Search Results (548)

Oxidative stress and chronic low-grade inflammation are recognized key drivers of diabetic complications. Lysosomal dysfunction, cellular senescence, and inter-organ stress signaling further aggravate the Redox–Inflammation–Organ Stress Axis in type 2 diabetes mellitus (T2DM). Recent studies suggest that reactive oxygen species (ROS) are not always harmful. Through mitohormesis, mild and transient increases in ROS levels can trigger antioxidant defenses, strengthen mitochondrial function, and limit chronic inflammation. Evidence from caloric restriction, exercise, and ketone body studies supports this adaptive redox balance, underscoring the importance of maintaining a “hormetic window” rather than indiscriminate antioxidant supplementation. In our prospective study, sodium-glucose cotransporter 2 inhibitor treatment significantly reduced albuminuria and serum levels of inflammatory markers, e.g., tumor necrosis factor receptors 1 and 2, while paradoxically increasing urinary 8-hydroxy-2′-deoxyguanosine levels and biological antioxidant potential (BAP), suggestive of adaptive ROS responses consistent with mitohormesis. Concomitant glucagon-like peptide-1 receptor agonist use emerged as an independent explanatory factor for increased urinary levels of oxidative stress markers, suggesting that multiple metabolic therapies converge on shared hormetic pathways. Emerging evidence that stressed adipocytes can communicate mild ROS signals via extracellular vesicles expands this paradigm to inter-organ mitohormesis. Collectively, these insights caution against indiscriminate antioxidant use and underscore the therapeutic potential of controlled redox modulation to disrupt the vicious cycle of senescence, inflammation, and organ stress. Incorporating redox biomarkers like urinary 8-hydroxy-2′-deoxyguanosine, reactive oxygen metabolite derivatives, and BAP into clinical monitoring, alongside pharmacological and lifestyle interventions, may facilitate the realization of precision metabolic medicine for multi-organ protection in T2DM. Full article

β-Hydroxy-β-methylbutyrate (HMB), a natural metabolite derived from the essential amino acid leucine, is primarily recognised for its anabolic and anti-catabolic effects on skeletal muscle tissue. Recent studies indicate that HMB may also play a role in influencing the structural organisation of extracellular matrix (ECM) components, particularly collagen, which is crucial for maintaining the mechanical integrity of connective tissues. In this investigation, bovine type I collagen was polymerised in the presence of two concentrations of HMB (0.025 M and 0.25 M) to explore its potential function as a molecular modulator of fibrillogenesis. The morphology of the resulting collagen fibres and their molecular architecture were examined using atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy. The findings demonstrated that lower levels of HMB facilitated the formation of more regular and well-organised fibrillar structures, exhibiting increased D-band periodicity and enhanced stabilisation of the native collagen triple helix, as indicated by Amide I and III band profiles. Conversely, higher concentrations of HMB led to significant disruption of fibril morphology and alterations in secondary structure, suggesting that HMB interferes with the self-assembly of collagen monomers. These structural changes are consistent with a non-covalent influence on interchain interactions and fibril organisation, to which hydrogen bonding and short-range electrostatics may contribute. Collectively, the results highlight the potential of HMB as a small-molecule regulator for soft-tissue matrix engineering, extending its consideration beyond metabolic supplementation towards controllable, materials-oriented modulation of ECM structure. Full article

Background and Objectives: Anthocyanin-rich barley varieties have recently gained attention due to their high (poly)phenolic content and potential health benefits, yet human data on their bioavailability remain scarce. This study aimed to characterize the absorption, metabolism, and excretion of (poly)phenolic compounds from a novel hull-less purple whole-grain barley (WGB) genotype. Methods: Eleven healthy volunteers consumed 140 g of purple WGB biscuits, and plasma and urine samples were collected over 6 h and 48 h, respectively. Results: UPLC-MS/MS analysis revealed a broad range of metabolites, with 11 (poly)phenolic compounds identified in plasma and 80 in urine. The biscuits were particularly rich in flavones (217 mg/140 g, mainly chrysoeriol derivatives), followed by hydroxycinnamic acids (~54 mg, mainly 4′-hydroxy-3′-methoxycinnamic acid), anthocyanins (44.8 mg), and flavan-3-ols (16.8 mg). In plasma, glycosylated anthocyanins and flavone conjugates (e.g., peonidin-3-O-glucuronide, chrysoeriol-O-glucuronide) were detectable within 1–2 h, consistent with early absorption. In contrast, microbial-derived catabolites—including valerolactones, phenylacetic and benzoic acids—were mainly excreted in urine between 8 and 24 h, reaching concentrations above 1000 nM. Conclusions: These findings provide novel insights into the bioavailability and metabolic fate of barley (poly)phenols, supporting their potential contribution to host and gut health. As a proof-of-concept study, it complements the limited data available from pigmented cereals and underscores the need for validation in larger cohorts. Full article

