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Emerging research suggests that the intrauterine environment plays a critical role in predisposing individuals to metabolic syndrome (MetS), a constellation of conditions that heightens the risk for heart disease, stroke, and diabetes. Traditionally linked to lifestyle, the risk for MetS is now understood to be also influenced by fetal exposures. The environment in which a child lives offers abundant potential sources that can contribute to an increased risk of developing various diseases, and in some cases, these factors can be avoided. This review integrates findings from both epidemiological and experimental research to underscore the impact of prenatal factors, including maternal nutrition, obesity, gestational diabetes (GDM), and birth size, on the subsequent development of metabolic derangements in offspring, particularly during puberty. The progression of genetic and epigenetic studies has enlightened the pathophysiology of these conditions starting in the intrauterine period and continuing into early life. By examining data and studies, this article elucidates the prenatal influences and underlying mechanisms that contribute to the pathogenesis of MetS. The updated understanding of the link between the intrauterine environment and future health comorbidities will draw attention to intrauterine care and maternal health and contribute to the prevention of serious diseases in adulthood. Full article

Background/Objectives: Millions of new diagnoses of breast cancer are made each year, with many cases having poor prognoses and limited treatment options, particularly for some subtypes such as triple-negative breast cancer. Resveratrol, a naturally occurring polyphenol, has demonstrated many anticancer properties in breast cancer studies. However, the mechanism of action of this compound remains elusive, although prior evidence suggests that this compound may work through altering cancer cell metabolism. Our objective for the current study was to perform untargeted metabolomics analysis on resveratrol-treated breast cancer cells to identify key metabolic targets of this compound. Methods: MCF-7 and MDA-MB-231 breast cancer cells were treated with varying doses of resveratrol and extracted for mass spectrometry-based untargeted metabolomics. Data preprocessing and filtering of metabolomics data from MCF-7 samples yielded 4751 peaks, with 312 peaks matched to an in-house standards library and 3459 peaks matched to public databases. Results: Pathway analysis in MetaboAnalyst identified significant (p < 0.05) metabolic pathways affected by resveratrol treatment, particularly those involving steroid, fatty acid, amino acid, and nucleotide metabolism. Evaluation of standard-matched peaks revealed acylcarnitines as a major target of resveratrol treatment, with long-chain acylcarnitines exhibiting a 2–5-fold increase in MCF-7 cells and a 5–13-fold increase in MDA-MB-231 cells when comparing the 100 µM treated cells to vehicle-treated cells (p < 0.05, VIP > 1). Notably, doses below 10 µM showed an opposite effect, possibly indicating a biphasic effect of resveratrol due to a switch from anti-oxidant to pro-oxidant effects as dose levels increase. Conclusions: These findings suggest that resveratrol induces mitochondrial metabolic reprogramming in breast cancer cells in a dose-dependent manner. The biphasic response indicates a potential optimal dosage for therapeutic effectiveness. Further research is warranted to explore the mechanisms underlying these metabolic alterations and their implications for precision nutrition strategies in cancer treatment. Full article

Background: The World Health Organization has indicated that airport noise is strongly associated with cardiovascular disease, with vascular inflammation identified as the primary mechanism. Therefore, long-term exposure to airport noise is considered far more harmful than other types of noise. However, there remains a lack of research into the mechanisms underlying long-term exposure to airport noise and harm to the human body. Methods: A mouse model was established and exposed to airport noise at a maximum sound pressure level of 95 dB(A) and an equivalent continuous sound pressure level of 72 dB(A) for 12 h per day over a period of 100 days. Quantitative polymerase chain reaction (qPCR) was used to detect the mRNA expression levels of pro-inflammatory and anti-inflammatory factors. Enzyme-linked immunosorbent assay (ELISA) was used to detect LPS, LTA, TMA, and TMAO levels. Intestinal flora composition was analyzed by 16S rDNA sequencing, and targeted metabolomics was employed to determine the levels of serum short-chain fatty acids. Results: Long-term airport noise exposure significantly increased systolic blood pressure, diastolic blood pressure, and mean blood pressure (p < 0.05); significantly increased the mRNA expression levels of oxidative stress parameters (nuclear matrix protein 2, 3-nitrotyrosine, and monocyte chemoattractant protein-1) (p < 0.05); significantly increased pro-inflammatory factors (interleukin 6 and tumor necrosis factor alpha) (p < 0.05); significantly decreased the mRNA expression level of anti-inflammatory factor interleukin 10 (p < 0.05); and significantly increased the content of LPS and LTA (p < 0.05). The composition of the main flora in the intestinal tract was structurally disordered, and there were significant differences between the noise-exposed and control groups at the levels of the phylum, family, and genus of bacteria. β-diversity of the principal component analysis diagrams was clearly distinguished. Compared with those of the control group, TMA-producing bacteria and levels of TMA and TMAO were significantly reduced, and the serum ethanoic acid and propanoic acid levels of the noise-exposed group were significantly decreased (p < 0.05). Conclusions: Long-term airport noise exposure causes significant elevation of blood pressure and structural disruption in the composition of the intestinal flora in mice, leading to elevated levels of oxidative stress and inflammation, resulting in metabolic disorders that lead to significant changes in the production of metabolites. Full article

