Metabolites最新文献

Background/Objectives: Reduced serotonin transporter (SERT) function is associated with increased vulnerability to emotional and metabolic dysregulation, particularly in elderly women. Most preclinical studies relied on young male rodents with complete Sert deficiency; the Western diet (WD) acerbates these abnormalities. However, complete Sert loss does not fully reflect the human condition of partial SERT dysfunction. Here, we examined the effects of WD in aged female Sert^+/- mice on metabolic, biochemical, molecular, and behavioral outcomes. Methods: Wild-type (WT) and Sert^+/- mice were fed WD or a control diet. Emotionality, cognition, glucose tolerance (GT), plasma ¹HNMR spectroscopy metabolome and biochemical parameters were studied. Gene expression analyses of nitric oxide (NO)-related markers were performed in the hypothalamus, dorsal raphe, and liver. Results: WD-exposed WT mice showed impaired GT and reduced plasma lactate and branched-chain amino acid levels; metabolome changes were more pronounced in mutants, while GT was unchanged. Naïve Sert^+/- mice exhibited lower lactate and alanine levels compared with WT controls. WD increased leptin and cholesterol levels in both genotypes, whereas triglyceride concentrations were reduced in Sert^+/- mice. Both WD and Sert deficiency increased Nos expression, while arginase expression was differentially regulated by genotype and diet. Malondialdehyde levels were elevated in the prefrontal cortex of Sert^+/- mice regardless diet. WD also impaired object recognition memory and induced anxiety- and depression-like behaviors, with more pronounced effects in Sert^+/- mice, except marble test behavior. Conclusions: Partial Sert deficiency aggravates some but not all WD-induced metabolic alterations, enhances oxidative stress, dysregulates arginine-NO signaling, and modifies behavior, highlighting the translational relevance of Sert^+/- mice for modeling SERT dysfunction.

Background/Objectives: Chronic heat stress impairs lipid mobilization from adipocytes, which reduces substrate availability for muscle metabolism. Systemic inflammation is a key facilitative response to heat stress, and we sought to determine if mitigating inflammation in heat-stressed wether lambs would improve lipid flux. Methods: Two cohorts of commercial feedlot lambs were heat stressed for 30 days. In study 1, heat-stressed lambs received dexamethasone injections every 3 days, fish oil capsules twice daily, or no intervention. In study 2, heat-stressed lambs received daily boluses of ω-3 polyunsaturated fatty acid Ca²⁺ salts (ω-3 PUFA) or no intervention. Results: In both studies, heat stress reduced ex vivo epinephrine-stimulated free fatty acid and glycerol mobilization from visceral adipose tissue. These deficits were partially resolved by fish oil and fully resolved by ω-3 PUFA. In study 1, fish oil recovered heat stress-induced deficits in circulating triglycerides and HDL-cholesterol but not in circulating free fatty acids. Fish oil and dexamethasone resolved the increase in muscle PPARα, indicating less lipid utilization for metabolism. In study 2, ω-3 PUFA resolved heat stress-induced deficits in muscle CD36 and PPARγ, indicating improved lipid uptake capacity. However, interventions did not resolve reduced intramuscular lipid content in either study. Conclusions: We conclude that inflammation was a primary facilitator of impaired lipid mobilization in heat-stressed lambs but was not the sole driver of lipid dysregulation. Nevertheless, targeting inflammation was a beneficial strategy for improving lipid flux during chronic heat stress.