Benzene, toluene, ethylbenzene, and xylene (BTEX) are a common class of volatile organic compounds linked to adverse health outcomes. Although BTEX have been shown to have endocrine disrupting properties, their potential impacts on pubertal development in children remain unclear. In this study, for the first time, we investigated the possible association of BTEX exposure with precocious puberty (PP) and early puberty (EP) in children. We conducted a case–control study that included 246 children diagnosed with PP or EP and a controls category matched for sex and age. Urinary concentrations of seven BTEX metabolites and the oxidative DNA damage biomarker 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured by high-performance liquid chromatography-tandem mass spectrometry. Compared with the control groups, urinary catechol (1,2-DB) levels were significantly higher in both PP (median: 85.3 vs. 42.4 μg/g creatinine) and EP children (median: 62.0 vs. 48.1 μg/g creatinine). Binary logistic regression models showed that 1,2-DB was positively associated with EP (OR = 1.36, 95% CI: 1.10, 1.69), while trans,trans-muconic acid (MU) was negatively correlated with PP (OR = 0.47, 95% CI: 0.24, 0.92), and PGA was negatively correlated with EP (OR = 0.73, 95% CI: 0.56, 0.93) adjusted for confounders. Stratified analyses showed that the relationship between BTEX metabolites and EP varied by parental education level. Our findings revealed that exposure to BTEX, especially benzene, may influence pubertal timing in children, but there was no relationship between oxidative DNA damage and PP or EP. The biological mechanism of BTEX exposure affecting pubertal development requires further investigation. Full article

Background/Objectives: 1,8-Cineole, an epoxy monoterpene, is a key volatile component of Sugmel-3, a traditional Mongolian medicine used for treating insomnia. Although previous studies suggest that 1,8-Cineole can cross the blood–brain barrier (BBB), its precise spatiotemporal distribution in the brain and its in situ association with alterations in neurotransmitter (NT) levels remain unclear. This study utilized ambient mass spectrometry imaging (AFADESI-MSI) to investigate the dynamic brain distribution of 1,8-Cineole and its major metabolite, as well as their correlation with NT levels. Methods: Sprague Dawley rats (n = 3 per time point) received oral administration of 1,8-Cineole (65 mg/kg). Brain tissues were harvested 5 min, 30 min, 3 h, and 6 h post dose and analyzed using AFADESI-MSI. The spatial and temporal distributions of 1,8-Cineole, its metabolite 2-hydroxy-1,8-Cineole, key neurotransmitters (e.g., 5-HT, GABA, glutamine, melatonin), and related endogenous metabolites were mapped across 13 functionally distinct brain microregions. Results: AFADESI-MSI demonstrated rapid brain entry of 1,8-Cineole and its metabolite, with distinct spatiotemporal pharmacokinetics. The metabolite exhibited higher brain exposure, with 1,8-Cineole predominant in the cortex (CTX) and hippocampus (HP), while its metabolite showed pronounced accumulation in the pineal gland (PG), alongside CTX/HP. Region-dependent alterations in neurotransmitter levels (notably in PG, HP) correlated with drug concentrations, with observed increases in key molecules of the serotonergic and GABAergic pathways. Conclusions: Using AFADESI-MSI, this study provides the first spatiotemporal map of 1,8-Cineole and its metabolite in the brain. The correlation between their region-specific distribution and local neurotransmitter alterations suggests a direct mechanistic link to Sugmel-3′s sedative–hypnotic efficacy, guiding future target identification. Full article

