Search Results (413)

The plasma membrane plays essential roles in cellular transport and signaling. One of its fundamental structural features is the asymmetric distribution of lipids between the inner and outer leaflets. This asymmetry is actively maintained by lipid transport systems, including flippases, floppases, and scramblases, and is critical for membrane integrity and signaling regulation. Accumulating evidence indicates that membrane lipid asymmetry is frequently altered in cancer cells, leading to the externalization of normally inner-leaflet phospholipids such as phosphatidylserine and phosphatidylethanolamine. These alterations can influence tumor signaling, immune interactions, and membrane-associated biological processes. Recent studies further suggest that metabolic reprogramming in cancer may play an important role in regulating membrane lipid asymmetry. Changes in cellular energy status, oxidative stress, calcium signaling, and lipid metabolism can modulate lipid transport systems and membrane organization. In addition, tumor metabolism generates diverse circulating metabolites, including lactate, lysophospholipids, and acylcarnitines, which may influence membrane properties and lipid redistribution. These observations raise the possibility that membrane lipid asymmetry functions as a metabolically responsive interface linking intracellular metabolic state to cell surface signaling and tumor–microenvironment interactions. In this review, we propose a conceptual framework in which cancer-associated metabolic reprogramming influences lipid transport systems and membrane organization, thereby reshaping phospholipid distribution across the plasma membrane. We discuss how metabolic perturbations—including changes in energy metabolism, redox balance, calcium signaling, and lipid remodeling—may regulate membrane lipid asymmetry and explore the implications of these processes for tumor signaling, immune interactions, and emerging membrane-targeted therapeutic strategies. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with colorectal liver metastasis (CRLM) being the major determinant of poor prognosis. Tumor metabolic reprogramming and spatial heterogeneity complicate biomarker discovery and clinical management. This study aimed to characterize the spatial metabolomic landscape of CRC and identify progression-associated metabolic alterations and potential metabolic signatures for liver metastasis. Methods: A total of 23 tissue samples were collected from patients with CRC, with and without liver metastasis. Air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was used to map the spatial metabolite distributions. Region-of-interest analysis guided by histopathology enabled comparative metabolomic profiling across different tissue types. Multivariate statistical analysis, pathway enrichment, and receiver operating characteristic (ROC) curve analyses were performed to identify key metabolic alterations and evaluate potential biomarker performance. Results: Distinct spatial metabolomic profiles were observed across normal mucosa, primary tumors, liver metastases, and normal liver tissues. In primary colorectal tumors, amino acid, purine, and choline metabolism were significantly upregulated, whereas liver metastases were characterized by elevated levels of triglycerides, diglycerides, cholesteryl esters, and acylcarnitines, indicating enhanced lipid synthesis, incomplete fatty acid oxidation, and/or mitochondrial dysfunction. Progression-associated analyses across tissue types revealed consistently increasing trends in glycerides and acylcarnitines, along with heterogeneous alterations in amino acids and phospholipids. Furthermore, 122 differential metabolites were identified between metastatic and non-metastatic CRC, and a four-lipid panel demonstrated strong discriminatory performance. Conclusions: This study provides a spatially resolved characterization of metabolic reprogramming during CRC progression and liver metastasis, highlighting lipid and amino acid metabolism as key features and revealing the metabolic signatures of CRLM. Full article

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results. Full article

Blood metabolism in dairy cows is crucial for milk quality, functioning primarily through the “blood–milk” metabolic axis. Allium mongolicum Regel (AMR), a functional Allium herb, has been shown to regulate on ruminant lipid metabolism. This study investigated the impact of AMR ethanol extract (AME) on lactation performance, blood lipid parameters, and blood–milk metabolomes. Twelve mid-lactation Holsteins (606 ± 11 kg; milk yield 33.14 ± 2.08 kg/d) of parity 2–3 were assigned to either a basal diet (CON) or a diet supplemented with 54 g/d of AME (AEE). Results indicated that AME significantly decreased plasma triglycerides (TG), C15:0, C16:1, C18:1 n-9 c, C18:3 n-6, monounsaturated fatty acids (p < 0.05) and significantly increased C18:2 n-6 c, polyunsaturated fatty acids (p < 0.05). Lactation performance, including the average daily dry matter intake, daily yields of milk fat, protein and lactose, remained unaffected by the AME addition (p > 0.05). Metabolomic profiling revealed that AME significantly enriched the glycerophospholipid metabolism pathway in plasma, upregulating key phospholipid precursors such as L-serine and Sphinganine. Concurrently, milk metabolomics showed an upregulation of short-chain Acylcarnitines. Plasma TG correlated negatively with both plasma L-serine and milk Acylcarnitines, whereas low-density lipoprotein correlated positively with these energy-driven milk metabolites. These findings suggest that AME may contribute to remodeling the plasma lipid metabolic profile in a manner that could facilitate plasma-to-milk lipid flux. This appears to occur through enhanced hepatic lipid processing and increased mammary lipid utilization, offering preliminary insights into potential nutritional strategies for supporting lipid metabolism in dairy cows. Full article

