Search Results (1,064)

Background/Objectives: Acute exercise remodels many interconnected biochemical pathways in metabolically active tissues. This remodeling involves the activation of the energy-sensing AMP-activated protein kinase (AMPK) to maintain cellular energy homeostasis. Critical energy reserves of glycogen, primarily stored in liver and skeletal muscle and known to interact with AMPK, are utilized to help meet increased energy demands with exercise. However, the breadth of metabolic pathways regulated by acute exercise and AMPK’s interactive roles with glycogen remain incompletely understood. This study therefore aimed to map mouse liver and skeletal muscle metabolite responses to continuous acute exercise and disruption of AMPK-glycogen interactions. Methods: Liquid chromatography–mass spectrometry-based untargeted metabolomics was used to measure the relative abundance of liver and gastrocnemius muscle metabolites at rest and following an acute bout of continuous treadmill running in wild type (WT) and AMPK transgenic mice with double knock-in (DKI) mutations in the β subunit carbohydrate binding module that mediates glycogen binding. Results: Over 200 total metabolites were identified/annotated across liver and skeletal muscle, including 45 metabolites responsive to exercise (p < 0.05; FDR < 0.1). Exercise-regulated metabolites included known metabolic pathways and metabolites never associated or with only emerging evidence related to exercise (e.g., ergothioneine) and/or AMPK-glycogen interactions (N6,N6,N6-trimethyl-L-lysine, a precursor of L-carnitine). Conclusions: Liver and skeletal muscle metabolomic profiles displayed shifts between WT and DKI mice at rest, with shifts also detected following a continuous acute exercise bout. An interaction effect was also observed in skeletal muscle, suggesting differential muscle metabolite responses to acute exercise in DKI mice that may contribute to their functional impairments in metabolic control and exercise capacity versus WT. Collectively, these findings expand the molecular landscape of acute exercise and reveal liver and muscle metabolites underlying exercise-induced metabolic responses. Full article

Background: Tyrosine kinase inhibitors (TKIs) have transformed cancer therapy; however, they are associated with cardiovascular toxicity. Metabolomics provides a comprehensive framework for identifying early biochemical disruptions that precede clinical manifestations and for formulating mechanism-based intervention strategies. Methods: We conducted a narrative synthesis of published preclinical and translational studies on TKI cardiotoxicity, focusing on untargeted and targeted metabolomic findings and complementary proteomic and transcriptomic data. Functional validation was performed using rodent and cellular models. Mechanistic themes were identified, and implications for biomarker panels, multi-omic integration, and metabolomics-guided interventions were proposed. Conclusions: Metabolomic analyses of various TKIs identified convergent signatures along three interconnected axes: (1) mitochondrial bioenergetic dysfunction characterized by impaired long-chain fatty acid oxidation and adenylate depletion; (2) disruption of endothelial nitric oxide signaling with redox imbalance, including increased nitrotyrosine, Nox activation, and eNOS uncoupling; and (3) an inflammatory metabolic profile marked by elevated branched-chain and aromatic amino acids, creatine, and osmolytes. Rodent models of sunitinib and sorafenib replicate these signatures and demonstrate histological injury, contractile dysfunction, and fibrosis. Preclinical intervention data, particularly restoration of myocardial carnitine, AMPK signaling, and fatty acid oxidation by L-carnitine, provide proof of concept for metabolomics-guided cardioprotection. Metabolomics can identify mechanistic biomarkers that facilitate the early detection, risk stratification, and targeted prevention of TKI-induced cardiovascular injury. Translation into precision cardio-oncology requires prospective validation, standardized assays, and biomarker-driven interventional trials. Full article

