelial Dysfunction

by Yucong Shi, Baotian Zhao, Yuhong Wei, Dongxu Lu, Haixia Liu and Yinzhu Chu

Metabolites 2026, 16(5), 329; https://doi.org/10.3390/metabo16050329 - 15 May 2026

Abstract

Background: Diabetic vascular complications are a major cause of poor prognosis in patients with diabetes mellitus (DM). Mitophagy activation is a potential therapeutic target for type 2 diabetes mellitus (T2DM), but the role of low-intensity pulsed ultrasound (LIPUS) in this context remains [...] Read more.

Background: Diabetic vascular complications are a major cause of poor prognosis in patients with diabetes mellitus (DM). Mitophagy activation is a potential therapeutic target for type 2 diabetes mellitus (T2DM), but the role of low-intensity pulsed ultrasound (LIPUS) in this context remains unclear. Methods: The biological effects of LIPUS on endothelial cells under high glucose conditions were systematically evaluated using high glucose-treated human umbilical vein endothelial cells (HUVECs) and aortic tissues from diabetic rats as models, in combination with bioinformatics analysis and standard molecular and cellular biology techniques. Histological staining was further used to assess the protective role of LIPUS in the aortas of diabetic rats. Results: Bioinformatics analysis predicted that high glucose induces mitochondrial dysfunction, suppresses autophagy in HUVECs, impairs endothelial cell function, and activates fibroblasts. In vitro results were in agreement with these predictions. LIPUS treatment significantly counteracted these effects, restoring migration (p < 0.001) and angiogenesis (p < 0.05), increasing proliferation (p < 0.001), and decreasing apoptosis (p < 0.05). Mechanistically, LIPUS enhanced mitophagy, and its therapeutic effects were markedly diminished upon addition of the autophagy inhibitor 3-Methyladenine (3-MA). In vivo, LIPUS attenuated aortic endothelial damage and reduced collagen deposition in diabetic rats (p < 0.01). Conclusions: LIPUS may ameliorate hyperglycemia-induced endothelial cell dysfunction by activating mitophagy, and it also attenuates pathological damage in the abdominal aorta of diabetic rats, thereby providing experimental evidence for its application in the treatment of diabetic macrovascular complications. Full article

(This article belongs to the Special Issue Metabolic Modulators in Cardiovascular Disease Management)

► Show Figures

Graphical abstract

10 pages, 235 KB

Open AccessArticle

Exploratory Associations of Inflammatory Cytokines, Brain-Derived Neurotrophic Factor, and Vascular Endothelial Growth Factor with Clinical Outcomes in Patients with Bipolar Disorder

by Fumito Hamada, Leo Gotoh, Yuko Tomiyama, Hiroko Sugawara, Muneaki Ogata, Hiroki Kumagai, Ryo Asada, Ryusei Hatae, Kiyohiro Yasumatsu and Hikaru Hori

Metabolites 2026, 16(5), 328; https://doi.org/10.3390/metabo16050328 - 14 May 2026

Abstract

Background/Objectives: Bipolar disorder is characterized by psychosocial dysfunction, cognitive impairment, and incomplete recovery. Although inflammatory and neurotrophic mechanisms have been implicated, their relationships with multidimensional recovery outcomes remain unclear. We examined the relationships of inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and vascular endothelial [...] Read more.