Background: Quantification of metabolites from nuclear magnetic resonance (NMR) spectra in an accurate, high-throughput manner requires effective data processing tools. Neural networks are relatively underexplored in quantitative NMR metabolomics despite impressive speed and throughput compared to more conventional peak-fitting metabolomics software. Methods: This work investigates practices for dataset and model development in the task of metabolite quantification directly from simulated NMR spectra for three neural network models: the multi-layered perceptron, the convolutional neural network, and the transformer. Model architectures, training parameters, and training datasets are optimized before comparing each model on simulated 400-MHz ¹H-NMR spectra of complex mixtures with 8, 44, or 86 metabolites to quantify in spectra ranging from simple to highly complex and overlapping peaks. The optimized models were further validated on spectra at 100- and 800-MHz. Results: The transformer was the most effective network for NMR metabolite quantification, especially as the number of metabolites per spectra increased or target concentrations were low or had a large dynamic range. Further, the transformer was able to accurately quantify metabolites in simulated spectra from 100-MHz up to 800-MHz. Conclusions: The methods developed in this work reveal that transformers have the potential to accurately perform fully automated metabolite quantification in real-time and, with further development with experimental data, could be the basis for automated quantitative NMR metabolomics software. Full article

Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota–lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities. Full article

Background: Severe acute asthma (SAA) in children can be life-threatening. There has been a significant rise in paediatric intensive care unit (PICU) admissions due to SAA over the past two decades. While asthma is a heterogeneous disease, its underlying pathophysiological pathways remain underexplored. This study aimed to assess the value of non-invasive targeted exhaled breath metabolomics analysis to better characterise SAA. Methods: Breath samples from 17 children admitted to the PICU with SAA (cases) and 27 children with controlled severe asthma (controls) were analysed using thermal desorption gas chromatography–mass spectrometry (TD-GC-MS). Results: A targeted volatile organic compound (VOC) analysis identified 25 compounds, of which 16 were shared between groups. Four VOCs were significantly more often present in SAA, and nine VOCs exhibited higher concentrations in SAA. Longitudinal analysis of VOCs from follow-up samples of 10 cases showed no significant temporal differences, reinforcing the reproducibility of identified biomarkers. Conclusions: This study exemplifies the potential of exhaled breath analysis to provide insights into the molecular background of SAA. Breath metabolomics may enable early recognition of severe asthma attacks and preventive therapeutic interventions in children with severe asthma. Full article

Background: Post-production storage plays a pivotal role in developing the characteristic flavor profile of Baijiu, a traditional alcoholic beverage in China. While aging markers remain crucial for quality authentication, the identification of reliable metabolic indicators for chronological determination requires further exploration. Methods: This study establishes a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology for quantifying five linoleic acid-derived oxidative metabolites in Baijiu: 9,12,13-trihydroxy-10(E)-octadecenoic acid (9,12,13-TriHOME), 9,10-Dihydroxy-12-octadecenoic acid (9,10-DiHOME), 9-oxo-(10E,12Z)-octadecadienoic acid (9-OxoODE), 9-hydroxy-(10E,12Z)-octadecadienoic acid (9-HODE) and 13-hydroxyoctadeca-(9Z,11E)-octadecadienoic acid (13-HODE). Results: The optimized protocol demonstrated exceptional sensitivity with limits of detection at 0.4 ppb through membrane-filtered direct dilution. Calibration curves exhibited excellent linearity (R² > 0.9990) across 1.0–100.0 ppb ranges. Method validation revealed satisfactory recovery rates (87.25–119.44%) at three spiking levels (10/20/50 ppb) with precision below 6.96% RSD. Application to authentic samples showed distinct temporal accumulation patterns. Light-aroma Baijiu exhibited storage duration-dependent increases in all five oxides. Strong aroma variants demonstrated significant positive correlations for 9,12,13-TriHOME, 9,10-DiHOME, and 9-OxoODE with aging time. Conclusions: These findings systematically characterize linoleic acid oxidation products as potential aging markers, providing both methodological advancements and new insights into Baijiu aging mechanisms. Full article