Functional analysis of SLC22A5 variants can improve diagnostic accuracy in patients with primary carnitine deficiency (PCD). Herein, we performed a genetic analysis of three neonates with PCD. Two of the patients harbored a novel synonymous SLC22A5 variant that has not been previously reported, and the other patient harbored a classical splice site variant. The splicing patterns of the two SLC22A5 variants were evaluated using three in silico tools, and in vitro minigene analysis was performed to verify the impact of variants on RNA splicing mechanisms. All three in silico tools predicted that both SLC22A5 variants could alter normal RNA splicing. Functional studies using minigene assays demonstrated that the c.450C>T (p.F150=) leads to partial exon 2 skipping, and c.394-1G>A leads to intron 1 retention and exon 2 skipping. Intron 1 retention of 65 nucleotides and exon 2 skipping were confirmed by sequencing cDNA amplification products. These results, along with functional evidence, led to reclassification of c.450C>T (p.F150=) and c.394-1G>A as likely pathogenic and pathogenic, respectively. This is the first reported synonymous variant in the SLC22A5 gene that has been functionally validated to affect RNA splicing, thus enriching the variant spectrum of SLC22A5 and aiding accurate PCD diagnosis. Full article

Background/Objectives: This exploratory study (n = 6 per group) investigated the associations between supplementation with α-lipoic acid (AL), betaine (BT), and L-carnitine (LC) and gut microbiota composition in a high-fat diet (HFD)-induced obesity mouse model. Methods: Four-week-old male C57BL/6J mice were fed a control diet (10% fat), HFD (60% fat), or HFD supplemented with AL, BT, or LC (300 mg/kg BW/day) for nine weeks. Results: All three compounds were associated with shifts in microbial composition compared to the HFD-only group. While AL and BT supplementation moderately modulated specific Firmicutes and Bacteroidetes taxa, LC supplementation was linked to a more pronounced reduction in the Firmicutes/Bacteroidetes ratio and a decreased abundance of genera such as Christensenellaceae, Lachnospiraceae, and Coprococcus 3. These microbial changes were correlated with obesity-related metabolic and adiposity markers, including leptin and lipid parameters. Furthermore, functional profiling via PICRUSt suggested potential alterations in amino acid metabolism; however, these findings represent inferred metabolic potential rather than direct metagenomic measurements. Conclusions: Collectively, these results indicate differential associations between dietary supplementation and gut microbiota composition in HFD-fed mice. Although this study was conducted within an exploratory framework and utilized a modest sample size, the observed microbial shifts consistently paralleled metabolic alterations, supporting biologically plausible associations that warrant further mechanistic investigation. Full article

Diabetic neuropathy is a frequent and disabling complication of diabetes, encompassing distal symmetric polyneuropathy and cardiovascular autonomic neuropathy, both associated with reduced quality of life and increased cardiovascular risk. Beyond its traditional interpretation as a direct consequence of chronic hyperglycaemia, oxidative stress has emerged as a central integrative mechanism linking metabolic overload, inflammation, mitochondrial dysfunction, and microvascular injury to progressive neural damage. These processes converge within the neurovascular unit, promoting a self-perpetuating cycle of axonal degeneration, impaired nerve perfusion and altered neuronal excitability. This narrative review synthesises experimental and clinical evidence on oxidative stress-related pathways implicated in diabetic neuropathy, including hyperglycaemia-activated metabolic routes, mitochondrial dysfunction, endoplasmic reticulum stress, and chronic inflammatory signalling. Classical antioxidant and mitochondrial-supportive interventions are evaluated alongside pleiotropic glucose-lowering agents, with particular emphasis on sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, integrating mechanistic insights with biomarker and clinical outcome data. Conventional antioxidant strategies, such as α-lipoic acid, acetyl-L-carnitine, coenzyme Q10 and N-acetylcysteine, show reproducible benefits on neuropathic symptoms and oxidative stress markers, but evidence for sustained structural or disease-modifying effects remains limited. In contrast, incretin-based therapies and sodium–glucose cotransporter-2 inhibitors exert broader pleiotropic actions by attenuating oxidative and inflammatory signalling, improving mitochondrial homeostasis and endothelial function, with emerging evidence for modest but consistent neurophysiological and autonomic benefits. Overall, oxidative stress emerges as a key mechanistic hub in diabetic neuropathy. Future progress will depend on mechanism-aligned, neuropathy-specific clinical trials incorporating multidimensional endpoints and validated biomarkers. Full article

