Metabolites

16 pages, 2436 KB

Open AccessCase Report

Lipodystrophy in Central Asia: A Regional Literature Review with a Case Series of Congenital and Acquired Generalized Lipodystrophy

by Marzhan Rakhimzhanova, Bikadisha Bimurat, Aimira Jangashkarova, Assel Issabayeva, Aigul Durmanova, Alina Alzhaxina, Tatyana Ivanova-Razumova and Gulmira Rapilbekova

Metabolites 2026, 16(9), 678; https://doi.org/10.3390/metabo16090678 - 14 Sep 2026

Abstract

Background: Lipodystrophy syndromes are a group of rare disorders characterized by partial or generalized loss of adipose tissue, severe insulin resistance, and multiple metabolic complications. Despite increasing global awareness, lipodystrophy remains underrepresented in the published literature from Central Asia, and its true [...] Read more.

Background: Lipodystrophy syndromes are a group of rare disorders characterized by partial or generalized loss of adipose tissue, severe insulin resistance, and multiple metabolic complications. Despite increasing global awareness, lipodystrophy remains underrepresented in the published literature from Central Asia, and its true regional prevalence remains unknown. This study presents a case series of patients from Central Asia with congenital and acquired generalized lipodystrophy, reviews the existing regional literature, and determines challenges and future directions to improve lipodystrophy care in this region. Methods: We conducted a targeted regional literature review focusing on published reports from five Central Asian countries: Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan. A literature search was performed in electronic databases, including PubMed/MEDLINE, Scopus, and Web of Science, from the earliest available records to 20 July 2026. Results: Reported cases of lipodystrophy from Central Asia were extremely scarce. Our cases also highlighted important barriers to effective care, including limited disease awareness and access to specialized therapies. Discussion: These findings indicate that lipodystrophy is underrepresented in the literature, and the true disease burden and extent of underdiagnosis in Central Asia remain unknown. Improving clinical awareness, developing international collaborations, widening access to genetic testing, and establishing multidisciplinary referral systems could significantly enhance patient outcomes. Conclusions: Lipodystrophy remains an underreported, rare condition in Central Asia. Our findings emphasize the urgent need for improved awareness, regional cooperation, development of expert clinics, and better access to specialized diagnostic and therapeutic resources to optimize care for affected patients. Full article

(This article belongs to the Special Issue Diabetes and Metabolic Diseases: From Prevention to Clinical Management, 2nd Edition)

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14 pages, 11221 KB

Open AccessArticle

Biosynthesis-Informed Putative Annotation Reveals Alkaloid Profiles Across Tissues of Anisodus luridus

by Fangyu Zhao, Yuanjiang Xu, Xiaozhong Lan and Zhen Li

Metabolites 2026, 16(9), 677; https://doi.org/10.3390/metabo16090677 - 14 Sep 2026

Abstract

Background/Objectives: Tropane alkaloids (TAs) and phenylpropanoid polyamine alkaloids (PPAs) are major alkaloid constituents of solanaceous plants; however, the tissue-specific distribution of these compounds in Anisodus luridus, a medicinal plant native to southeastern Xizang, remains incompletely characterized. Methods: A biosynthesis-informed putative [...] Read more.

Background/Objectives: Tropane alkaloids (TAs) and phenylpropanoid polyamine alkaloids (PPAs) are major alkaloid constituents of solanaceous plants; however, the tissue-specific distribution of these compounds in Anisodus luridus, a medicinal plant native to southeastern Xizang, remains incompletely characterized. Methods: A biosynthesis-informed putative annotation workflow was developed using ultra-performance liquid chromatography–high-resolution mass spectrometry (UPLC-HRMS) to characterize alkaloid profiles across seven tissues (root, stem, leaf, calyx, corolla, ovary, and seed). Putative annotations were guided by substrate–product structural relationships, predicted enzyme-catalyzed modifications, and diagnostic tandem mass spectrometry (MS/MS) fragmentation patterns. Results: Eighteen alkaloid features were characterized, comprising 6 TAs and 12 PPAs. Hyoscyamine and scopolamine were identified using authentic standards, and the remaining 16 features were putatively annotated, including dihydroanisodamine, hexosylhyoscyamine, and several PPAs not previously reported in A. luridus. TAs were predominantly enriched in roots and ovaries, whereas PPAs accumulated in floral tissues and leaves. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified scopolamine (variable importance in projection (VIP) = 1.30) as a principal variable associated with separation among tissue metabolic profiles. Conclusions: This workflow supports the putative annotation of alkaloids in non-model medicinal plants. The observed tissue-specific distribution patterns provide a basis for future comparative studies with A. belladonna and for evaluating cultivation, tissue-selective harvesting, and extraction strategies. Full article

(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites, 2nd Edition)

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20 pages, 6840 KB

Open AccessArticle

Phenotype-Associated Renal and Systemic Patterns During Short-Term Reduced-Tidal-Volume Mechanical Ventilation in Obese and Endotoxemic Rats: An Exploratory Study

by Luciana Jorge, Bianca Castino Junqueira Silva, Marcia Bastos Convento, Clara Versolato Rasvisckas, Maria Aparecida da Glória, Cassiane Dezoti da Fonseca, Eloiza de Oliveira Silva, Maria de Fatima Fernandes Vattimo and Fernanda Teixeira Borges

Metabolites 2026, 16(9), 676; https://doi.org/10.3390/metabo16090676 - 14 Sep 2026

Abstract

Background: Mechanical ventilation (MV) may be associated with extrapulmonary responses shaped by the host inflammatory-metabolic background. Methods: This exploratory study characterized renal changes during 1 h of reduced-tidal-volume mechanical ventilation in male Wistar rats with diet-induced obesity or lipopolysaccharide (LPS)-induced endotoxemia, together with [...] Read more.