Marshmallows are confectioneries that are popular among children and teenagers around the world. Barbecues and the consumption of grilled marshmallows, especially by children, have become fashionable in many countries. Grilled marshmallows may contain carcinogenic polycyclic aromatic hydrocarbons (PAHs). Hydroxy-PAHs (OH-PAHs) concentration in the urine of volunteers after the consumption of grilled marshmallows, as biomarkers of exposure to PAHs, have been determined. A total of 24 participants consumed marshmallows grilled under similar conditions. Urine samples were collected before and after the consumption of grilled marshmallows. 1-hydroxypyrene and 9-hydroxyphenanthrene concentrations in urine samples were determined using the HPLC-FLD technique after enzymatic hydrolysis and isolation by solid-phase extraction (SPE). The average concentration of 1-hydroxypyrene was 0.21 ± 0.16 µg/g creatinine and of 9-hydroxypenanthrene was 2.78 ± 2.55 µg/g creatinine. The concentrations of OH-PAHs in the urine of volunteers eating colored grilled marshmallows were higher compared to the consumption of white ones. In the case of 9-hydroxyphenanthrene this difference was statistically significant p < 0.05. Grilled marshmallows constitute a source of exposure to PAHs, especially in the group of children and adolescents. Even consumption of small or moderate amounts of grilled marshmallows resulted in a significant increase in concentrations of PAH metabolites in the urine compared to the level of these compounds before the intake. Full article

This study investigates the impact of light exposure on the biotransformation of chalcones in yeast cultures. 4′-Hydroxychalcones, with a hydroxyl group in the A-ring, are characteristic substrates efficiently converted into 4′-hydroxydihydrochalcones—compounds naturally occurring in medicinal plants such as Glycyrrhiza glabra (licorice), Stevia rebaudiana, and Angelica keiskei (ashitaba). These compounds are valued for their bioactivity and are relevant to natural product research. In this research, we present the outcomes of the selective microbial reduction of chalcones to dihydrochalcones using the yeast Yarrowia lipolytica KCh 71, cultivated under both light and dark conditions. The aim was to determine whether light exposure affects the efficiency or selectivity of the transformation. Furthermore, the effect of substrate photoisomerisation induced by light was investigated, as the trans–cis isomerisation of chalcones may affect their availability and affinity toward enzymatic systems. The resulting metabolites were analysed using chromatographic and spectroscopic methods. No significant differences in transformation efficiency were observed between light and dark conditions. In all tested conditions, the 4′-hydroxydihydrochalcones were obtained with high yield, typically exceeding 90% conversion. Additionally, the selective bioreduction of the α,β-unsaturated bond in selected 4′-hydroxychalcones by the studied yeast culture is an exceptionally efficient process. The primary factor influencing the reaction rate is the structure of the substrate, particularly the number and distribution of methoxyl groups on the B-ring. In addition, we establish biocatalytic access to three target dimethoxy dihydrochalcones—4′-hydroxy-2,4-dimethoxydihydrochalcone (5a), 4′-hydroxy-2,5-dimethoxydihydrochalcone (6a), and 4′-hydroxy-3,5-dimethoxydihydrochalcone (7a)—under mild conditions using Yarrowia lipolytica KCh 71. Under preparative-scale conditions (7-day incubation), a minor additional product (≤10%) was detected only for the 4′-hydroxy-2,5-dimethoxydihydrochalcone transformation and identified as 4′,5-dihydroxy-2-methoxydihydrochalcone (6b); no such side reaction was observed in short-term experiments. Full article

The complexity of human exposure to surrounding chemicals warrants developing analytical methods that are capable of the simultaneous quantitation of many diverse environmental pollutants and their biomarkers for the needs of human biomonitoring (HBM). Examples include pesticides used in veterinary medicine, such as fipronil (FIP), imidacloprid and pyrethroids, as well as other chemicals, like bisphenols and flame retardants. The goal of this paper was to develop and validate a liquid chromatography-tandem mass spectrometry method for the quantification of selected organic contaminants in human urine. The method was then applied to real samples and used to assess the potential of a new FIP biomarker, fipronil-hydroxy (FIP-OH), for HBM. As a sample preparation protocol, enzymatic deconjugation followed by solid phase extraction were used. The method was successfully developed and validated for 16 organic pollutants and/or their metabolites, with lower limits of quantitation ranging from 0.5 to 2000 pg/mL. FIP-OH could not be included in the method, possibly due to its chemical instability. In an application study among pet owners, the detection rate for FIP was 71% (median: 3.32 pg/mL); several other chemicals were also commonly detected. The results of validation and application experiments confirm that the method can be used in HBM studies to quantify organic pollutants in urine. Full article