Insulin resistance (IR) is a metabolic disorder characterized by an impaired response to insulin. This condition is associated with excess adiposity and metabolic inflammation, contributing to an increased risk for related chronic diseases. Single-nucleotide polymorphisms (SNPs) can affect genes related to metabolic pathways which are related to IR and the individual response to nutrients and dietary patterns, affecting metabolic inflammation and insulin sensitivity. This narrative review explores the current evidence on interactions between genetic variants and dietary factors, specifically their effects in modulating IR and metabolic inflammation. A comprehensive search of the literature was conducted in PubMed, Google Scholar, and Web of Science, and a total of 95 articles were reviewed. The key findings reveal that SNPs in the TCF7L2, ADIPOQ, and TNF genes significantly influence metabolic responses and modulate the effects of the Mediterranean diet on biomarkers of inflammation and IR. Genotype-dependent variations in IR and inflammation biomarkers were observed in the response to different diets for SNPs in the TCF7L2, ADIPOQ, and TNF genes. Additionally, polygenic risk scores (PRSs) can also predict the response to the intake of nutrients and specific diets, and offer a promising tool for assessing genetic predisposition to IR. This review underscores the pivotal role of an individual’s genetic background in the effects of their nutrient intake and in the responses to dietetic interventions, thereby laying the foundation for personalized and effective nutritional strategies tailored to each individual’s necessity in mitigating IR and its associated risk factors for chronic diseases. Full article

Background: Fibroblast activation protein (FAP) is a cell surface glycoprotein expressed by myofibroblastic cells in areas of active tissue remodeling, such as wound healing, fibrosis, and certain chronic inflammatory lesions. As FAP is uniquely present in chronic inflammatory lesions and has an important role in extracellular matrix (ECM) turnover, it appears to have all the characteristics necessary for involvement in atherosclerosis and atherosclerotic plaque rupture and has become a potential target in the treatment of myocardial infarction. Methods: To further understand the role of FAP, its expression in atherosclerotic plaques was examined in a genetically modified mouse model of accelerated atherosclerosis (Apobec1 −/− Ldlr −/− double-knockout mice). The immunohistochemical Fap staining of atherosclerotic plaques in a mouse model of atherosclerosis was correlated with quantification of Fap mRNA obtained from the atherosclerotic plaques of the aortic arch. Fap distribution was characterized in mouse atherosclerotic plaques relative to other markers of activated smooth muscle cells, such as alpha smooth muscle actin and myosin heavy chain (Acta2 and Myh2), ECM turnover (Ki-67, procollagen III and Mmp-9), and inflammation in atherosclerosis (Cd-44, Il-12 and Tgf beta) using immunohistochemistry (IH) and RT-PCR analysis. Results: The mouse model of accelerated atherosclerosis showed an increasing presence of Fap with the progression of atherosclerosis and a high expression level in advanced atherosclerotic lesions compared with other markers of ECM turnover and inflammation in atherosclerosis. Conclusions: FAP exhibits a distinct pattern of expression in a mouse model of atherosclerosis as compared to other markers of activated vascular smooth muscle cells, ECM degeneration, and inflammatory cytokines. Full article