Background: Mechanical ventilation (MV) may be associated with extrapulmonary responses shaped by the host inflammatory-metabolic background. Methods: This exploratory study characterized renal changes during 1 h of reduced-tidal-volume mechanical ventilation in male Wistar rats with diet-induced obesity or lipopolysaccharide (LPS)-induced endotoxemia, together with concurrent respiratory, acid–base, metabolic, and hemodynamic alterations. Arterial blood gas, biochemical, hemodynamic, and urinary variables were assessed at the pre-MV and post-MV time points. Renal protein expression was evaluated only at the post-MV time point. Results: The arterial partial pressure of carbon dioxide (PaCO₂) decreased significantly in both groups. In the Obese group, metabolic acid–base abnormalities persisted and were accompanied by increases in serum urea and the urinary protein-to-creatinine ratio. In the LPS group, lactate increased, bicarbonate decreased, and mean arterial pressure and serum creatinine increased. At the post-MV time point, renal interleukin-6 expression was lower in the LPS group than in the Obese group, whereas renal tumor necrosis factor-alpha expression was higher in the LPS group than in the Obese group. Conclusions: These results support interpreting the physiological and renal changes observed in association with the integrated experimental protocol, including mechanical ventilation, in relation to the host’s underlying pathophysiology and inflammatory-metabolic context. Full article

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

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16 pages, 1930 KB

Open AccessArticle

Urinary Metabolic Profiles Before and After the Winter Training Season in Female Soccer Players

by Hyang Yeon Kim, Jung Dae Lee, Ho-Seong Lee, Ji-Suk Chang, Suhkmann Kim, Gi-Wook Hwang and Kyu-Bong Kim

Metabolites 2026, 16(9), 675; https://doi.org/10.3390/metabo16090675 - 14 Sep 2026

Abstract

Background/Objectives: Female soccer players differ from males in body composition, muscular strength, and hormonal fluctuations, which may influence performance, fatigue, recovery, and injury risk. This study aimed to characterize the time course of urinary metabolic perturbation and its persistence during a 20-day [...] Read more.

Background/Objectives: Female soccer players differ from males in body composition, muscular strength, and hormonal fluctuations, which may influence performance, fatigue, recovery, and injury risk. This study aimed to characterize the time course of urinary metabolic perturbation and its persistence during a 20-day winter training season (WTS) using urinary metabolomics. Methods: Urinary metabolites in female soccer players were analyzed before (Bef) and 1 (After_1D) and 7 days after completion (After_7D) of the 20-day WTS using nuclear magnetic resonance (NMR) spectroscopy combined with multivariate analysis. Results: A total of 84 metabolites were identified in urine samples, and distinct group separation was observed by partial least squares discriminant analysis (PLS-DA) in targeted profiling. Among these, 13 metabolites, including adenine, alanine, citrate, creatine, creatine phosphate (PCr), formate, glutamine, glycine, malonate, mannitol, taurine, trimethylamine N-oxide (TMAO), and urea, showed significant changes in the three groups (Bef, After_1D and After_7D). Conclusions: Of the identified metabolites, six metabolites—alanine, PCr, formate, glutamine, glycine, and malonate—were significantly increased at 1 day post-WTS (After_1D) compared with pre-WTS (Bef) levels. These metabolites were lower at 7 days post-WTS (After_7D) than at 1 day post-WTS (After_1D). However, the metabolic profile had not fully returned to pre-WTS levels by day 7, suggesting that recovery following WTS may require longer than at least 7 days after a 20-day WTS. Full article

(This article belongs to the Section Advances in Metabolomics)

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18 pages, 826 KB

Open AccessArticle

The Effects of Different Dietary and Glycogen-Loaded Two-a-Day Training Approaches on Muscle Damage and Inflammatory Markers for Enhancing Metabolic Efficiency

by Serdar Şerare, Serkan Paçacı, Necip Arman, Ahmet Karadağ and Anıl Şahin

Metabolites 2026, 16(9), 674; https://doi.org/10.3390/metabo16090674 - 13 Sep 2026

Abstract

Background/Objective: Insufficient research has examined the muscle damage and inflammatory effects of training performed in a fasted state with reduced (low) glycogen reserves. Methods: This study aimed to investigate the acute effects of exercise sessions performed under fasting (FST) and liquid nutrient-supplemented postprandial [...] Read more.

Background/Objective: Insufficient research has examined the muscle damage and inflammatory effects of training performed in a fasted state with reduced (low) glycogen reserves. Methods: This study aimed to investigate the acute effects of exercise sessions performed under fasting (FST) and liquid nutrient-supplemented postprandial (PPD) conditions, as well as with full and reduced body glycogen stores, on muscle damage markers creatine kinase (CK) and lactate dehydrogenase (LDH), and the inflammatory marker interleukin-6 (IL-6). Eleven male amateur football players (mean age 19.91 ± 1.64 years) were included in the study. Participants performed a single 60 min aerobic endurance exercise session at 70% VO₂max under the liquid nutrient-supplemented PPD condition, and two 60 min sessions with a 60 min recovery interval under 10–12 h FST conditions. Data were analyzed using paired samples t-test, ANOVA, Wilcoxon, and Friedman tests, depending on parametric and nonparametric assumptions. Results: In pre-exercise (PRE-FE) measurements, no significant differences were observed between the FST and PPD conditions for GLU, CK, LDH, and IL-6 levels. In postexercise (POST-FE) measurements, GLU levels were significantly higher in the PPD condition than in the FST condition (p < 0.05), whereas LA, CK, LDH, and IL-6 levels did not differ significantly between the two conditions. In the FST condition, following the second exercise session performed with default reduced glycogen availability (POST-SE), CK levels significantly increased from 279.36 ± 16.7 U/L to 335.63 ± 20.3 U/L, LDH levels from 178.72 ± 38.1 U/L to 208.09 ± 50.7 U/L, and IL-6 levels from 2.60 ± 2.4 pg/mL to 8.69 ± 5.8 pg/mL (p < 0.05). In the PPD condition, no significant changes were observed in any of the parameters following a single exercise session (p > 0.05). Conclusions: The two-a-day training approach performed with default reduced glycogen availability may increase muscle damage and inflammatory responses. These findings are considered as an inference that low-glycogen training should not be implemented during the pre-competition period because of the risk of inducing muscle damage. Full article

(This article belongs to the Special Issue Precision Exercise, Metabolic Health and Personalized Performance)

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17 pages, 6022 KB

Open AccessArticle

Causal Effects of Plasma Metabolites on Intervertebral Disc Degeneration and Low Back Pain: A Mendelian Randomization Study

by Shouhe Zhu, Chuanzhi Tang, Weiguo Ding, Junxia Wen, Xinwei Xu, Xinhui Wang and Weixing Xu

Metabolites 2026, 16(9), 673; https://doi.org/10.3390/metabo16090673 - 13 Sep 2026

Abstract

Background: Metabolic disturbances have been implicated in intervertebral disc degeneration (IVDD) and low back pain, but the contribution of circulating metabolites remains uncertain. Objectives: We examined associations of genetically proxied plasma metabolites and metabolite ratios with IVDD outcomes defined at different anatomical locations [...] Read more.