Background: This study investigated the hypolipidemic and hepatoprotective effects of refined soybean oil supplemented with an Ocimum basilicum L. extract, characterized by HPLC and found to be rich in caftaric, caffeic, chicoric, and rosmarinic acids. Methods: After a 12-week model of diet-induced hyperlipidemia, we examined the plasma levels of TC, TG, Glucose, HDL-C, and LDL-C and the LDL-C/HDL-C ratio using enzymatic kits. The Plasma Hepatic and Biliary Marker Analysis was analysed following standardized hospital protocols with quality-controlled instrumentation. Results: The supplementation with Basil-Enriched Oil (BEO) resulted in a notable redistribution of lipids, significantly reducing the plasma total cholesterol (-75%), triglycerides (-96%), and glucose (-22%), while enhancing their hepatic sequestration. This was accompanied by a marked improvement in the LDL-C/HDL-C ratio and a reduction in hepatic oxidative stress (measured by MDA). Importantly, BEO preserved liver structure and prevented steatosis, despite inducing an increase in adaptive hepatomegaly. Conclusions: The results reveal a dual mechanism whereby the antioxidant properties of BEO collaborate with reprogrammed lipid metabolism, promoting safe hepatic storage rather than harmful circulating levels. These findings strongly advocate for the extract's potential as a nutraceutical for addressing hyperlipidemia and related metabolic disorders by targeting both oxidative stress and lipid imbalance. Further research is required to confirm these effects in clinical settings and to confirm its long-term efficacy.

Background/Objectives: The micronutrient iron is closely connected to inflammation and is among the complex factors contributing to beta-cell failure in diabetes. High levels of dietary iron increase the risk of developing type 2 diabetes, and excessive iron uptake by beta-cells can cause oxidative stress and inhibit function. Elevated levels of proinflammatory cytokines in obese individuals, such as interleukin (IL)-1beta and IL-6, increase the risk of developing type 2 diabetes, and there is evidence that these low levels of circulating cytokines can lead to islet dysfunction. Methods: In this study, gene microarray and other data were analyzed for expression differences in islets treated for 48 h with 10 pg/mL IL-1beta + 20 pg/mL IL-6 as a model of low-grade inflammation versus untreated. Results: Three iron-associated genes were among the most cytokine-sensitive in the mouse genome: Hamp, Steap4, and Lcn2. These proteins are all involved with increasing/retaining cellular iron. We hypothesized that increased cellular iron would lead to increased susceptibility to ferroptosis. Surprisingly, 24 h pre-exposure to low-grade inflammation, which upregulates this iron-gene network, prevented subsequent erastin-induced ferroptosis. We also found that Steap4 overexpression reduced islet dysfunction caused by high-dose proinflammatory cytokines (10× low-dose), suggesting an overall protective effect. Steap4 overexpression also upregulated Hamp and Lcn2, suggesting Steap4 regulates these cytokine-sensitive iron genes.; in contrast, ferritin and ferroportin gene expression, which are not sensitive to cytokines, were unchanged. Conclusions: These data suggest an inflammation-induced network of genes involved in cellular iron uptake and retention plays a protective role in islets against oxidative stress and ferroptosis.

Background/Objectives: The stability of metabolites and lipids in feces varies depending on the storage temperature and duration. Methods: We examined the stability of various metabolites and lipids in human feces under 10 different storage conditions (room temperature for 2, 6, 24, and 48 h, 4 °C for 6, 24, and 48 h, -20 °C for 1 week, 2 weeks and 1 month) and explored markers useful for quality control of fecal samples, using metabolites and lipids that vary depending on temperature and time. Results: There was generally more variation at 4 °C than at -20 °C, and more at room temperature than at 4 °C, and variation also increased as the storage duration was extended under each temperature condition. Some metabolites and lipids were found to be unstable, even over short periods (2 or 6 h) at room temperature or 4 °C storage. However, storage at -20 °C generally maintained the stability of most of them for up to two weeks. Our results suggest that the following ratios can serve as useful quality control markers: methionine to S-methyl-5-thioadenosine, xanthine to inosine and N-linoleoyl leucine to 1,2-dilinoleoyl-sn-glycerol. Conclusions: For comprehensive metabolite and lipid analysis, we recommend promptly transferring samples to -80 °C storage, except when stored at -20 °C for no longer than two weeks, with checks on markers for quality control. When measuring specific metabolites or lipids, our catalog data can be consulted to determine acceptable storage conditions.