Background: The cell-free DNA (cfDNA) is an extracellular fragmented DNA found in body fluids in physiological and pathophysiological contexts. In cancer, cfDNA has been pointed out as a marker for disease diagnosis, staging, and prognosis; however, little is known about its biological role. Methods: The role of cfDNA released by ES-2 ovarian cancer cells was investigated, along with the impact of glucose bioavailability and culture duration in the cfDNA-induced phenotype. The effect of cfDNA on ES-2 cell proliferation was evaluated by proliferation curves, and cell migration was assessed through wound healing. We explored the impact of different cfDNA variants on ES-2 cells’ metabolic profile using nuclear magnetic resonance (NMR) spectroscopy and cisplatin resistance through flow cytometry. Moreover, we assessed the protein levels of DNA-sensitive Toll-like receptor 9 (TLR9) by immunofluorescence and its colocalization with lysosome-associated membrane protein 1 (LAMP1). Results: This study demonstrated that despite inducing similar effects, different variants of cfDNA promote different effects on cells derived from the ES-2 cell line. We observed instant reactions of adopting the metabolic profile that brings back the cell functioning of more favorable culture conditions supporting proliferation and resembling the cell of origin of the cfDNA variant, as observed in unselected ES-2 cells. However, as a long-term selective factor, certain cfDNA variants induced quiescence that favors the chemoresistance of a subset of cancer cells. Conclusions: Therefore, different tumoral microenvironments may generate cfDNA variants that will impact cancer cells differently, orchestrating the disease fate. Full article

Background: Estrogen plays a crucial role in adipose tissue homeostasis, influencing fat distribution, lipid metabolism, and insulin sensitivity. Through estrogen receptor (ER) activation, particularly ERα, estradiol (E2) regulates adipogenesis, inhibits adipocyte hypertrophy, and promotes insulin signaling. It enhances lipid oxidation, reduces lipogenesis, and suppresses pro-inflammatory cytokine production, thereby maintaining metabolic health. Primary ovarian insufficiency (POI), characterized by estrogen deficiency before the age of 40, disrupts this regulatory network, leading to adverse metabolic effects. Objetives: This review examines the effects of estrogen on adipose tissue, lipid metabolism, and carbohydrate metabolism, with a particular focus on clinical evidence in women with POI. Methods: A narrative review of the metabolic alterations associated with POI, emphasizing the molecular, biochemical, and metabolic mechanisms underlying estrogen deficiency, with a special focus on adipose tissue. Results: Women with POI exhibit increased visceral fat accumulation, reduced lean mass, and alterations in adipokine secretion, resembling the metabolic phenotype of postmenopausal women. The decline in estrogen levels contributes to central adiposity, impaired lipid metabolism, and insulin resistance, exacerbating the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). The loss of estrogenic regulation leads to enhanced lipolysis in visceral fat, raising free fatty acid flux to the liver, promoting hepatic steatosis, and worsening insulin resistance. Studies indicate that POI patients have significantly higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides compared to age-matched controls, reinforcing their heightened CVD risk. Reduced sex hormone-binding globulin (SHBG) levels increase free androgen availability, aggravating central fat deposition. These metabolic disturbances can potentially accelerate atherosclerosis and vascular aging, increasing morbidity and mortality in POI patients. Conclusions: Understanding the role of estrogen in adipose tissue and its disruption in POI highlights the importance of early intervention. Although the available evidence is limited and largely extrapolated from menopause studies, strategies such as hormone replacement therapy, lifestyle modifications, and lipid profile optimization are essential to mitigate metabolic consequences and improve long-term health outcomes in women with POI. Full article

Background: The natural differences in running capacities among rats remain poorly understood, and the mechanisms driving these differences need further investigation. Methods: Twenty male Sprague-Dawley (SD) rats were selected. High and low running capacity rats were identified using Treadmill Exhaustion Tests. Peripheral blood was collected for serum isolation, followed by a metabolomics analysis using LC-MS/MS. Data were preprocessed, and a principal component analysis (PCA) and a partial least squares-discriminant analysis (PLS-DA) were applied to identify metabolic profile differences. Significant metabolites were screened, and a pathway enrichment analysis was conducted using the KEGG database to determine key metabolic pathways. Forty SD rats (equal male and female) were randomly divided into an inosine triphosphate (ITP) group (24.29 mg/kg.bw daily) and a control group. Running capacity was assessed after one week of continuous treatment. Results: Three independent measurements showed consistent differences in running capacity. A total of 519 differential metabolites were identified, with 255 up-regulated and 264 down-regulated. The KEGG pathway analysis revealed a significant enrichment of the Purine Metabolism pathway (ITP-ATP) in the high running capacity group (p < 0.05). The ITP-treated group exhibited a significantly higher running capacity than the controls (p < 0.05), confirming the efficacy of dietary ITP supplementation. Conclusions: The running capacity of rats is influenced by the ITP-ATP pathway, and exogenous ITP administration through dietary intervention significantly improves running ability. Full article