Background: Metabolic disturbances have been implicated in intervertebral disc degeneration (IVDD) and low back pain, but the contribution of circulating metabolites remains uncertain. Objectives: We examined associations of genetically proxied plasma metabolites and metabolite ratios with IVDD outcomes defined at different anatomical locations and with a related pain phenotype. Methods: Summary statistics for metabolite exposures were obtained from the Canadian Longitudinal Study on Ageing (CLSA) plasma metabolome genome-wide association study (GWAS). The outcomes were Intervertebral Disc Degeneration of Cervical Spine (IVDD_Cervical), Intervertebral Disc Degeneration of Thoracic, Thoracolumbar, and Lumbosacral Spine (IVDD_TTL), and Low Back Pain (Pain_Lowback). IVDD_Cervical and IVDD_TTL represented IVDD outcomes defined at different anatomical locations of the spine, whereas Pain_Lowback was analysed separately as an IVDD-related pain phenotype. One genome-wide significant sentinel single-nucleotide variant (SNV) was used for each exposure, and Mendelian randomization (MR) estimates were calculated with the Wald ratio. The within-outcome Bonferroni threshold was 6.25 × 10⁻⁴. Results: Eighty metabolites and metabolite ratios were evaluated. Two associations were significant, both for IVDD_TTL. Higher genetically proxied dimethylarginine (SDMA + ADMA), mapped to DDAH1, was associated with lower IVDD_TTL risk (odds ratio [OR] = 0.80; 95% confidence interval [CI]: 0.72–0.90; p = 2.5 × 10⁻⁴), whereas higher alpha-hydroxyisovalerate, mapped to LDHA, was associated with higher risk (OR = 1.08; 95% CI: 1.04–1.13; p = 4.6 × 10⁻⁴). No significant association was identified for IVDD_Cervical or Pain_Lowback; 23 associations were classified as suggestive significant. DrugBank annotation identified compounds interacting with DDAH1 and LDHA. Conclusions: The results highlight DDAH1-linked methylarginine metabolism and LDHA-linked glycolytic and lactate-related biology as candidate pathways for IVDD_TTL. Findings for IVDD_Cervical, Pain_Lowback, and cross-outcome overlap remain exploratory. Full article

(This article belongs to the Special Issue Biomarkers and Metabolites in Clinical Practice and Research)

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16 pages, 2878 KB

Open AccessArticle

Longitudinal Plasma Lipidomic Changes in Chinese Patients with Nonvalvular Atrial Fibrillation During 12 Weeks of Edoxaban Treatment

by Cheng Cui, Junhao Chen, Haodi Chai and Dongyang Liu

Metabolites 2026, 16(9), 672; https://doi.org/10.3390/metabo16090672 - 11 Sep 2026

Abstract

Introduction: Altered lipid metabolism is implicated in atrial fibrillation, but longitudinal lipidomic changes during anticoagulation remain poorly characterized. Objectives: To characterize plasma lipidomic changes during 12 weeks of edoxaban treatment and explore associated metabolic pathways in Chinese patients with nonvalvular atrial fibrillation (NVAF). [...] Read more.

Introduction: Altered lipid metabolism is implicated in atrial fibrillation, but longitudinal lipidomic changes during anticoagulation remain poorly characterized. Objectives: To characterize plasma lipidomic changes during 12 weeks of edoxaban treatment and explore associated metabolic pathways in Chinese patients with nonvalvular atrial fibrillation (NVAF). Methods: This prespecified substudy of a prospective multicenter study analyzed fasting predose plasma collected at baseline and week 12 from 74 patients receiving protocol-assigned edoxaban doses (15 mg, n = 3; 30 mg, n = 23; 60 mg, n = 48). Widely targeted UPLC-MS/MS lipid profiling, with laboratory quality control (QC CV < 30%), yielded 1099 lipid features retained for statistical analysis. Differential lipids were defined by paired testing with Benjamini–Hochberg correction (|log₂FC| > 0.58 and q < 0.05). Results: The overall, 30 mg, and 60 mg analyses identified 25, 15, and 35 FDR-significant features, respectively; none was significant in the exploratory 15 mg group. Twelve features were shared across the primary analyses and increased at week 12; they comprised mainly acylcarnitines, together with docosadienoic acid and DG (21:0/16:0/0:0), and four lacked HMDB identifiers. The corresponding FDR panels yielded participant-grouped out-of-fold AUCs of 0.918 (95% CI 0.890–0.963), 0.786 (0.701–0.890), and 0.891 (0.835–0.950) for discriminating baseline from week 12, respectively. Pathway mapping identified no multi-compound enriched pathways (q < 0.05). Observed annotations represented single-metabolite signals—most notably DG (21:0/16:0/0:0) (HMDB0094301) and octanoylcarnitine (HMDB0000791)—rather than coordinated, pathway-level alterations. Conclusions: Paired analyses identified consistent longitudinal plasma lipidomic changes in patients receiving edoxaban. The 12 shared features provide focused candidates for targeted validation. Controlled studies are needed to determine whether these changes are specific to edoxaban and to establish their biological and clinical relevance. Full article

(This article belongs to the Section Lipid Metabolism)

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14 pages, 1271 KB

Open AccessArticle

Insulin Resistance Modifies the Glycemic Impact of Carbohydrate Across Distinct Meal Contexts: A Repeated-Measures Dual-CGM Study

by Buket Yilmaz Bulbul, Burak Andac and Mehmet Celik

Metabolites 2026, 16(9), 671; https://doi.org/10.3390/metabo16090671 - 11 Sep 2026

Abstract

Background/Objectives: Postprandial glycemic responses vary markedly among individuals, but it remains unclear whether the glycemic effect of incremental carbohydrate exposure is systematically modified by insulin resistance. We examined whether insulin resistance alters the carbohydrate–postprandial glucose dose-response across distinct meal contexts. Methods: We performed [...] Read more.