Water salinization severely limits agriculture in semiarid regions. This study evaluated the efficacy of exogenous carnitine (CAR) application in mitigating salt stress in two gherkin cultivars (Cucumis anguria L.), ‘Liso Gibão’ and ‘Do Norte’. The experiment used a randomized block design (3 × 3 factorial), combining three electrical conductivity levels of irrigation water (ECiw: 0.5, 2.5, and 4.5 dS m⁻¹) and three foliar carnitine concentrations (0.0, 0.5, and 1.0 mM). The results indicated that increasing ECiw to 4.5 dS m⁻¹ caused drastic reductions in growth, production, and photosynthetic efficiency, resulting in a 54.87% decrease in the number of fruits, due to toxic accumulation of Na⁺ and Cl⁻. However, carnitine supplementation (optimally at 0.5 mM) attenuated such damage, promoting significant increases in biomass (up to 55.43% for total dry mass), fruit number (by 23.37%), and gas exchange rates. The CAR application was associated with reduced Na⁺ accumulation (reducing leaf Na⁺ by 40.23% under moderate stress) and improved K⁺ and Ca²⁺ homeostasis. The cultivar ‘Do Norte’ showed higher carnitine-mediated tolerance, outperforming ‘Liso Gibão’. Carnitine acts as an effective biostimulant, with its application associated with improved ionic balance and gas exchange, supporting gherkin production under saline conditions. Full article

Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a high mortality rate upon rupture (85–90%). Surgical repair remains the most effective intervention, whereas pharmacological treatments to prevent aneurysm expansion or rupture are limited. Vascular smooth muscle cells (VSMCs) play a crucial role in AAA pathogenesis, and metabolic dysregulation is increasingly recognized as a contributor to disease progression. This study investigated metabolic changes in VSMCs and their association with AAA pathology using untargeted metabolomics. Methods: Angiotensin II (Ang II) was used to stimulate rat VSMCs and induce AAA in ApoE−/− mice. Untargeted metabolomic analysis was performed using liquid chromatography–tandem mass spectrometry to detect metabolite changes. Differential metabolites were identified using orthogonal partial least squares discriminant analysis, and metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes and metabolic set enrichment analysis. Results: In Ang II-treated VSMCs, 54 differential metabolites (24 upregulated; 30 downregulated) were identified, whereas 470 differential metabolites (206 upregulated; 264 downregulated) were detected in mouse aortas. Three metabolites—carnitine, lysophosphatidylcholine (0:0/20:4), and 5-hydroxyeicosatetraenoic acid—were common in both models and were enriched in bile secretion and tryptophan metabolism pathways. The carnitine–FXR signaling axis emerged as a potential therapeutic target. Conclusions: This study revealed Ang II-induced metabolic changes in VSMCs and their association with AAA pathology. The carnitine–FXR signaling axis may contribute to AAA development, providing new directions for diagnostic biomarkers and therapeutic targets. Future studies should validate these findings in human AAA samples to determine their clinical relevance. Full article