Background and Objectives: This study investigated whether capillary and intravenous sampling affect acylcarnitine and amino acid profile results analyzed by tandem mass spectrometry. Methods: The study included 120 patients either diagnosed with an inherited metabolic disease or undergoing evaluation for a suspected metabolic disorder at the Department of Pediatric Nutrition and Metabolism, Selçuk University Faculty of Medicine. Paired capillary and intravenous blood samples were collected simultaneously, applied to filter paper, and analyzed by LC-MS/MS to determine acylcarnitine and amino acid profiles. Results: Significant differences were observed between capillary and intravenous samples for several acylcarnitines, including C0, C2, C8, C8.1, C10, C10.1, C14.1, C16, and C18.1 (p < 0.05). In the amino acid profile, arginine, aspartic acid, citrulline, glutamic acid, glycine, leucine + isoleucine, methionine, tyrosine, and the methionine/phenylalanine ratio differed significantly between sampling methods (p < 0.05). Despite these differences, Cohen’s kappa analysis showed high agreement between capillary and venous samples for most parameters (78.3–100%) when categorized as low, normal, or high based on reference ranges. Additionally, no significant discrepancies were found in key diagnostic parameters among patients with specific inherited metabolic diseases. Conclusions: Although certain acylcarnitine and amino acid levels differed between capillary and intravenous samples, overall diagnostic agreement was high. However, since the study group did not include any patients with fatty acid oxidation disorders, a separate confirmatory study is needed for this condition. Larger multicenter studies involving more patients and a wider range of metabolic disorders are needed to better understand the clinical impact of sampling method on dried blood spot analyses. Full article

Taurine is abundant in seminal plasma and is involved in redox balance, osmoregulation, and sperm membrane stability. However, its role in protecting dairy goat bucks against heat stress-associated declines in sperm quality remains unclear. In this study, eighteen Guanzhong dairy goat bucks were assigned to three groups: control (NC), field heat stress (HS), and HS with taurine supplementation (HS + Tau). Heat stress reduced seminal plasma taurine abundance and was associated with metabolic reprogramming, impaired sperm quality, disturbed redox homeostasis, and decreased LH and testosterone levels. Specifically, HS reduced sperm motility, viability, membrane integrity, and kinematic performance, increased sperm abnormalities, and shortened in vitro sperm survival time. Taurine supplementation alleviated these adverse changes and shifted the seminal plasma metabolome toward a more homeostatic profile. Metabolomic analysis indicated that HS was associated with the accumulation of long-chain acylcarnitines in seminal plasma. Complementary mouse and TM4 Sertoli cell experiments provided preliminary mechanistic support, suggesting that taurine may partially protect Sertoli cell tight-junction proteins, particularly ZO-1, under heat- and acylcarnitine-related stress, and may be associated with the modulation of p38/AKT signaling. Collectively, these findings suggest that taurine alleviates heat stress-induced declines in sperm quality in dairy goat bucks, at least in part, by modulating seminal plasma metabolism. Full article