Background/Objectives: Postprandial glycemic responses vary markedly among individuals, but it remains unclear whether the glycemic effect of incremental carbohydrate exposure is systematically modified by insulin resistance. We examined whether insulin resistance alters the carbohydrate–postprandial glucose dose-response across distinct meal contexts. Methods: We performed a secondary repeated-measures analysis of the publicly available CGMacros cohort. Forty-five adults spanning normoglycemia, prediabetes, and type 2 diabetes wore blinded FreeStyle Libre Pro and Dexcom G6 Pro continuous glucose monitors while recording meals for approximately 10 days. The primary outcome was 2-h incremental area under the glucose curve (iAUC). Mixed-effects models tested carbohydrate × HOMA-IR interactions, adjusted for protein, fat, fiber, premeal glucose, age, sex, and BMI. Breakfast was the primary structured context, lunch provided within-cohort contextual confirmation, dinner was a free-living contrast, and Dexcom analyses assessed cross-device robustness. Results: The primary Libre analysis included 423 breakfasts and 414 lunches from 44 participants. Higher HOMA-IR significantly amplified the iAUC associated with each 10-g increment in carbohydrate during breakfast (interaction β = 178.5 mg·min/dL per 1-SD higher HOMA-IR; 95% CI 79.5–277.5; p < 0.001) and lunch (β = 109.8; 95% CI 34.2–185.3; p = 0.004). The direction was supported with Dexcom during breakfast (β = 165.3; 95% CI 45.0–285.6; p = 0.007) and lunch (β = 87.9; 95% CI 2.6–173.1; p = 0.043) and remained robust in GEE, participant fixed-effects, random-slope, activity-adjusted, and other sensitivity analyses. No positive interaction was observed during dinner. Conclusions: In this observational secondary analysis, insulin resistance modified the glycemic impact of carbohydrate across two structured meal contexts, with supportive cross-device evidence. These findings are hypothesis-generating and do not establish HOMA-IR-based dietary prescriptions; prospective external validation is required. Full article

(This article belongs to the Special Issue Effects of Nutrition Intake and Lifestyle Intervention on Human Metabolic Health)

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18 pages, 1005 KB

Open AccessArticle

Search for Novel Biomarkers to Predict Cytochrome P450 2C19 Activity Using Untargeted Metabolomics of Human Plasma

by Ayako Oda, Yosuke Suzuki, Teruhide Koyama, Jun Negami, Sakura Suzuki, Koudai Iino, Nao Yamagishi, Natsuki Kamio, Etsuko Ozaki, Yasuyuki Yamamoto, Masahiro Nakatochi, Yukihide Momozawa, Ryota Tanaka, Hiroyuki Ono, Takahiro Sumimoto, Ryosuke Tatsuta, Hiroki Itoh, Naoyuki Takashima, Keitaro Matsuo and Keiko Ohno

Metabolites 2026, 16(9), 670; https://doi.org/10.3390/metabo16090670 - 11 Sep 2026

Abstract

Background/Objectives: Cytochrome P450(CYP)2C19 activity varies widely among individuals. As genetic factors, CYP2C19*2 and CYP2C19*3 alleles reduce CYP2C19 activity, while the CYP2C19*17 allele increases CYP2C19 activity. However, environmental and physiological factors can also influence individual CYP2C19 activity. In this study, we searched for [...] Read more.

Background/Objectives: Cytochrome P450(CYP)2C19 activity varies widely among individuals. As genetic factors, CYP2C19*2 and CYP2C19*3 alleles reduce CYP2C19 activity, while the CYP2C19*17 allele increases CYP2C19 activity. However, environmental and physiological factors can also influence individual CYP2C19 activity. In this study, we searched for novel endogenous biomarkers for CYP2C19 activity using CYP2C19 gene polymorphism data combined with results of untargeted metabolomic analysis. Methods: 431 general adults analyzed in the Kyoto J-MICC Study and 255 patients who visited Oita University Hospital were studied. Plasma samples were pretreated by solid-phase and liquid-liquid extraction and subjected to untargeted metabolomic analysis using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Based on CYP2C19 gene polymorphism data, participants were classified into extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). Compounds showing significant differences in abundance among the three groups were considered candidate compounds for predicting CYP2C19 activity. The predictive performance of candidate compounds for CYP2C19 PM status was evaluated using covariate-adjusted receiver operating characteristic (ROC) analysis. Results: The normalized abundance of compounds with m/z 160.1342, 303.2319 (a fatty acyl or prenol lipid), 314.2309, 449.3238, 653.3021, 792.5744, and 811.5988 (a glycerophospholipid or sphingolipid), and 902.5404 (a fatty acyl) differed significantly among CYP2C19 EM, IM, and PM groups (p < 0.05), and these eight compounds were considered candidate compounds. Covariate-adjusted ROC analysis showed that none of the candidate compounds significantly improved the discrimination of CYP2C19 PM status. Conclusions: Untargeted metabolomics combined with CYP2C19 gene polymorphism data yielded eight compounds associated with CYP2C19 phenotype. Further studies are needed to evaluate the usefulness of these compounds as biomarkers of CYP2C19 activity. Full article

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

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21 pages, 15764 KB

Open AccessArticle

Wheat Bran Stir-Frying Reshapes the Metabolome of Euryale Ferox Seeds and Predicts Enhanced Bioactive Potential for Spleen and Kidney Tonifying

by Panpan Li, Yaojia Zou, Yinghao Mao, Fan Ye and Tao Luo

Metabolites 2026, 16(9), 669; https://doi.org/10.3390/metabo16090669 - 10 Sep 2026

Abstract

Background: Euryale ferox Salisb. seed (Euryales Semen) is a traditional Chinese medicine whose therapeutic application is modulated by wheat bran stir-frying, a process that enhances its effects on tonifying the spleen and kidney. The molecular mechanisms and alterations in bioactive components underlying this [...] Read more.