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is characterized by dysregulated apoptosis and metabolic reprogramming, including alterations in lipid metabolism. However, the plasma lipidome of newly diagnosed, treatment-naïve CLL patients remains insufficiently characterized. This study aimed to define disease-specific plasma lipidomic alterations, identify discriminatory lipid species, and investigate associated metabolic pathways. Methods: The study cohort consisted of 41 participants (median age 75 years, range: 40–86), including 30 newly diagnosed, treatment-naïve CLL patients (median age 75 years, range: 40–86) and 11 age- and sex-matched healthy controls (median age 75 years, range: 41–85). Targeted lipidomic profiling was performed on plasma samples using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Data processing was conducted in R using LipidSigR. Statistical analyses employed the Wilcoxon–Mann–Whitney test with Benjamini–Hochberg correction. To address data dimensionality, Boruta machine learning and pathway enrichment analyses were applied. Gene–lipid associations were further explored using GATOm, followed by Metascape analysis to identify enriched biological processes. Results: A total of 124 lipid species from five major classes (phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, ether-linked phosphatidylcholines, and acylcarnitines) were quantified. CLL patients exhibited significant enrichment of acylcarnitines, saturated phosphatidylcholines, and sphingolipids compared with controls. Principal component analysis showed partial separation by disease status. Machine learning identified carnitines and ether-linked phospholipids as key discriminators. Integrated gene–lipid analyses revealed significant enrichment of lipid metabolism-related pathways, particularly glycerolipid and phosphatidylcholine metabolism, as well as lipid catabolism, ether lipid metabolism, and fatty acid metabolism. Conclusions: Treatment-naïve CLL patients display distinct plasma lipidomic signatures indicative of disease-specific metabolic reprogramming. Integrated lipidomic and predictive pathway analyses suggest disruptions in lipid metabolic pathways and highlight carnitines and ether-linked phospholipids as biological markers warranting further investigation as potential CLL biomarkers. Full article

Background: Palmitate, a long-chain fatty acid, is well known to be a significant risk factor for cardiovascular diseases. In our current study, we wanted to determine whether palmitate treatment further aggravates ischemic endothelial cell (EC) injury and can serve as an in vitro model that emulates diabetic peripheral artery disease (diabetic-PAD). Short-chain fatty acid (SCFA) treatment was used as an additional comparator for palmitate-induced vascular dysfunction in normal or ischemic ECs in vitro. Methods: Hypoxia serum starvation (HSS) was used as an in vitro model for PAD. Cell survival or proliferation was determined by the CCK8 kit. EC angiogenic capacity was determined by in vitro tube formation assays on growth factor-reduced Matrigel. EC barrier integrity was determined by trans-endothelial electrical resistance measurements by EVOM3. EC metabolic phenotyping was performed by Seahorse glycolysis, mitochondrial respiration, and fatty acid oxidation metabolic assays. Results: Palmitate dramatically decreased the survival of normal and ischemic ECs, whereas SCFAs did not have a significant effect on ischemic EC survival. In vitro angiogenic assays showed that palmitate significantly decreased the angiogenic capacity of ischemic ECs, whereas SCFAs significantly induced their angiogenic capacity. While palmitate significantly decreased normal and ischemic EC barrier integrity, SCFAs improved normal and ischemic EC barrier integrity. Metabolic assays showed that palmitate significantly decreased normal EC mitochondrial respiration but not glycolysis. However, palmitate significantly decreased overall metabolic health, including mitochondrial respiration and glycolysis in ischemic ECs. On the contrary, SCFAs increased both mitochondrial respiration and glycolysis in normal ECs. In ischemic ECs, SCFAs induced mitochondrial respiration with a concomitant decrease in glycolysis. Fatty acid oxidation analysis showed that, unlike palmitate, which depends on carnitine palmitoyl transferases (CPTs) for β-oxidation in both normal and HSS ECs, SCFAs depend partly on CPTs to undergo β-oxidation in HSS ECs but not in normal ECs. Conclusions: While palmitate inhibits ischemic EC angiogenic capacity by decreasing overall metabolic health, SCFAs induce glycolysis–mitochondria OxPhos coupling to induce ischemic EC angiogenic capacity. Full article