Background/Objectives: Bipolar disorder is characterized by psychosocial dysfunction, cognitive impairment, and incomplete recovery. Although inflammatory and neurotrophic mechanisms have been implicated, their relationships with multidimensional recovery outcomes remain unclear. We examined the relationships of inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) with depressive symptoms, psychosocial functioning, cognitive performance, personal recovery, and quality of life (QOL) in patients with bipolar disorder. Methods: This cross-sectional study of 24 patients with bipolar disorder assessed depressive symptoms, psychosocial functioning, cognitive functions, personal recovery, and QOL. Plasma tumor necrosis factor alpha, interleukin (IL)-6, IL-1β, IL-2, BDNF, and VEGF-A were measured by assay. Results: Subjective cognitive dysfunction was significantly associated with depressive symptom severity (rho = 0.53, p = 0.0083) and reduced QOL (rho = −0.56, p = 0.0042). Depressive symptoms were also associated with lower WHO-QOL-26 scores (rho = −0.43, p = 0.038). Significant interrelationships were observed among objective cognitive measures, and after false discovery rate (FDR) correction, the associations between FAST and PDQ-5-D, Symbol Check and Codebreaker, and Codebreaker and Trail remained statistically significant. High plasma IL-6 levels were associated with worse executive function (rho = 0.43, p = 0.0068). Higher VEGF levels were associated with better attentional performance (rho = −0.42, p = 0.042). Plasma IL-1β levels were positively associated with QOL (rho = 0.54, p = 0.02). After FDR correction, only the association between IL-1β and QOL remained statistically significant. Conclusions: This pilot study suggests that there may be associations between cognitive impairment and cytokines, as well as between quality of life and VEGF, in bipolar disorder. Further studies with larger sample sizes are needed. Full article

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

25 pages, 2618 KB

Open AccessArticle

Unveiling the Brain-Penetrating Material Basis of Dragon’s Blood: Identification of Active Metabolites and Metabolic Pathways for Ischemic Stroke Therapy

by Yu Zhu, Jiahui Ren, Meijia Chen, Jianglong Chen and Guang Li

Metabolites 2026, 16(5), 327; https://doi.org/10.3390/metabo16050327 - 14 May 2026

Abstract

Background: Dragon’s blood (dried resin of Dracaena cochinchinensis (Lour.) S.C.Chen) is a classic traditional medicine for treating ischemic stroke, yet its bioactive components capable of penetrating the blood–brain barrier (BBB) remain ill-defined. This study aims to elucidate its material basis and the [...] Read more.

Background: Dragon’s blood (dried resin of Dracaena cochinchinensis (Lour.) S.C.Chen) is a classic traditional medicine for treating ischemic stroke, yet its bioactive components capable of penetrating the blood–brain barrier (BBB) remain ill-defined. This study aims to elucidate its material basis and the synergistic mechanism of Borneol as a “guide drug.” Methods: A systematic strategy integrating UHPLC-Q-TOF-MS/MS and metabolomics was employed to map the chemical profile of dragon’s blood and identify its migrating constituents in rats. Results: A total of 96 compounds were characterized in vitro. In vivo analysis of the cerebrospinal fluid (CSF) revealed a brain-penetrating profile that was significantly enriched by Borneol, with the number of detected constituents increasing from 11 in the DB group to 16 in the DB + B group. The results demonstrated that demethylation, glycoside hydrolysis, and oxidation are primary metabolic pathways, validating a “pro-drug” mechanism where aglycones and hydroxylated derivatives act as the central effectors. Notably, Borneol not only enhanced the BBB permeability of lipophilic flavonoids but also facilitated unique metabolic transformations, such as the cyclization of berberrubine to coptisine. Conclusions: This study elucidates the brain-penetrating material basis of dragon’s blood and reveals the dual synergistic mechanism of Borneol involving both physical permeation enhancement and metabolic modulation, offering scientific evidence for its clinical application in central nervous system diseases. Full article

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

► Show Figures

Figure 1

19 pages, 3816 KB

Open AccessArticle

Untargeted Metabolomics Reveals Region-Specific Metabolic Signatures and Discriminative Markers in Goji Berry (Lycium barbarum L.)

by Yan Yan, Wei Ma, Yage Li, Chen Zhang, Fang Li, Tianqing Huang, Beibei Gao, Huihui Meng, Yunfei Hu and Huan Wu

Metabolites 2026, 16(5), 326; https://doi.org/10.3390/metabo16050326 - 14 May 2026

Abstract

Background/Objectives: Goji berry (Lycium barbarum L.), renowned as a typical medicinal and edible plant, is mainly cultivated across four agroclimatic zones in China, including semi-arid, arid, monsoon, and high-altitude regions. Ningxia has long been recognized as the daodi production area for [...] Read more.