Background: Euryale ferox Salisb. seed (Euryales Semen) is a traditional Chinese medicine whose therapeutic application is modulated by wheat bran stir-frying, a process that enhances its effects on tonifying the spleen and kidney. The molecular mechanisms and alterations in bioactive components underlying this processing-enhanced efficacy remain to be fully elucidated. This study aimed to systematically investigate the impact of wheat bran stir-frying on the metabolite profile of Euryales Semen and to reveal its potential pharmacological mechanisms. Methods: An integrated strategy combining UPLC-MS/MS-based metabolomics, network pharmacology, and molecular docking was employed. First, differential metabolites between raw and processed Euryales Semen were identified and quantified. Second, a “metabolite-target-disease” network was constructed to predict core targets and pathways. The docking protocol was validated by re-docking of co-crystallized ligands, with all RMSD values below 2.0 Å. Finally, molecular docking was used to predict the binding interactions between key metabolites and potential protein targets. Results: A total of 1597 metabolites were identified, and 244 were defined as differentially expressed (VIP > 1, |log2(FC)| ≥ 1). Processing significantly upregulated 19 of the 22 key metabolites identified, with Urolithin B showing the most dramatic increase (168-fold), which was identified with Level 1 confidence using an authentic standard. Network pharmacology analysis identified 10 core targets (e.g., MMP2, MMP9, AKR1B1) primarily associated with tumors, diabetes, and other chronic diseases. Molecular docking predicted strong binding affinities (<−9.0 kcal·mol⁻¹) between these core targets and key upregulated metabolites, including Urolithin B, Tangeretin, and Syringetin. Conclusions: This study suggests that wheat bran stir-frying fundamentally reshapes the metabolic profile of Euryales Semen, leading to the enrichment of bioactive metabolites (e.g., Urolithin B) and suggesting a potential for enhanced tonifying, anti-tumor, and anti-diabetic activities that warrants further experimental investigation. The dramatic increase in the content of Urolithin B, a metabolite not commonly found in plants, raises the hypothesis of a processing-induced chemical transformation, which warrants further experimental validation, and highlights its potential as a critical component for the herb’s efficacy. The findings offer a preliminary computational basis for understanding traditional processing practices, linking traditional knowledge with modern scientific evidence. Full article

(This article belongs to the Special Issue Metabolomics in Plant Natural Products Research, 2nd Edition)

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20 pages, 1026 KB

Open AccessArticle

Blood Metabolic Profile and Hemogram across Lactation in an Extensively Managed Flock of Dalmatian Pramenka Ewes: Influence of Stage of Lactation and Litter Size

by Zvonko Antunović, Lucija Bronić, Željka Klir Šalavardić, Mislav Đidara, Luka Šramek and Josip Novoselec

Metabolites 2026, 16(9), 668; https://doi.org/10.3390/metabo16090668 - 10 Sep 2026

Abstract

Background/Objectives: Determination of blood metabolic profile and hemogram are particularly valuable in animals kept in extensive and semi-intensive farming systems, as within those systems, it is not possible to properly monitor animals. This research investigated changes in the hemogram indicators and blood [...] Read more.

Background/Objectives: Determination of blood metabolic profile and hemogram are particularly valuable in animals kept in extensive and semi-intensive farming systems, as within those systems, it is not possible to properly monitor animals. This research investigated changes in the hemogram indicators and blood metabolic profile of Dalmatian Pramenka ewes by comparing different lactation stage and litter size. Methods: This study investigated changes in the hemogram indicators and blood metabolic profile of 33 Dalmatian Pramenka ewes during lactation as influenced by the lactation stage (taken on the 40th, 70th and 100th day of lactation) and the litter size (1 or 2 lambs in litter). Referring to the litter size, 11 ewes had twins, and 22 ewes had one lamb in litter. Results: This study confirmed the significant influence of stage of lactation on the blood metabolic profile (minerals: Ca, P-inorganic, Mg, Fe, metabolites: urea, glucose, triglycerides, ALB, GLOB and A/G ratio, and ALT enzyme) and most of the hemogram indicators (RBC and WBC content of HGB and HCT and portion of monocytes) in the blood of lactating ewes. The influence of litter size on the hemogram and blood metabolic profile was insignificant, yet its only statistically significant effect was determined for urea concentrations in the blood of ewes. Conclusions: When planning quality monitoring procedures of a herd, a blood metabolic profile and hemogram of the animals should be implemented as routine herd-monitoring tools for indigenous sheep breeds raised under extensive production systems. Full article

(This article belongs to the Special Issue Metabolomics Studies in Ruminant Models: Unraveling Nutritional Physiology and Health)

14 pages, 1656 KB

Open AccessArticle

Association Between Serum 25-Hydroxyvitamin D Levels and Neuropathic Pain Features in Adults Presenting with Musculoskeletal Pain: A Cross-Sectional Study

by Candost Ege Satilmis, Bulent Akyuz and Serpil Demir

Metabolites 2026, 16(9), 667; https://doi.org/10.3390/metabo16090667 - 10 Sep 2026

Abstract

Background/Objectives: The association between vitamin D status and neuropathic pain in musculoskeletal disorders remains uncertain. This study examined the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and neuropathic pain features in adults with musculoskeletal pain. Methods: This single-center analytical cross-sectional study included 300 [...] Read more.