Background: HyperCKemia, defined as elevated serum creatine kinase, commonly reflects muscle injury but may also indicate underlying metabolic disease. Metabolic aetiologies, including glycogen storage disorders, fatty acid oxidation defects, mitochondrial cytopathies, and purine metabolism disorders, are clinically important owing to diagnostic complexity, therapeutic implications, and potential reversibility. Objective: To summarise current evidence on metabolic causes of hyperCKemia in adults, with emphasis on disorders of carbohydrate, lipid, and purine metabolism and mitochondrial disease. Methods: Semi-systematic narrative review of pathophysiology, clinical features, diagnostic approaches, and management of metabolic disorders associated with hyperCKemia. Results: Metabolic myopathies often present with nonspecific or exercise-related symptoms, with creatine kinase levels ranging from mild-to-severe elevations. Conditions such as McArdle disease, carnitine palmitoyltransferase II deficiency, and mitochondrial cytopathies demonstrate characteristic metabolic vulnerabilities leading to episodic or persistent hyperCKemia. Medications, including statins and antiretrovirals, may precipitate symptoms in predisposed individuals. Diagnosis requires a structured, multidisciplinary approach incorporating biochemical testing, genetic analysis, functional studies, and muscle biopsy. Many causes are amenable to targeted therapy, including dietary modification, endocrine correction, and medication withdrawal. Conclusion: Metabolic causes of hyperCKemia are under-recognised but clinically significant. Early identification allows targeted treatment and prevention of complications. Full article

Background: Postpartum cardiomyopathy (PPCM) is a rare but life-threatening condition characterized by left ventricular dysfunction occurring in the peripartum period. Alterations in carnitine metabolism have been implicated in myocardial energy dysregulation, yet targeted metabolic profiling in PPCM remains limited. Methods: We conducted a targeted metabolomics study comparing serum carnitine and acylcarnitine profiles between 40 PPCM patients and 40 age-matched healthy controls. Samples were analyzed using LC–MS/MS. Multivariate analyses (PCA and PLS-DA), univariate statistics (t-test, ANOVA, and Tukey’s HSD), and ROC curve analysis were applied to identify discriminatory metabolites and their diagnostic potential. Results: PPCM patients showed significantly decreased free carnitine (C0, p < 0.001) and elevated short-chain acylcarnitines such as acetylcarnitine (C2, p < 0.001) and propionylcarnitine (C3, p < 0.001) compared to controls. Notably, C14:1 and C18:1 were significantly reduced, whereas C6DC was elevated in PPCM (p < 0.001). PLS-DA and VIP analyses highlighted C2, C6DC, and C16 as key discriminators between groups. ROC analysis confirmed limited but notable diagnostic performance for C2 (AUC = 0.633), C6DC (AUC = 0.635), and C16 (AUC = 0.623). Conclusions: Our findings demonstrate that PPCM is associated with profound alterations in carnitine metabolism, particularly reductions in long-chain acylcarnitines and increases in short-chain species. Specific metabolites such as C2, C6DC, and C16 may serve as potential biomarker candidates for PPCM diagnosis and prognosis. These results highlight the utility of targeted metabolomics in uncovering novel metabolic signatures of cardiomyopathy. Full article

Gilts have a lower capacity for voluntary feed intake and body reserves than multiparous sows, which limits their ability to cope with the needs of gestation and lactation. In this study, a nutritional supplement was formulated to support gilts during the peripartum period. Both control (C, n = 64) and treatment (T, n = 63) groups received standard commercial diets. Group T received 300gr of supplement per gilt and day for the last 35 days of gestation until the fifth day of lactation. This supplement contained calcium (Ca; 4.1%), sodium (Na; 4.0%), lysine (Lys; 1.96%), methionine (Met; 1.32%), vitamin B₁₂ (0.3 mg/kg), choline chloride (600 mg/kg), betaine (475 mg/kg), and L-carnitine (500 mg/kg). Supplementation significantly reduced (p < 0.050) stillbirth rate, neonatal diarrhea, postpartum hypophagia, and both β-hydroxybutyrate (BHBA) and creatinine (CREA) concentrations (effect sizes: 0.240–0.993). Also, supplementation significantly increased (p < 0.050) piglet weight at birth and at 15 days of lactation and maternal backfat thickness at 26 days of lactation (effect sizes: 0.491–0.719). The concentrations of BHBA and CREA showed significant and negative associations with several productive parameters (p < 0.05); the strength of the associations was low–medium. Targeted peripartum supplementation represents a feasible nutritional strategy for commercial herds characterized by large litter sizes and limited voluntary feed intake capacity. Full article