Background: Metabolic syndrome (MetS) is a constellation of components that includes type 2 diabetes/hyperglycemia, central obesity, hypertension, and dyslipidemia. Its prevalence is increasing dramatically in Africa, where it is predominant in obese females. Incomplete fatty acid β-oxidation is among the complex mechanisms that increase MetS risk. However, it remains unclear whether MeS components are associated with increased acylcarnitine categories. Objective: The aim of this study was to analyze the relationship between acylcarnitines and all components of metabolic syndrome in females with obesity from two populations with distinct ethnicities and dietary habits. Methods: We investigated the association of obesity (BMI > 35) with acylcarnitines determined by LC–MS/MS with MetS components in women from Benin, West Africa, and French women. Acylcarnitines and biological and clinical outcomes of MetS according to International Diabetes Federation (IDF) criteria were assessed in 428 ambulatory women recruited at the market of Dantokpa, Cotonou, and 220 women of Aldepi/Obesepi cohort recruited in the North-East of France. Results: Compared to those without MetS, we observed an association of short-, medium-, and long-chain acylcarnitines (SC, MC, LC) with MetS (p = 0.0001; p < 0.0001 and p = 0.0004, respectively) in African women and of SC acylcarnitines with MetS (p < 0.0001), blood glucose (p < 0.001), low HDL-cholesterol (p < 0.05) and high triglycerides (p < 0.01) in French women. We also observed significant associations of MC and LC total and mono-unsaturated acylcarnitines with hypertension in both African and French populations (p < 0.001 and p < 0.01, respectively). The independent determinants of systolic blood pressure were age, body mass index, glycemia, long-chain acylcarnitines, LDL-C and HDL-C. Conclusions: An association of acylcarnitine indexes of altered SC, MC, LC fatty acid β-oxidation with hypertension was reported in the two contrasted women populations, while an association of altered SC fatty acid β-oxidation with glucose and hypertriglyceridemia was reported in French women only. The association of altered acylcarnitine indexes with high SBP could be related to the effects of impaired β-oxidation on endothelial dysfunction. This study was registered at clinical trials.gov as NCT02663388. Full article

Background: Epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process characterized by coordinated changes in signaling, membrane organization and metabolism. In a previously established and deeply characterized Huh7 EMT model, it was demonstrated that TGF-β stimulation induces a reproducible shift toward a mesenchymal state accompanied by lipidomic and metabolic remodeling. Building on this framework, the present study evaluates whether extracellular vesicles (EVs)-enriched fractions derived from Capparis spinosa can modulate these EMT-associated alterations. Methods: After detailed physicochemical, molecular, lipidomic and metabolomic characterization, C. spinosa EVs were applied to EMT-induced Huh7 cells. The vesicles were efficiently internalized and, while not inducing a complete epithelial reversion, they attenuated mesenchymal features, indicating a modulatory rather than inhibitory action. Results: Lipidomic profiling showed a partial correction of TGF-β-induced changes including diacylglycerols, phosphoinositides and triglycerides, suggesting interference with lipid signaling and membrane turnover. Metabolomic data further points to reduced mitochondrial and fatty acid oxidation stress, reflected in the re-equilibration of carnitine and acylcarnitine species. Conclusions: Together, these findings indicate that C. spinosa EVs are able to attenuate EMT-associated metabolic and membrane remodeling, positioning them as promising modulators of tumor cell plasticity. Full article

Heart failure (HF) is associated with substantial morbidity and mortality. Metabolic abnormalities are increasingly recognized as integral to HF pathophysiology and may provide incremental value for phenotyping and prediction of outcomes. However, a comprehensive synthesis of metabolic alterations and their prognostic implications remains limited. This scoping review aimed to map metabolic changes in HF, describe analytical methods, and evaluate their diagnostic and prognostic relevance for clinical risk assessment. Methods: We systematically searched PubMed, Scopus, Web of Science, Cochrane Central, and grey literature from January 2010 to December 2024 to identify studies evaluating metabolic profiling in patients with HF. Two independent reviewers screened studies using predefined inclusion criteria and data were extracted using a customized charting form. Discrepancies were resolved by consensus or a third reviewer. We reported and synthesized findings narratively in accordance with scoping review methodology. Results: Seventy-two studies (66 observational and 6 randomized) were included, encompassing HF phenotypes including HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). The analytical approaches included mass spectrometry and nuclear magnetic resonance (¹H-NMR) platforms. The main metabolite classes that demonstrated prognostic significance were amino acids, acylcarnitines, and lipids, and gut-derived metabolites, which were associated with mortality, HF hospitalization, or disease progression. Several studies reported incremental prognostic value beyond conventional biomarker; however, most were exploratory, with modest sample sizes, limited external validation, and heterogeneous methodologies. Conclusions: Metabolomic profiling identifies biologically relevant alterations predicted worse clinical outcomes in HF and may complement existing risk assessment strategies. Nevertheless, standardized workflows and large prospective validation studies are required before clinical implementation can be considered. Full article