Background/Objectives: The association between vitamin D status and neuropathic pain in musculoskeletal disorders remains uncertain. This study examined the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and neuropathic pain features in adults with musculoskeletal pain. Methods: This single-center analytical cross-sectional study included 300 adults aged 18–79 years who presented between June and December 2024. Participants were classified as vitamin D deficient (<20 ng/mL; n = 105), insufficient (20–<30 ng/mL; n = 117), or sufficient (≥30 ng/mL; n = 78). Neuropathic pain was assessed using DN4, LANSS, painDETECT, and the Short-Form McGill Pain Questionnaire. Multivariable logistic regression adjusted for age, sex, body mass index, diabetes mellitus, inflammatory rheumatic disease, cervical/lumbar discopathy, and fibromyalgia. Results: Neuropathic pain scores increased as 25(OH)D levels decreased. DN4 positivity occurred in 53.3%, 43.6%, and 25.6% of the deficient, insufficient, and sufficient groups, respectively (p < 0.001). Compared with sufficiency, vitamin D deficiency and insufficiency were associated with DN4 positivity (adjusted odds ratio [aOR] 3.53, 95% confidence interval [CI] 1.76–7.08; and aOR 2.38, 95% CI 1.22–4.64, respectively). Each 10 ng/mL decrease in 25(OH)D was associated with 46% higher odds of DN4 positivity (aOR 1.46, 95% CI 1.14–1.86). Similar associations were observed for LANSS and painDETECT ≥13 and persisted in sensitivity analyses. Conclusions: Lower 25(OH)D levels were associated with higher neuropathic pain scores and more frequent positive screens. The cross-sectional design, modest effect sizes, and unmeasured supplementation and calcium–parathyroid hormone variables preclude conclusions regarding causality, diagnostic utility, or treatment efficacy. Full article

(This article belongs to the Special Issue Vitamin D Metabolism and Human Health, 2nd Edition)

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14 pages, 1608 KB

Open AccessReview

Exercise as a Multisystem Adjunct for Alcohol-Associated Liver Disease: Inflammatory Mechanisms, Muscle–Liver Crosstalk, and Translational Gaps

by Jing Xu, Kai Sang and Junjun Zhang

Metabolites 2026, 16(9), 666; https://doi.org/10.3390/metabo16090666 - 10 Sep 2026

Abstract

Background: Alcohol-associated liver disease (ALD) involves ethanol-related metabolic injury, inflammation, gut–liver dysfunction, and progressive loss of skeletal muscle and functional reserve. Exercise could influence several of these pathways, but ALD-specific evidence remains limited. We therefore evaluated exercise as an adjunct, not a substitute [...] Read more.

Background: Alcohol-associated liver disease (ALD) involves ethanol-related metabolic injury, inflammation, gut–liver dysfunction, and progressive loss of skeletal muscle and functional reserve. Exercise could influence several of these pathways, but ALD-specific evidence remains limited. We therefore evaluated exercise as an adjunct, not a substitute for established care, across the ALD spectrum. Methods: We conducted a structured narrative review of PubMed/MEDLINE, Google Scholar, and publisher records updated through 20 August 2026. Evidence was classified as direct human ALD/MetALD evidence, direct preclinical alcohol-injury evidence, indirect clinical evidence from MASLD or mixed-etiology cirrhosis, or mechanistic evidence from broader exercise biology. Results: Direct human evidence is predominantly observational. Leisure-time physical activity is associated with lower liver mortality across drinking patterns and with lower odds of at-risk advanced fibrosis in MetALD/ALD. These associations do not establish the efficacy of structured exercise training. Preclinical alcohol-injury models support redox- and Nrf2-mediated hepatoprotection, whereas proposed effects on AMPK-SIRT1-PGC-1α signaling, mitochondrial quality, gut microbial metabolites, myokines, and ammonia handling remain largely extrapolated. Metabolomic studies identify disturbances in redox balance, lipid intermediates, acylcarnitines, bile acids, and amino acid and tryptophan metabolism. These alterations provide candidate endpoints for future trials. Myostatin and decorin are associated with ALD severity, but their responsiveness to exercise is unknown. We therefore propose a stage-specific research and practice framework with explicit safety considerations. Conclusions: Exercise is a promising but unproven multisystem adjunct for ALD. It should complement abstinence support, alcohol use disorder care, nutrition, and standard medical management. ALD-specific trials should integrate metabolomics, liver outcomes, functional measures, sex, alcohol exposure, disease stage, and adverse events. Full article

(This article belongs to the Special Issue Nutrition, Metabolism and Clinical Management of Liver Diseases)

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15 pages, 1415 KB

Open AccessArticle

Inhibitory Effects and Mechanisms of Thymol Against Fusarium oxysporum, a Pathogen of Stem Base Rot

by Xiangyu Hou, Peng Huang, Jun Wang, Yangxin Chen, Benjin Li and Feng Chen

Metabolites 2026, 16(9), 665; https://doi.org/10.3390/metabo16090665 - 9 Sep 2026

Abstract

Background/Objectives: Stem base rot caused by Fusarium oxysporum is a devastating soil-borne disease, yet long-term chemical pesticide application has raised serious environmental and ecological concerns. Thymol, a plant-derived fungicide, demonstrates a favorable safety profile for humans and environmental systems while exhibiting broad-spectrum [...] Read more.

Background/Objectives: Stem base rot caused by Fusarium oxysporum is a devastating soil-borne disease, yet long-term chemical pesticide application has raised serious environmental and ecological concerns. Thymol, a plant-derived fungicide, demonstrates a favorable safety profile for humans and environmental systems while exhibiting broad-spectrum antifungal efficacy. This study aimed to evaluate the inhibitory effects of thymol against F. oxysporum and to elucidate its underlying mechanisms of action. Methods: The antifungal activity of thymol was assessed in vitro against F. oxysporum by measuring colony and mycelial growth inhibition, sporulation, and spore germination at varying concentrations. Microscopic examination was performed to observe morphological changes in hyphae. Biochemical assays were conducted to quantify soluble protein content, DNA synthesis, ergosterol levels, and fusaric acid production in treated mycelia. Dose–response data were used to calculate median effective concentrations (EC₅₀) for relevant parameters. Results: Thymol significantly inhibited F. oxysporum growth, with EC₅₀ values of 51.02 μg/mL for colony growth and 57.30 μg/mL for mycelial growth. Microscopy revealed abnormal, shorter, thicker hyphae with enlarged vacuoles. Sporulation and spore germination were also effectively suppressed, with EC₅₀ of 39.37 μg/mL and 53.55 μg/mL, respectively. At 100 μg/mL, thymol reduced soluble protein content by 36.73%, inhibited DNA synthesis by 47.29%, decreased ergosterol content by 48.11%, and reduced fusaric acid production by 76.86%. Conclusions: Thymol exerts multi-targeted inhibitory effects against F. oxysporum through disruption of cellular structure, impairment of macromolecular synthesis, interference with ergosterol biosynthesis, and suppression of toxin production. These findings provide a strong theoretical foundation for developing thymol as a novel biopesticide for sustainable management of stem base rot. Full article