Background/Objectives: Goji berry (Lycium barbarum L.), renowned as a typical medicinal and edible plant, is mainly cultivated across four agroclimatic zones in China, including semi-arid, arid, monsoon, and high-altitude regions. Ningxia has long been recognized as the daodi production area for goji berries. However, the metabolic diversity of goji berries from other core cultivation regions and how these differences are shaped by local environments remain poorly understood. Methods: In this study, untargeted metabolomics was employed to comprehensively investigate the metabolic difference in goji across seven production regions. By integrating multivariate analysis with KEGG pathway enrichment (p < 0.05), 49 discriminative markers enriched in 10 key pathways were putatively identified, and their roles in plant stress tolerance were elucidated. In addition, we conducted targeted quantification of key bioactive components and antioxidant capacity. Results: Significant regional differences were revealed. Redundancy analysis further identified rainfall, temperature, and UV radiation as the key climatic drivers of this variation. Conclusions: These findings provide insights into the metabolic adaptation of goji to local environments and serve as a basis for further functional studies. Full article

(This article belongs to the Special Issue Metabolites and Plant Stress Resistance)

► Show Figures

Figure 1

14 pages, 1807 KB

Open AccessArticle

Polystyrene Microplastics and Lead Co-Exposure Disturbed Hepatic Lipid Metabolism in C57BL/6 Mice

by Bei Gao, Mengru Wei, Meng Zhao, Weichen Xu, Guangyuan Liu, Weishou Shen, Pengcheng Tu and Jinjun Shan

Metabolites 2026, 16(5), 325; https://doi.org/10.3390/metabo16050325 - 13 May 2026

Abstract

Background: Microplastics and lead are ubiquitous pollutants in the environment, frequently found in soil, water and food. Although the toxicity of individual exposure to microplastics and lead has been well studied, research on their co-exposure effects is still emerging. Methods: In this [...] Read more.

Background: Microplastics and lead are ubiquitous pollutants in the environment, frequently found in soil, water and food. Although the toxicity of individual exposure to microplastics and lead has been well studied, research on their co-exposure effects is still emerging. Methods: In this study, we investigated the impacts of polystyrene microplastics and lead co-exposure on hepatic lipid metabolism through transcriptomics and untargeted lipidomics profiling in C57BL/6 mice. Results: Gene set enrichment analysis of the transcriptomics data revealed the fatty acid metabolism was significantly disrupted by the co-exposure in male mice. Consistently, pathway analysis of lipidomics data showed that several fatty acid pathways were activated by the co-exposure in male mice, including fatty acid (20:1) → fatty acid (22:1) → fatty acid (24:1), fatty acid (20:0) → fatty acid (22:0) → fatty acid (24:0), fatty acid (18:1) → fatty acid (18:2) → fatty acid (20:2), fatty acid (18:1) → fatty acid (18:2) → fatty acid (18:3) → fatty acid (18:4); meanwhile, fatty acid (18:4) → fatty acid (20:4) → fatty acid (22:4), fatty acid (18:4) → fatty acid (20:4) → fatty acid (20:5) were suppressed. Transition from diacylglycerol to phosphatidylethanolamine and from phosphatidylserine to phosphatidylethanolamine were activated by the co-exposure in male mice; meanwhile transition from phosphatidylserine to phosphatidylethanolamine was activated in female mice. Conclusions: Our findings suggested that hepatic lipid metabolism was disturbed by the co-exposure of polystyrene microplastics and lead, which provide insights into the combined exposure risks of microplastics and heavy metals. Full article

(This article belongs to the Section Environmental Metabolomics)

13 pages, 1695 KB

Open AccessArticle

Chronic Nitrous Oxide Exposure Disrupts Metabolism in Mice: A Plasma Untargeted Metabolomics Study

by Juan Jia, Fenglin Zhang, Wen Zhang, Congying Liu, Keming Yun, Yujin Wang and Jiangwei Yan

Metabolites 2026, 16(5), 324; https://doi.org/10.3390/metabo16050324 - 13 May 2026

Abstract

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O [...] Read more.