Background/Objectives: Conventional diagnosis of inborn errors of metabolism (IEMs) requires multiple specimen types—urine organic acids, plasma amino acids, and serum acylcarnitines—analyzed on distinct analytical platforms. This multi-assay approach is labor-intensive and limits timely clinical decision making. We aimed to develop a fully automated serum-based LC–MS/MS platform for integrated quantitative metabolite profiling and to establish pediatric reference intervals (RIs) to support diagnostic interpretation. Methods: A fully automated LC–MS/MS system integrated with the CLAM-2030 automated pretreatment module was developed to enable simultaneous quantification of 25 organic acids, 8 amino acids, and 21 acylcarnitines. Analytical performance was assessed for linearity, limits of detection and quantification, precision and accuracy. Serum samples from 296 non-IEM children aged 0–6 years were analyzed to establish pediatric RIs using Box–Cox transformation and Gaussian modeling. Clinical utility was evaluated in sera from 89 patients diagnosed with IEM using z-score-based logistic regression models. Results: The method demonstrated excellent performance, with linearity (r² > 0.99) across calibration ranges, limits of detection and quantification defined by signal-to-noise ratios > 3 and >10, and intra- and inter-assay precision < 15% CV for all 54 analytes. Twenty-one analytes met the acceptance criterion of ±20% accuracy at all quality-control levels. Pediatric RIs provided a quantitative framework for interpreting the metabolic abnormalities. In IEM patients, disease-specific metabolites were consistently outside the established ranges, and z-score-based logistic regression models successfully distinguished major IEM categories, including organic acidemias and long-chain fatty acid oxidation disorders. Conclusions: This fully automated, serum-based LC–MS/MS platform provides a clinically practical and quantitative framework for integrated metabolic profiling using pediatric RIs, supporting diagnosis and monitoring of IEMs in pediatric settings. 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: 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

Background/Objectives: Human milk (HM) is recognized as the optimal source of infant nutrition, particularly during the first six months of life. While its nutritional aspects and bioactive components are well studied, the HM metabolome remains less understood, particularly in low- and middle-income countries. This study utilized targeted metabolomics for HM profiling and investigated associations of the HM metabolome with maternal and infant characteristics. Methods: In total, 267 HM samples and demographic data from mothers participating in the Maternal and environmental Impact assessment on Neurodevelopment in Early childhood years (MINE) study were collected during enrolment (up to 6-months postpartum) and analyzed using the MxP^® Quant 500 targeted metabolomics kit from Biocrates. Results: A total of 440 metabolites were quantified, mostly lipids such as triglycerides (59.73%), phosphatidylcholines (14.25%), and diglycerides (8.49%), and small molecules including amino acids (26.67%), amino acid-related compounds (21.33%), hexosylceramides (17.33%), and fatty acids (14.67%). Maternal age was positively correlated with a wide range of metabolites, mainly cholesteryl esters, sphingomyelins, triglycerides, and acylcarnitines, while child age was associated with metabolites belonging to acylcarnitine, phosphatidyl-choline, ceramide, diacylglycerol, sphingomyelin, and triglyceride classes. Child’s gender was associated with metabolites, including ceramides, phosphatidylcholines, and sphingomyelins. Pathway enrichment analysis revealed that the metabolites were significantly enriched in valine, leucine, and isoleucine biosynthesis; arginine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and glutathione metabolism; however, these reflect annotation-based clustering rather than evidence of active metabolic processes in HM. Conclusions: The HM metabolome varies with maternal and infant characteristics, particularly infant age, reflecting cross-sectional differences in milk composition among mother–infant dyads. Enrichment of metabolites annotated to amino acid and antioxidant-related pathways highlights coordinated representation of nutritionally relevant compounds. These findings provide new insight into the factors shaping HM composition in a low- and middle-income populations. 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

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, enabling cancer cells to sustain proliferation and survival under physiological stress. While aerobic glycolysis is well characterized, fatty acid oxidation (FAO) has emerged as a decisive driver of oncogenic progression and therapeutic resistance. Acylcarnitines (ACs), obligatory intermediates for the mitochondrial transport of long-chain fatty acids, have transcended their traditional categorization as passive metabolic byproducts to function as potent signaling entities and functional readouts of mitochondrial oxidative throughput. This review delineates the AC metabolic axis in oncology, examining the coordinated biochemical machinery, including the carnitine palmitoyltransferase (CPT) system, carnitine–acylcarnitine translocase (CACT; SLC25A20), and organic cation/carnitine transporter 2 (OCTN2), that governs cellular AC homeostasis. We further evaluate the clinical utility of altered AC profiles as non-invasive biomarkers for early diagnosis and risk stratification across diverse malignancies, highlighting their capacity to reflect metabolic bottlenecks and flux dynamics. Additionally, we scrutinize therapeutic strategies targeting the AC-FAO axis, demonstrating how the inhibition of key transporters and enzymes sensitizes tumors to conventional chemotherapy and immunotherapy. Ultimately, deciphering the systemic and spatial dynamics of ACs remains essential for advancing precision metabolic oncology and developing personalized therapeutic strategies based on metabolic profiling. Full article