Chilled yak meat is becoming more and more popular with the improvement in living standards, and the flavor of chilled meat is closely related to storage time. The effect of storage time on the flavor of chilled yak meat was explored in this study. We used GC-MS, HS-GC-IMS, and LC-MS/MS to detect changes in the metabolites in yak meat during storage at 4 °C and constructed storage time-dependent metabolite fingerprints of the yak meat. The results showed that low-temperature storage promoted the degradation of proteins and lipids, nucleotide release, and the production of the volatile compounds heptanal, octanal, n-nonanal, benzaldehyde, 2,3-pentanedione, 3-hydroxy-2-butanone, and 2-butanone. With an increase in the chilled storage time of yak meat, the total volatile basic nitrogen and total viable count of the meat were significantly increased. The short-term storage time of yak meat at 4 °C should not exceed 5 days. Full article

Cannabidiol (CBD) has been reported in medical applications for various indications. The enzymatic metabolism of CBD is not fully understood in the different routes of administration. This research aimed to identify the CBD metabolites after incubation of CBD with derived hepatocyte cells (HepG2), bronchial epithelial cells (NCI-H358), alveolar cells (A549), and alveolar macrophage cells (NR8383). A liquid chromatography–mass spectrometry technique was developed to quantify the CBD and its metabolites. Molecular docking was employed to evaluate the binding affinity of CBD with different cytochrome P-450 (CYP-450) enzymes and further predict the implication of drug–drug interactions. CBD and major metabolites of CBD were also docked with cannabinoid receptors. The results revealed that only HepG2 cells metabolized CBD to 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), whereas other respiratory cell lines and alveolar macrophages were found to have mainly CBD in the incubated samples without any metabolites. The CYP2C19 and CYP3A4 enzymes were responsible for CBD conversion to hydroxylated CBD metabolites. The 7-OH-CBD and 7-COOH-CBD metabolites were found to bind to cannabinoid receptors with different affinities. The relative abundance of CBD and major metabolites may indicate the potential route of CBD administration. Full article

Background: Atherosclerosis is a chronic vascular disease triggered by lipid accumulation. Auricularia heimuer is rich in various bioactive compounds that have anti-inflammatory, antioxidant, and hypolipidemic properties. The specific beneficial effects of A. heimuer on atherosclerosis and its underlying mechanisms require further investigation. Methods: In this study, ApoE^−/− mice were utilized as models of atherosclerosis induced by a high-fat diet (HFD) to investigate the effects of A. heimuer. Analyses of gut microbiota and serum metabolomics were conducted to elucidate the potential mechanism. Results: In HFD-fed ApoE^−/− mice, A. heimuer significantly inhibited the increase in body weight, regulated lipid levels, and alleviated aortic lesions. A. heimuer also modulated the abundance of intestinal flora such as Akkermansia and Ruminococcus and altered the levels of serum metabolites, including 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE) and N-acetyl galactosamine 4-sulfate. Furthermore, A. heimuer alleviated oxidative stress and inflammatory responses, thereby mitigating atherosclerosis via the Nrf2/NF-κB signaling pathway. Conclusions: These findings suggest that A. heimuer may serve as a potential therapeutic strategy for atherosclerosis. Full article

Lyngbyabellins O and P are complex natural products derived from non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) biosynthetic pathways and have been isolated from marine cyanobacterial sources. Both metabolites are characterized by the presence of two thiazole rings and a distinctive dichlorinated β-hydroxy acid side chain. Notably, lyngbyabellin P is further distinguished by the incorporation of a (3R,4S)-statine moiety. Herein, we report the first total syntheses of lyngbyabellins O and P, which are achieved through the convergent coupling of three key synthetic fragments, namely, two enantiomerically enriched thiazole subunits and a hydroxycarboxylic acid derivative, the latter constructed via a stereoselective aldol reaction. The total syntheses were completed in 12 and 13 longest linear steps (LLSs) for lyngbyabellins O and P, respectively, furnishing the natural products in overall yields of 5.6% and 2.5%. Full article

Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine drug screening data. Methods: We conducted a retrospective analysis of a raw mass spectrometry (MS) dataset from urine comprehensive drug screening (UCDS) from 363 patients at the University of Pittsburgh Medical Center Clinical Toxicology Laboratory. The liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-qToF-MS) data were preprocessed with MS-DIAL and subjected to multiple statistical analyses to identify features significantly associated with cocaine-enzyme immunoassay (EIA) results. Significant features were further evaluated using MS-FINDER for feature annotation. Results: Among 14,883 features, 262 were significantly associated with cocaine-EIA results. A subset of 37 more significant features, including known cocaine metabolites and impurities, nicotine metabolites, norfentanyl, and a tryptophan-related metabolite (3-hydroxy-tryptophan), was annotated. Cluster analysis revealed co-varying features, including parent compounds, metabolites, and related ion species. Conclusions: Features associated with cocaine exposure, including previously underrecognized cocaine metabolites and impurities, co-exposure markers, and alterations in an endogenous metabolic pathway, were identified. Notably, norfentanyl was found to be significantly associated with cocaine -EIA, reflecting current trends in illicit drug use. This study highlights the potential of repurposing real-world clinical toxicology data for biomarker discovery, providing a valuable approach to identifying exposure biomarkers and expanding our understanding of drug-induced metabolic disturbances in clinical toxicology. Further validation and exploration using complementary analytical platforms are warranted. Full article

Fermented vinegars have been highlighted globally for their health benefits. The benefits can differ according to the type of vinegar; therefore, we investigated the differences of 15 grain (GV), 10 persimmon (PV), and 14 apple vinegars (AV) using integrated non-targeted and targeted metabolome analyses. We profiled non-volatile and volatile metabolites using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS), ultra-high-performance liquid chromatography–orbitrap–tandem mass spectrometry, and headspace–solid-phase microextraction–GC-TOF-MS. Among the 132 identified metabolites, 73 non-volatile and 40 volatile metabolites showed significant differences across the three vinegar types. Amino acids, hydroxy fatty acids, phenolic compounds, aldehydes, pyrazines, and sulfides were abundant in GV. Some phenolic compounds, alcohols, and esters were abundant in PV, whereas carbohydrates, flavonoids, and terpenoids were abundant in AV, contributing to nutrients, tastes, and flavors. Bioactivity assays revealed that GV showed notable antioxidant activity, whereas PV and AV had the highest total phenolic and flavonoid contents, respectively. Through quantitative analysis, we revealed that acetic acid, propionic acid, butanoic acid, lactic acid, and alanine were major components in the three types of vinegar, although their composition was different in each vinegar. Our comprehensive qualitative and quantitative metabolite comparison provides insights into the differences among the three vinegar types, classified according to their raw materials. Full article

Background/Objectives: This study investigated the correlation of oxidative stress biomarkers with the activity of idiopathic nephrotic syndrome (INS) in Slovenian children. Methods: In this prospective study, sequential plasma and urine samples from 20 children with INS in different phases of disease activity were taken: at first disease presentation or relapse (before glucocorticoid (GC) treatment), at time of remission achievement, and after discontinuation of GC treatment. This study measured oxidative stress biomarkers, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL) adduct, dityrosine (DiY), and 15-isoprostane F2t, using competitive enzyme-linked immunosorbent assay (ELISA) and assessed oxidative status using the FRAS 5 analytical system, which enables rapid photometric measurement of both oxidative and antioxidant capacity from biological fluids. Two complementary tests were performed: the d-ROMs test (derivatives of reactive oxygen metabolites) and the PAT (plasma antioxidant test). The oxidative stress index (OSI) was calculated as the ratio between them. Results: Concentrations of isoprostanes in urine were statistically significantly lower in patients at first disease presentation or relapse compared to time of remission achievement. Values of PAT test in serum were significantly highest after GC treatment. Values of d-ROMs test in serum were significantly lower at time of remission achievement compared to first disease presentation or relapse. Values of 8-OHdG, HEL, DiY (in plasma and urine), isoprostanes, and OSI in plasma did not statistically significantly differ in various phases of disease activity. Conclusions: Isoprostanes in urine and PAT in serum could serve as potential biomarkers of oxidative stress and disease activity in children with INS. Full article