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O exposure. Method: In this study, we investigated the effects of chronic N₂O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N₂O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites. Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism. Conclusions: Our data indicate that chronic N₂O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B₁₂, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N₂O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N₂O exposure. Full article

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

► Show Figures

Figure 1

23 pages, 9939 KB

Open AccessArticle

Extraction Temperatures Shape Water-Soluble Metabolite Profiles of Nepeta nuda L. and thus Modulate the Bioactive Properties

by Desislava Mantovska, Alexandra Kapogianni, Ginka Cholakova, Ivanka Tsacheva, Anton Hinkov, Detelina Petrova, Zlatina Gospodinova, Georgi Antov, Danijela Mišić, Krasimir Rusanov, Mila Rusanova, Kalina Shishkova, Momchil Paunov, Zhenya Yordanova and Miroslava Zhiponova

Metabolites 2026, 16(5), 323; https://doi.org/10.3390/metabo16050323 - 13 May 2026

Abstract

Background: Plants of the genus Nepeta are widely used in ethnomedicine for treating inflammatory disorders due to their rich content of bioactive compounds. This study investigated how extraction temperature specifically affects the bioactive potential of aqueous extracts from wild-grown Nepeta nuda L. Methods: [...] Read more.

Background: Plants of the genus Nepeta are widely used in ethnomedicine for treating inflammatory disorders due to their rich content of bioactive compounds. This study investigated how extraction temperature specifically affects the bioactive potential of aqueous extracts from wild-grown Nepeta nuda L. Methods: The previously used maceration approach for this plant was applied at 30–60 °C to flowers, leaves, and stems. Phytochemical profiling included spectrophotometric assays, metabolite identification, and quantification. Biological activities reported for this plant were assessed, including antioxidant, anti-inflammatory, antiviral, antiproliferative, and antibacterial capacities. Results: Extraction yield was highest in flowers and leaves, where it increased significantly with rising temperature, while stems were less productive. All plant organs exhibited notable bioactivity falling into two groups: lower temperatures (30 and 40 °C) were optimal for antiviral and anti-inflammatory effects, whereas and higher temperatures (50 and 60 °C) enhanced antioxidant potential. The phytochemical composition, evaluated at representative extraction temperatures, revealed differential accumulation of p-coumaric acid and luteolin in all organs at 40 °C, while extraction at 60 °C corresponded to elevated levels of phenolic compounds. Flower extracts were confirmed to have the richest metabolic composition and were therefore subjected to further investigation. Extracts obtained at 40 °C influenced C1q binding, supporting their anti-inflammatory activity, whereas extraction at 60 °C resulted in stronger antiproliferative activity in colon cancer cell line. Antibacterial effects were similar at both temperatures. Conclusions: These findings highlight the importance of optimizing extraction conditions for future pharmacological applications of N. nuda. Full article

(This article belongs to the Special Issue Bioactive Metabolites from Natural Sources (2nd Edition))

► Show Figures

Figure 1

22 pages, 1821 KB

Open AccessArticle

Targeting Leishmania Fe-SOD and Glucose Metabolism with Tripodal and Pyridinacyclophane Polyamines as a Chemotherapeutic Strategy

by Álvaro Martín-Montes, Estefanía Delgado-Pinar, Irene Bonastre, M. Paz Clares, Begoña Verdejo, Álvaro Martínez-Camarena, Rafael Ballesteros-Garrido, Rubén Martín-Escolano, Mª José Rosales-Lombardo, Enrique García-España and Clotilde Marín

Metabolites 2026, 16(5), 322; https://doi.org/10.3390/metabo16050322 - 12 May 2026

Abstract

Background/Objectives: Many parasitic diseases remain without an effective treatment and cause many deaths worldwide. Leishmaniasis is a complex disease that belongs to the category of Neglected Tropical Diseases, as its treatment relies on outdated drugs that also lead to resistance and negative [...] Read more.