Background/Objectives: Propolis is a complex bee product with a composition that varies according to local vegetation, environmental conditions, and bee foraging behaviours. Recently, gas chromatography-mass spectrometry (GC-MS) has been employed in Uganda to analyse its volatile components. This study examined Ugandan propolis non-volatile metabolites to determine chemotypes and identify antibacterial compounds. Methods: Ethanolic extracts were analysed using liquid chromatography-high-resolution quadrupole time-of-flight mass spectrometry (LC-HR-QTOF-MS) in an untargeted MS/MS mode. Data processing was carried out using MZmine, then annotated with Global Natural Products Social Molecular Networking (GNPS) and SIRIUS. Chemometric methods assisted in identifying regional chemical signatures. Metabolites highlighted by the heatmap were evaluated for antibacterial activity using molecular docking against bacterial targets, followed by ADMET (absorption, distribution, metabolism, excretion, and toxicity) assessments. Results: Out of 3252 features, 234 and 52 putative compounds were annotated in GNPS and SIRIUS, respectively, as indicated by molecular networking, suggesting high chemical complexity. The chemical space mainly comprises flavonoids (including glycosides, aglycones, methylated, and prenylated derivatives), phenolic acids, amides, hydroxycinnamate derivatives, lignans, megastigmanes, and various diterpenoid skeletons. Multivariate analyses clearly distinguish geographical chemotypes, separating flavonoid-rich regions from diterpenoid-rich regions. Docking studies revealed flavonoids, diterpenoids, and lignans with strong predicted antibacterial activities and favourable ADMET profiles. Conclusions: This study provides the first LC-MS characterisation of the non-volatile metabolome of Ugandan propolis, thereby expanding its chemical diversity. Metabolomics and computational approaches lay a foundation for future ecological, chemotaxonomic, and pharmacological research.

Background: Ischemic stroke remains the most feared complication of atrial fibrillation (AF), and thromboembolic risk is commonly estimated using clinical scores that may not fully capture the cardiometabolic dimension of cerebrovascular vulnerability. The aim of this research was to assess whether additional parameters can be used, to predict ischemic stroke risk in patients with AF, in order to explore whether TG/HDL-C may complement conventional clinical risk scores for ischemic stroke risk stratification in PAF, and to better characterize a metabolically high-risk phenotype beyond the recommendations provided by the CHA₂DS₂-VA score, which is useful but still far from perfect in predicting AF-associated ischemic stroke risk. Methods: In this retrospective, single-center observational study, we evaluated whether the triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDLc), a simple surrogate of atherogenic dyslipidemia and insulin resistance, is associated with ischemic stroke risk in patients with paroxysmal atrial fibrillation (PAF). We screened 1111 consecutive AF admissions between 1 January 2015 and 31 December 2016 and, from these 1111 AF cases, we extracted only the patients with PAF for analysis. Patients were stratified based on TG/HDLc values into two groups, Group 1 (TG/HDLc > 2.5; n = 155) and Group 2 (TG/HDLc < 2.5; n = 194). Statistical analysis was performed with MedCalc v23.4.0 using Chi-square and unpaired/Welch's t-tests as appropriate, Pearson correlations, Kaplan-Meier analysis with log-rank testing, Cox regression for first ischemic stroke, and multivariable logistic regression to identify independent correlates of TG/HDLc > 2.5. Results: Patients with TG/HDLc > 2.5 had a significantly higher prevalence of ischemic stroke after AF onset compared with those with TG/HDLc < 2.5 (37.4% vs. 21.1%, p = 0.0008), despite similar CHA₂DS₂-VA and HAS-BLED scores, and also exhibited a higher burden of cerebrovascular and neurodegenerative findings, including cortical atrophy and cerebral lacunarism. Ischemic stroke-free survival curves diverged significantly over time (log-rank p = 0.0186), and an elevated TG/HDLc ratio was associated with a 68% higher hazard of first ischemic stroke (HR 1.68; 95% CI 1.09-2.60). In multivariable analysis, type 2 diabetes mellitus (OR 4.53), hyperuricemia (OR 3.83), dyslipidemia (OR 1.94), stroke (OR 1.77), and cortical atrophy (OR 4.48) were independently associated with TG/HDLc > 2.5. Conclusions: These findings suggest that TG/HDLc identifies a metabolically high-risk PAF phenotype associated with greater cerebrovascular burden and reduced ischemic stroke-free survival, providing an inexpensive and broadly available marker that may complement conventional clinical risk scores.