Tripterygium glycoside (TG) is known to disrupt the oxidative balance in bio-systems, inducing oxidative stress-mediated toxic effects on testicular tissue. This study aimed to explore the therapeutic potential of coumestrol (COU) against these adverse effects. Sixty-four male Sprague–Dawley rats were randomized into control and Tripterygium glycoside (TG) groups for four weeks. Following initial intervention, eight rats per group were sacrificed to verify the establishment of the oligospermia model and hormonal dysfunction. The remaining rats were subdivided into five therapeutic subgroups, TG, TG + L-carnitine, and three COU dosage groups (low, medium, and high) to evaluate potential protective effects. The present study comprehensively analyzed its impacts on testicular histomorphology, circulating testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and redox balance status, as well as a suite of serum biochemical and physiological biomarkers. Our results revealed that TG induced oligospermia in rats, causing significant testicular oxidative stress characterized by excessive accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), alongside depleted superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC). Conversely, COU treatment effectively mitigated these impairments by significantly downregulating ROS and MDA levels while restoring SOD activity and T-AOC. Full article

This study was conducted to explore the impacts of L-carnitine (CAR) on growth performance, antioxidant capacity, hepatic lipid deposition and fatty acid β-oxidation in farmed fish fed a high-fat diet (HFD). A total of 150 juvenile tiger puffer (15.23 ± 0.01 g) were randomly assigned into six tanks (three tanks each group) and fed with a control diet (HFD, 16% lipid) and a HFD supplemented with 1.5% CAR for eight weeks, respectively. The results indicated that the growth performance and the most proximate compositions were not influenced by dietary CAR. However, compared to the control group, the hepatosomatic index and crude lipid content in the liver were significantly reduced in the CAR group, indicating that CAR performed a lipid-lowering effect in tiger puffer. Serum lipid profiles remained stable, implying that the cholesterol metabolism was not influenced by dietary CAR. Furthermore, dietary CAR activated fatty acid β-oxidation (FAO) in both the mitochondria and peroxisomes and drove lipolysis and fatty acid intracellular transport to supply sufficient substrates for FAO, manifested by the activation of related genes, proteins and enzyme activity. Additionally, CAR lowered hepatic MDA levels, indicating improved antioxidant capacity. In conclusion, CAR shows potential as a lipid-lowering feed additive for marine fish under high-fat dietary conditions. Full article

Probiotics are widely consumed as health-promoting agents, with probiotic supplements (PS) and yogurt (YG) representing formulated products and fermented foods, respectively. Despite their broad consumption, systematic comparisons of their biochemical characteristics remain limited. In this study, integrated untargeted and targeted metabolomics approaches were applied to compare the comprehensive metabolite profiles of PS and YG. PS exhibited relatively higher levels of amino acids, dicarboxylic acids, and lysophospholipids, along with short-chain fatty acids such as acetate and propionate, and amino acid-derived bioactive metabolites, including γ-aminobutyric acid, branched-chain hydroxy acids, indole derivatives, and γ-glutamylpeptides. In contrast, YG showed higher relative abundances of carbohydrates, acylcarnitines, sphingolipids, and bioactive metabolites such as butyrate, creatine, carnitine, and orotic acid. Based on these metabolomic differences, 27 PS-specific and 17 YG-specific marker metabolites were identified. To explore their functional relevance, in vitro antioxidant and antiglycation activities were evaluated. PS exhibited significantly higher antioxidant and antiglycation activities than YG, which were positively correlated with amino acids and indole derivatives. Indole-3-acrylic acid, indole-3-acetic acid, and indole-3-propionic acid showed antiglycation activity and were identified as PS-specific bioactive marker metabolites. These findings reveal the distinct biochemical characteristics of PS and YG and highlight potential bioactive candidate metabolites that may contribute to their functional differences. Full article