Background/Objectives: Many parasitic diseases remain without an effective treatment and cause many deaths worldwide. Leishmaniasis is a complex disease that belongs to the category of Neglected Tropical Diseases, as its treatment relies on outdated drugs that also lead to resistance and negative side-effects. To address this problem, two new chemical families have been tested in vitro against three of the most common parasites from the genus Leishmania. Methods: One family is formed by the polyamine tris(2-aminoethyl)amine functionalised either in one or its three primary amines with different aryl group, and the other is a group of azamacrocyclic cyclophanes containing either one or two aromatic spacers. Results: From the first family, only one compound showed activity against Leishmania donovani, and from the second family, three compounds were selective, two of them for Leishmania braziliensis and a different one against L. donovani, another parasite of the studied genus. Conclusions: The anti-Leishmania activity seems to be related to the compounds’ ability to inhibit the iron superoxide dismutase activity and to alter the parasite metabolism by inhibiting glucose intake in L. braziliensis or by accelerating it in L. donovani and by attacking the parasite defences against ROS, both effects triggering a mitochondrial membrane depolarization that enhances damage, leading to cell death. Full article

(This article belongs to the Special Issue Metabolomics in Infectious Diseases)

13 pages, 848 KB

Open AccessReview

Pentose Phosphate Pathway Is Critical for Providing Energy by Bypassing 6-Phosphofructo-1-Kinase (PFK1) During Increased Neuronal Activity

by Tibor Kristian, Jaylyn Waddell and Mary C. McKenna

Metabolites 2026, 16(5), 321; https://doi.org/10.3390/metabo16050321 - 12 May 2026

Abstract

Glycolysis and the pentose phosphate pathway (PPP) are two metabolic pathways that play crucial roles in brain energy metabolism. The glycolytic pathway is differentially regulated in neurons compared to astrocytes. In neurons, the flux directly through the glycolytic pathway is reduced due to [...] Read more.

Glycolysis and the pentose phosphate pathway (PPP) are two metabolic pathways that play crucial roles in brain energy metabolism. The glycolytic pathway is differentially regulated in neurons compared to astrocytes. In neurons, the flux directly through the glycolytic pathway is reduced due to compromised ability to activate the key glycolytic enzyme 6-phosphofructo-1-kinase (PFK1). Consequently, potential increases in neuronal glucose metabolic flux can occur through the PPP, leading to the generation of NADPH, which is essential for the antioxidant defense system in these cells. Additionally, the PPP can supply glycolysis with intermediates downstream of PFK1, resulting in the production of pyruvate, which is used by mitochondria for oxidative phosphorylation and ATP production. In this review, we propose that during increased activity, neurons will preferentially metabolize glucose through the PPP. This allows them to support their antioxidant defense mechanisms and maintain bioenergetic metabolism by bypassing the limiting PFK1 enzyme and still forming pyruvate for mitochondrial oxidation. Full article

(This article belongs to the Section Advances in Metabolomics)

► Show Figures

Graphical abstract

11 pages, 1510 KB

Open AccessArticle

Predicting Prolonged Length of Stay in Acute Pancreatitis: Comparison of the CRP-to-Albumin Ratio with Other Inflammatory and Immunoutritional Indices

by Ümit Karatepe and Berçem Afşar Karatepe

Metabolites 2026, 16(5), 320; https://doi.org/10.3390/metabo16050320 - 11 May 2026

Abstract

Objective: Due to the varied clinical manifestations of acute pancreatitis (AP), prompt identification of patients predisposed to extended hospitalization is essential for efficient resource allocation. This study assessed the predictive efficacy of inflammatory and immunonutritional ratios—namely, C-reactive protein/albumin ratio (CAR), neutrophil-to-lymphocyte ratio [...] Read more.