(This article belongs to the Section Plant Metabolism)

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17 pages, 879 KB

Open AccessFeature PaperArticle

Longitudinal Changes in Body Composition, Resting Metabolic Rate, and Inflammation After Sleeve Gastrectomy: Associations with Dietary Polyunsaturated Fatty Acid Balance

by Ghazal Mohammad, Abeer S. Alzaben, Yazeed Alshuweishi, Sarah F. Faludah, Meshal Al-Sharafa, Shaima Alothman, Arwa S. Altalhi, Doaa S. Aljasser, Dalal F. ALShamri, Saeed Al Shlwi, Abdullah Aldriee, Latifah Alanzi, Fayzah S. Alotaibi, Hanaa A. Yamani, Ali A. Alshatwi and Alaa A. Al-Masud

Metabolites 2026, 16(9), 664; https://doi.org/10.3390/metabo16090664 - 9 Sep 2026

Abstract

Background/Objectives: Sleeve gastrectomy induces substantial changes in body composition, energy metabolism, and systemic inflammation, but their temporal patterns during early postoperative follow-up remain incompletely characterized. This pilot study primarily characterized longitudinal changes in body composition, resting energy metabolism, and inflammatory biomarkers during the [...] Read more.

Background/Objectives: Sleeve gastrectomy induces substantial changes in body composition, energy metabolism, and systemic inflammation, but their temporal patterns during early postoperative follow-up remain incompletely characterized. This pilot study primarily characterized longitudinal changes in body composition, resting energy metabolism, and inflammatory biomarkers during the first nine months following sleeve gastrectomy. A secondary exploratory objective examined associations between the dietary omega-6/omega-3 ratio and these outcomes. Methods: Thirty-seven adults (67.6% female; mean age 35.1 ± 11.3 years) undergoing sleeve gastrectomy were prospectively assessed at baseline and 3, 6, and 9 months postoperatively. Dietary intake was assessed using three-day food records. Body composition, resting metabolic rate (RMR), respiratory quotient, and inflammatory biomarkers (CRP, IL-6, and IL-10) were evaluated longitudinally. Linear mixed models adjusted for age, sex, and comorbidity were used to assess temporal changes and dietary associations. Results: Distinct postoperative trajectories were observed across outcomes. BMI declined progressively from 43.76 ± 6.44 to 28.49 ± 3.77 kg/m² and total body fat from 52.32 ± 5.76% to 39.62 ± 5.71% (both p < 0.001 for time). In contrast, RMR showed a marked early decline by 3 months, followed by relative stabilization (p < 0.001). CRP progressively decreased from 12.84 ± 12.60 to 2.96 ± 2.95 mg/L (p = 0.001), whereas IL-6 and IL-10 showed no significant temporal changes. Notably, no consistent associations were observed between the dietary PUFA measures and the evaluated outcomes. Conclusions: Postoperative adaptation following sleeve gastrectomy differed across physiological domains, with progressive reductions in adiposity and CRP, an early decline followed by relative stabilization of RMR, and no detectable longitudinal changes in IL-6 or IL-10. Dietary PUFA measures showed no significant associations with postoperative outcomes. Full article

(This article belongs to the Special Issue Biomarkers in Obesity, Metabolic Syndrome, and Weight Loss: Advances in Diagnosis, Risk Stratification, and Personalized Management)

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24 pages, 21523 KB

Open AccessFeature PaperArticle

Potential Mechanisms Linking Excessive Testosterone to PMOS: Insights from Network Toxicology and Machine Learning

by Chao Li, Zhe Su, Yiqian Li, Huili Liu, Mengyi Zheng, Hanjing Zhou, Cheng Wei, Feng Zhou, Cuiyu Yang, Chen Tang and Bin Chen

Metabolites 2026, 16(9), 663; https://doi.org/10.3390/metabo16090663 - 9 Sep 2026

Abstract

Background/Objectives: Polyendocrine metabolic ovarian syndrome (PMOS) is characterized by hyperandrogenism, particularly excessive testosterone, as a core clinical feature and a key pathogenic metabolite, yet its molecular mechanisms remain incompletely understood. Methods: This study integrated multi-omics data from Gene Expression Omnibus (GEO) databases with [...] Read more.

Background/Objectives: Polyendocrine metabolic ovarian syndrome (PMOS) is characterized by hyperandrogenism, particularly excessive testosterone, as a core clinical feature and a key pathogenic metabolite, yet its molecular mechanisms remain incompletely understood. Methods: This study integrated multi-omics data from Gene Expression Omnibus (GEO) databases with network toxicology, weighted gene co-expression network analysis (WGCNA), and machine learning to identify testosterone-associated core genes in PMOS. Results: Differential expression analysis and WGCNA yielded 42 candidate genes, from which five core genes, including GK5, CYP3A5, EGLN3, VCAM1, and AGTR1, were prioritized as top predictive features through ensemble modeling (RF + XGBoost). Molecular docking predicted favorable testosterone binding conformations. Regulatory network and drug enrichment analysis additionally predicted several upstream transcription factors, hub miRNAs, and potential repurposable drugs. Conclusions: These findings proposed a computational framework for a multi-target molecular landscape linking testosterone to PMOS. The identified genes, regulatory networks, and candidate drugs provided prioritized hypotheses for mechanistic exploration and future evaluation of potential diagnostic and therapeutic applications in hyperandrogenism-related PMOS. Full article

(This article belongs to the Special Issue Nutritional and Metabolic Regulation for One Health Across the Lifespan)

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11 pages, 2203 KB

Open AccessArticle

Anemia, Glycemia, and Inflammation in PAD-Related Tissue Necrosis

by Mehmet Aslan

Metabolites 2026, 16(9), 662; https://doi.org/10.3390/metabo16090662 - 9 Sep 2026

Abstract

Objective: To determine whether systemic inflammation in peripheral artery disease is primarily associated with necrosis or a secondary response, we evaluated the association of tissue oxygenation (red blood cells), acute metabolic stress (admission glucose, albumin), systemic inflammation (C-reactive protein), and the red blood [...] Read more.