Background/Objectives: Berberine is a naturally occurring compound found in several plants and has been traditionally used for its various health benefits. However, its poor bioavailability limits its therapeutic potential. Berberine LipoMicel^® is a novel micellar formulation of berberine, microencapsulated within an emulsified matrix, designed to enhance bioavailability and bioactivity. This study aims to evaluate its safety, ensuring that improved bioavailability does not introduce new safety concerns. Methods: To assess its safety, a randomized, double-blind, placebo-controlled crossover study with a minimum 4-week washout period was conducted in 19 healthy participants over 30 days. The participants received 1000 mg of the treatment daily (i.e., 2 capsules/d), and their capillary blood was analyzed every week to monitor for changes in established safety markers related to liver and kidney function, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), creatinine, fasting glucose (GLU), HbA1c, and various electrolytes. Additionally, potential side effects were recorded through the collection of weekly health questionnaires to determine treatment tolerability. Results: Compared to placebo, no statistically significant changes in any of the safety markers related to liver or kidney health were detected. Within-group analysis revealed a significant reduction of total cholesterol (TC) in females after 30 days of Berberine LipoMicel^® treatment. Although not significant, both male and female participants showed a noticeable improvement in the mean AST, potentially signaling a hepatoprotective effect. As for tolerability, no adverse events were reported by any of the participants. Conclusions: Based on these findings, despite higher bioavailability of berberine in a newly formulated delivery system (LipoMicel^®), the treatment was found to be safe and well tolerated by human participants, with no significant deviations in blood chemistry that would indicate safety concerns over a period of 30 days. Full article

Background: Aging is associated with the development of various disorders, including postural imbalance, which increases the risk of falls and related health complications. This study examines changes in static postural balance after a 4-week intervention involving appropriate exercise and an optimized daily regimen. Additionally, it explores the relationship between these changes and the steroidome. Methods: The study was conducted on a clinically homogeneous group of 41 females around their sixth decade, diagnosed with anxiety-depressive syndrome and treated with selective serotonin reuptake inhibitors (SSRIs). Postural balance was assessed using the dual-scales method (DLLL-DSM), which estimates postural imbalance by evaluating differences in the lower limb load in the standing position. Correlations between initial DLLL-DSM values, age, BMI, and the baseline levels of nine serum steroids, as well as post-intervention changes in five steroids, were analyzed using multivariate regression (OPLS model). Results: A significant reduction in lower limb load differences (-ΔDLLL-DSM), indicating improved postural balance, was observed. The -ΔDLLL-DSM strongly correlated with initial DLLL-DSM values, age, BMI, initial levels of nine serum steroids, and post-intervention changes in five steroids (R = 0.892, p < 0.001). Furthermore, initial DLLL-DSM values negatively correlated with adrenal androgen androstenediol sulfate and various sulfated 5α/β-reduced androgen metabolites (R = 0.323, p < 0.05), suggesting that the activity of steroid sulfotransferase (SULT2A1) and C17-hydroxylase-C17,20-lyase (CYP17A1) at the lyase step is negatively associated with postural imbalance in elderly females. Conclusions: The findings suggest that even severe postural imbalance can be effectively and relatively rapidly improved through an appropriate exercise-based intervention and an optimized daily regimen, provided that initial adrenal activity is not significantly impaired. Additionally, the identified associations between steroid levels and postural balance provide new insights into the hormonal mechanisms regulating balance control in older individuals. Full article

Background: SY0916 is a novel PAF receptor antagonist used to treat chronic immune-inflammatory diseases and is currently undergoing phase II clinical trials. However, SY0916 is rapidly transformed in vivo, suggesting a demand for metabolite screening. Methods: According to the similar MS fragmentation patterns of SY0916 and its five reported metabolites (M01, M02, M03, M05, and M06), a strategy based on two characteristic ions of m/z 170 and m/z 142 was employed to identify the potential metabolites in precursor screening in vivo, then LC-HRMS and NMR were applied to the metabolites characterization. Results: Two phase I metabolites (M07 and M08) were identified using LC-HRMS and NMR. Eight phase II metabolites, including six glutathione conjugates (M09-M14) and two sulfonate conjugates (M15 and M16), were identified using LC-HRMS. The possible metabolic pathways of SY0916 and fragmentation regularities of mass spectra of its metabolites were summarized. Conclusions: We preliminarily determined the metabolic profile of SY0916 in rats using LC-MS, providing insight into the metabolism of SY0916 in vivo and a basis for clinical studies and future applications. Full article