Objective: Due to the varied clinical manifestations of acute pancreatitis (AP), prompt identification of patients predisposed to extended hospitalization is essential for efficient resource allocation. This study assessed the predictive efficacy of inflammatory and immunonutritional ratios—namely, C-reactive protein/albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelet score (HALP)—in predicting hospitalizations lasting more than 7 days. Methods: A retrospective cohort analysis was performed on 306 patients treated at a tertiary center from June 2020 to June 2025. We used Mann–Whitney U tests, ROC analysis, and multivariate logistic regression models to evaluate the relationship between admission laboratory-derived ratios and length of stay. Results: In total, 27.5% (n = 84) of the cohort experienced prolonged hospitalization. Individual markers exhibited moderate discrimination; however, procalcitonin and CAR displayed high negative predictive values (>85%), demonstrating clinical utility in excluding prolonged hospital stays. Multivariate analysis revealed advanced age (p < 0.001) and increased CAR (p < 0.001) as the most significant independent predictors. On the other hand, the HALP score was much lower in the group that stayed longer, but it was not an independent predictor in the multivariate model. Conclusions: Older age and a higher CAR are both independent factors that can predict longer hospital stays in AP. The high negative predictive value of CAR is important because it represents a reliable way to exclude prolonged hospitalization. Low CAR levels at admission may help clinicians identify patients eligible for early discharge, thereby optimizing bed management. Full article

(This article belongs to the Special Issue Metabolite Profiles in Inflammatory Diseases)

► Show Figures

Graphical abstract

31 pages, 1331 KB

Open AccessReview

Unravelling Mechanisms of Oxinflammation Induced by Heavy Metals

by Luiz Otávio Guimarães-Ervilha, Mírian Quintão Assis, Izabela da Silva Lopes, Thainá Iasbik-Lima, João Victor Leles Faria, Ana Cláudia Ferreira Souza and Mariana Machado-Neves

Metabolites 2026, 16(5), 319; https://doi.org/10.3390/metabo16050319 - 9 May 2026

Abstract

Exposure to heavy metals remains a significant public health concern due to their environmental persistence, bioaccumulation, and ability to interfere with essential cellular processes. A large part of metal-induced toxicity converges on the establishment of a chronic oxinflammatory state, driven by the reciprocal [...] Read more.

Exposure to heavy metals remains a significant public health concern due to their environmental persistence, bioaccumulation, and ability to interfere with essential cellular processes. A large part of metal-induced toxicity converges on the establishment of a chronic oxinflammatory state, driven by the reciprocal interaction between oxidative stress and inflammation. In this review, we synthesize current mechanistic evidence describing how toxic metals, including aluminum, arsenic, cadmium, lead, mercury, and nickel, disrupt redox homeostasis, impair cellular integrity, and activate inflammatory signaling pathways. These metals promote the excessive generation of reactive oxygen and nitrogen species through multiple mechanisms, including mitochondrial dysfunction, displacement of essential metal cofactors, and inhibition of antioxidant systems. The resulting molecular damage leads to the formation of damage-associated molecular patterns (DAMPs), which activate redox-sensitive transcription factors and inflammatory cascades. Importantly, emerging metabolomic evidence indicates that these processes are accompanied by coordinated metabolic reprogramming involving amino acid, lipid, and energy metabolism, as well as microbiota-derived metabolites. These metabolic alterations not only reflect cellular adaptation to stress but also actively contribute to the propagation of a systemic inflammatory state. An integrated oxinflammatory and metabolic response underlies structural and functional alterations across multiple organ systems, including the liver, kidneys, cardiovascular system, nervous system, and reproductive organs. Persistent exposure, even at low doses, sustains this often subclinical and chronic process, reinforcing the need to understand metabolic changes as central components of metal-induced toxicity. Full article