Objectives: Systemic low-grade inflammation is associated with steatohepatitis in adults. We aim to explore if systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hs-CRP), is also linked to steatotic liver disease in adolescents. Methods: In the cross-sectional Early Vascular Ageing in the YOUth study, systemic low-grade inflammation was measured by hs-CRP and liver fat content was quantified by the controlled attenuation parameters (CAP) derived from FibroScan^® (Echosense, Paris, France) measurements in 14- to 19-year-old Austrian adolescents. Cardiovascular risk factors and anthropometric data were collected through face-to-face interviews, physical examinations, and comprehensive fasting blood analyses. Linear regression models were performed to analyze the association between hs-CRP and CAP values. Results: A total of 1300 adolescents (64.6% female) with a mean age of 17.2 ± 1.3 years were included in this analysis. hs-CRP was significantly associated with CAP values in the simple linear regression model (b = 1.35, p = 0.044) and after adjustment for sex and age (b = 1.84, p = 0.006), suggesting an increase in systemic low-grade inflammation with increasing liver fat content. However, further adjustment for major factors of the metabolic syndrome (Homeostatic Model Assessment for Insulin Resistance, non-high-density lipoprotein cholesterol, body mass index z-score, systolic blood pressure z-score) led to a loss of significance of the mentioned association (b = -0.55, p = 0.419). Conclusions: Systemic low-grade inflammation measured by hs-CRP is linked to higher liver fat content in our adolescent cohort. However, this association is largely driven by components of the metabolic syndrome and the overall metabolic milieu, rather than reflecting liver-specific inflammation.

Background: Visceral fat plays a central role in cardiometabolic risk among people with type 2 diabetes mellitus (T2DM), yet its assessment in routine clinical practice remains largely dependent on imaging techniques or indirect anthropometric measures. Identifying accessible blood-based markers that reflect visceral adiposity may facilitate improved phenotyping in this population. This study aimed to investigate whether circulating coiled-coil domain-containing protein 3 (CCDC3) reflects visceral fat accumulation in adults with T2DM. Methods: Public RNA-sequencing datasets and human adipose tissue samples were analyzed to identify CCDC3 as a visceral fat-enriched secretory gene. In this cross-sectional study of 160 adults with T2DM undergoing dual-energy X-ray absorptiometry, plasma CCDC3 was measured by ELISA. Associations between plasma CCDC3 and visceral fat area (VFA) were examined using multivariable regression. Logistic regression models for abdominal obesity (VFA ≥ 100 cm²), with and without CCDC3, were evaluated using receiver operating characteristic (ROC) analysis, calibration curves, decision curve analysis (DCA), and Shapley additive explanations (SHAP). Results: Circulating CCDC3 levels were positively associated with VFA (β = 3.11, p < 0.001), independent of demographic and metabolic factors. Incorporating CCDC3 into the baseline model significantly improved discrimination of abdominal obesity (AUC 0.820 vs. 0.663; p = 0.009). Calibration curves and DCA supported better model fit and higher net clinical benefit with CCDC3. SHAP analysis showed that CCDC3 contributed the greatest incremental importance beyond waist circumference, sex, and age. Conclusions: Circulating CCDC3 may serve as a blood-based biomarker reflecting visceral adiposity in adults with T2DM and provides complementary information beyond traditional anthropometric measures.