Objective: To determine whether systemic inflammation in peripheral artery disease is primarily associated with necrosis or a secondary response, we evaluated the association of tissue oxygenation (red blood cells), acute metabolic stress (admission glucose, albumin), systemic inflammation (C-reactive protein), and the red blood cell-to-albumin ratio. Materials and Methods: We retrospectively analyzed 375 patients undergoing endovascular interventions (58 with necrosis, 317 without). C-reactive protein-to-albumin and red blood cell-to-albumin ratios were calculated. Associations were assessed using parallel multivariate logistic regression models. Results: The necrosis group had significantly higher admission glucose and C-reactive protein-to-albumin ratio, but a lower red blood cell count and red blood cell-to-albumin ratio. In multivariate models of fundamental biomarkers, C-reactive protein lost independent significance; low red blood cells (Odds Ratio: 0.348, p = 0.0003) and elevated admission glucose (Odds Ratio: 1.008, p = 0.0018) were the strongest independently associated variables. In composite index models, the C-reactive protein-to-albumin ratio became a dominant associated factor, attenuating the red blood cell-to-albumin ratio’s statistical significance. Conclusions: Anemia and admission hyperglycemia are strong correlates of tissue necrosis. Systemic inflammation appears to act as a secondary consequence of ischemic injury but profoundly exacerbates tissue loss when combined with nutritional depletion. Comprehensive medical management, including anemia correction and metabolic optimization, is fundamental for limb salvage. Full article

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

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23 pages, 5662 KB

Open AccessArticle

Bioactive Constituents of Ginger and Potential Mechanisms Underlying Its Anti-Rheumatoid Arthritis Effects: Integrated Efficacy Evaluation, Chemical Profiling, Network Pharmacology, and Molecular Dynamics Simulation

by Hancheng Li, Jinwei Gan, Yuting Huang, Yangkai Wu, Chaohua Luo, Wenhua Liu, Hongwu Wang and Zhixian Mo

Metabolites 2026, 16(9), 661; https://doi.org/10.3390/metabo16090661 - 9 Sep 2026

Abstract

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and ginger contains phenolic constituents with anti-inflammatory potential. This study evaluated the antiarthritic efficacy of ginger ethanolic extract (GE) and explored its potential mechanisms through integrated pharmacological and computational approaches. Methods: GE was [...] Read more.

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and ginger contains phenolic constituents with anti-inflammatory potential. This study evaluated the antiarthritic efficacy of ginger ethanolic extract (GE) and explored its potential mechanisms through integrated pharmacological and computational approaches. Methods: GE was prepared by 70% ethanol reflux extraction and administered to adjuvant-induced arthritis (AIA) rats, with methotrexate as a positive control. Body weight; paw swelling; arthritis index; spleen index; and serum interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) were measured. Chemical profiling was performed by ultra-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS), followed by network pharmacology, molecular docking, and molecular dynamics (MD) simulation. Results: GE attenuated paw edema, arthritis index elevation, splenic enlargement, and elevated serum inflammatory mediators in AIA rats. UPLC-Q-TOF-MS/MS annotated 38 constituents, mainly gingerols, shogaols, gingerdiones, gingerdiols, and related phenolic derivatives. Network analysis identified 217 overlapping ginger- and RA-associated targets, with TNF, IL6, and matrix metalloproteinase 9 (MMP9) prioritized among inflammatory and matrix-remodeling nodes. Docking and MD simulations supported stable predicted interactions for 8-gingerol-TNF and 6-gingerol-MMP9. Conclusions: GE showed antiarthritic activity in AIA rats. The integrated chemical, in vivo, and computational data suggest that ginger phenolics may modulate inflammatory mediators and candidate RA-related pathways; however, these mechanisms remain exploratory and require histological, tissue-level, and molecular validation. Full article

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

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21 pages, 1614 KB

Open AccessReview

Gut Microbiota and Their Metabolites in Acute Kidney Injury: Classification, Mechanisms, and Therapeutic Potential

by Ziyi Qiu, Hao Zhang, Mengqing Ma, Binbin Pan and Changchun Cao

Metabolites 2026, 16(9), 660; https://doi.org/10.3390/metabo16090660 - 9 Sep 2026

Abstract

Acute kidney injury (AKI) is a common critical syndrome with high morbidity and mortality, and a subset of patients may progress to chronic kidney disease. Recent studies have revealed that gut microbiota and their metabolites play pivotal roles in the pathogenesis of AKI. [...] Read more.

Acute kidney injury (AKI) is a common critical syndrome with high morbidity and mortality, and a subset of patients may progress to chronic kidney disease. Recent studies have revealed that gut microbiota and their metabolites play pivotal roles in the pathogenesis of AKI. Under AKI conditions, the gut microbiota composition undergoes significant alterations, characterized by decreased beneficial bacteria and expansion of opportunistic pathogens, accompanied by impaired intestinal barrier and disordered microbial metabolism. Gut microbiota metabolites can be classified into protective metabolites (short-chain fatty acids, secondary bile acids, tryptophan metabolites, D-amino acids, and polyamines) and toxic metabolites (indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, and endotoxin). The former exert renoprotective effects through anti-inflammatory, antioxidant, and barrier-maintaining mechanisms, while the latter aggravate kidney injury via oxidative stress, inflammation activation, and hemodynamic disturbance. Based on the gut–kidney axis theory, interventions targeting gut microbiota (probiotics, prebiotics, fecal microbiota transplantation) and those targeting metabolites (supplementation of protective metabolites, removal of toxic metabolites) have shown promising prospects. This narrative review summarizes the characteristics of gut microbiota changes, classification and function of key metabolites, core mechanisms driving AKI, and microbiota-based intervention strategies, aiming to provide novel insights for early recognition and precision prevention of AKI. Full article

(This article belongs to the Special Issue The Role of Metabolites and the Gut Microbiota in Development, Homeostasis, and Diseases)

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