(This article belongs to the Special Issue Metabolic Change Regulated by Heavy Metals)

► Show Figures

Figure 1

25 pages, 25534 KB

Open AccessArticle

Anatomical Atlas of Kinase Responsiveness to Weight Gain: Adipose Depot Reprogramming in Diet-Induced Adiposity

by Wang-Hsin Lee, Zachary A. Kipp, Sally N. Pauss, Genesee J. Martinez, Mei Xu and Terry D. Hinds, Jr.

Metabolites 2026, 16(5), 318; https://doi.org/10.3390/metabo16050318 - 9 May 2026

Abstract

Background/Objectives: Adipose tissue depots located at different anatomical sites exert differential functions in response to adiposity and glucose intolerance. These fat depots exhibit distinct metabolic signaling patterns that may influence pathological fat accumulation, thereby affecting the efficacy of anti-obesity interventions. Nonetheless, the mechanisms [...] Read more.

Background/Objectives: Adipose tissue depots located at different anatomical sites exert differential functions in response to adiposity and glucose intolerance. These fat depots exhibit distinct metabolic signaling patterns that may influence pathological fat accumulation, thereby affecting the efficacy of anti-obesity interventions. Nonetheless, the mechanisms underpinning depot-specific signaling and pathway responsiveness remain insufficiently understood. Methods: Kinase activity was characterized during the progression of adiposity across five adipose tissue depots in obese versus lean mice using the advanced PamGene kinome technology. Furthermore, kinase pathways in human preadipocytes and mouse 3T3-L1 preadipocytes were analyzed and compared with those in their differentiated, mature adipocytes. The kinases most significantly altered across adipose tissue depots were identified, revealing depot-specific combinations of hyperactive and hypoactive kinase pathways involved in adiposity. Results: Our findings demonstrate distinct kinase families that regulate specific fat depots, with potential implications for drug discovery and therapeutic resistance. Conclusions: This research presents a comprehensive adipokinome atlas, elucidates potential targets for developing fat-depot-specific anti-obesity therapies, and offers novel insights into the functional heterogeneity of adipose tissues. Full article

(This article belongs to the Special Issue Interplay Between Metabolism, Oxidative Stress, and Cellular Signaling in Health and Disease)

► Show Figures

Figure 1

20 pages, 3367 KB

Open AccessArticle

Pet Exposure Is Associated with Altered Gut Microbiota and Higher Phospholipid and Protein Concentrations in the Breast Milk of Overweight/Obese Pregnant Women

by Yanpin Liu, Di Yang, Junying Zhao, Yan Liu, Yaling Wang, Yan Liu, Qian Liu, Xiaofei Fan, Bin Liu, Minghui Zhang, Weicang Qiao, Man Li, Jianyu Wang, Mengjing Du, Ling Guo and Lijun Chen

Metabolites 2026, 16(5), 317; https://doi.org/10.3390/metabo16050317 - 9 May 2026

Abstract

Background: The first 1000 days of a child’s life, from a woman’s pregnancy to her child’s second birthday, represent a critical window during which nutritional and environmental exposures shape long-term health. Gut microbiota play an important role in metabolic and overall health. Although [...] Read more.

Background: The first 1000 days of a child’s life, from a woman’s pregnancy to her child’s second birthday, represent a critical window during which nutritional and environmental exposures shape long-term health. Gut microbiota play an important role in metabolic and overall health. Although pet exposure during pregnancy affects neonatal microbiota, immunity, and development, its effects on maternal health remain unclear. This study investigated the associations of pet exposure with gestational health, maternal and infant microbiota, and breast milk composition in overweight/obese pregnant women. Methods: Fecal samples and breast milk samples were collected from pet-exposed participants (n = 22) and non-exposed controls (n = 32) for 16S rRNA sequencing. Breast milk lipids and proteins were also quantified. Results: Pet exposure before conception, during pregnancy, and postpartum was not associated with gestational diabetes mellitus or gestational weight gain. In the maternal gut, the relative abundances of Proteobacteria, Verrucomicrobia, Sutterellaceae, Enterobacteriaceae, Akkermansia muciniphila, and Parabacteroides were higher, whereas that of Ruminococcus was lower, in the pet-exposed group. In breast milk, the relative abundance of Escherichia-Shigella and the concentrations of phosphatidylinositol 36:2, phosphatidylethanolamine 38:3, lysine, and β-casein were higher, whereas the abundance of Rothia was lower, in the pet-exposed group. The relative abundance of Escherichia-Shigella was also lower in the infant gut of the pet-exposed group. Conclusions: In overweight/obese pregnant women, pet exposure was associated with differences in maternal gut and breast milk microbiota, higher concentrations of selected breast milk phospholipids and β-casein, and lower Escherichia-Shigella abundance in the infant gut. Full article

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

20 pages, 1383 KB

Open AccessArticle

Multomics Analysis of the Characteristic Changes in Polyphenol Accumulation and Cell Wall Polysaccharide Remodelling During the Development of Zingiber mioga Roscoe Flower Buds

by Chenglin Tang, Cheng Zhang, Xingyu Chen, Luolin Bao and Jiao Xie

Metabolites 2026, 16(5), 316; https://doi.org/10.3390/metabo16050316 - 8 May 2026

Abstract

Background/Objectives: At present, there are only a few studies on characteristic changes in polyphenols and cell wall polysaccharides and their correlations in Z. mioga flower buds during development. Methods: Polyphenols were analysed using ultra-performance liquid chromatography‒tandem mass spectrometry (UPLC-MS/MS). Content and enzyme activities [...] Read more.

Background/Objectives: At present, there are only a few studies on characteristic changes in polyphenols and cell wall polysaccharides and their correlations in Z. mioga flower buds during development. Methods: Polyphenols were analysed using ultra-performance liquid chromatography‒tandem mass spectrometry (UPLC-MS/MS). Content and enzyme activities of cell wall components were examined using a microplate reader. Expression of genes related to these components was detected using de novo-Seq. Results: Most polyphenols accumulated significantly, with the highest levels being found in cyanidin-3-O-glucoside and epicatechin. PCA results show that changes in polyphenols were largely dependent on the germination and ripening stage, which might represent its specific period. Additionally, the increased flavonoid and anthocyanin fractions might be due to the up-regulated expression of DFR1/2, ANS and BZl. During development, PME, PG and β-galactosidase synergistically break down protopectin to soluble pectin; PME coordinates with cellulase in cellulose degradation, while xylanase dominates hemicellulose degradation. Lac collaborated with PME, PG and cellulase to regulate lignin synthesis. Key upregulated genes driving cell wall polysaccharide alterations include PME35, PG and GAUT7 for pectin metabolism, CESA2/3 for cellulose synthesis, and Lac25, POD6/7/47/52 and CCR6 for lignin synthesis. Correlation analysis revealed that the synergistic effects of p-coumaric acid, chlorogenic acid, epicatechin, cyanidin-3-O-glucoside, peonidin-3-O-glucoside, protopectin, pectin, lignin and cellulose might be responsible for the sensory quality formation in Z. mioga. Conclusions: This study further investigates the binding mode of polyphenols and cell wall polysaccharides, providing a theoretical basis for understanding the development of sensory qualities in Z. mioga flower buds during growth and maturation. Full article

(This article belongs to the Section Plant Metabolism)

► Show Figures

Graphical abstract

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