Search Results (649)

Thermodynamic factors (supersaturation of substances that form crystals) and kinetic factors (heterogeneous nucleants and crystallization inhibitors) affect the formation of crystals and stones in the urinary tract. We studied the effect of five different polyhydroxycarboxylic acids and phytate on the formation of calcium oxalate crystals in artificial urine. All tested molecules are known to inhibit the crystallization of this calcium salt, and to also form complexes with calcium ions. Considering the typical concentration of polyhydroxycarboxylic acids in urine (similar to that of the calcium ion) and their ability to inhibit crystallization, their most important effect is the capacity to complex calcium—a thermodynamic effect. For phytate and its metabolites, which are present in concentrations much lower than that of the calcium ion, the most important effect is as a crystallization inhibitor—a kinetic effect. Among the five polyhydroxycarboxylic acids examined here, hydroxycitrate had the strongest complexing capacity, and the addition of phytate to hydroxycitrate led to greater inhibition of crystallization. Therefore, because oral consumption of hydroxycitrate does not increase the urinary pH, it is likely that the combined consumption of hydroxycitrate and phytate can provide certain benefits for patients with increased risk of developing calcium oxalate stones. We also discussed the effects of these different molecules on the different calcium oxalate stones, including papillary calcium oxalate monohydrate stones, cavity calcium oxalate monohydrate stones, calcium oxalate dihydrate stones, and mixed calcium oxalate dihydrate/hydroxyapatite stones. Full article

Background/Objectives: COVID-19 is a systemic viral infection that may lead to serious complications including acute kidney injury that requires kidney replacement therapy. The primary aim of this study was to evaluate urinary SerpinA3 (uSerpinA3) excretion as a biomarker of kidney recovery at 90 days, and the mortality in patients with critical COVID-19 and AKI requiring kidney replacement therapy (KRT). Methods: The study included patients with critical COVID-19 on invasive mechanical ventilation (IMV) requiring KRT. Blood and urine samples were obtained when KRT was initiated (day zero), and thereafter on days 1, 3, 7, and 14 post-replacement. uSerpinA3, kidney injury molecule-1 (uKIM-1), and neutrophil gelatinase-associated lipocalin (uNGAL) were measured in urine, and interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-α) in peripheral blood. In addition, metabolomics in sample days zero and 3, and in the survivors on sample day 90 was performed by employing gas chromatography coupled with mass spectrometry. Results: A total of 60 patients were recruited, of whom 29 (48%) survived hospitalization and recovered kidney function by day 90. In the survivors, 79% presented complete recovery (CRR) and the remaining (21%) recovered partially (PRR). In terms of uSerpinA3, levels on days 7 and 14 predicted CRR, with AUC values of 0.68 (p = 0.041) and 0.71 (p = 0.030), respectively, as well as mortality, with AUC values of 0.75 (p = 0.007) and 0.76 (p = 0.015), respectively. Among the other biomarkers, the excretion of uKIM-1 on day zero of KRT had a superior performance as a CRR predictor [(AUC, 0.71 (p = 0.017)], and as a mortality predictor [AUC, 0.68 (p = 0.028)]. In the metabolomics analysis, we identified four distinct profiles; the metabolite that maintained statistical significance in predicting mortality was p-cresol glucuronide. Conclusions: This study strongly suggests that uSerpinA3 and uKIM-1 can predict CRR and mortality in patients with critical COVID-19 and AKI requiring KRT. Metabolic analysis appears promising for identifying affected pathways and their clinical impact in this population. Full article

Cucurbita pepo (CP) seeds are traditionally used to alleviate lower urinary tract symptoms associated with benign prostatic hyperplasia and overactive bladder. While these effects are often attributed to lipophilic constituents, recent studies have highlighted the therapeutic potential of oil-free hydroethanolic extracts. However, their composition remains insufficiently characterized, considering the species’ significant phenotypic and phytochemical variability. This study aimed to characterize the phytochemical profile of hydrophilic hydroethanolic seed extracts from ten CP cultivars originating from different European regions, with a focus on compositional variability. The elemental composition, along with primary and secondary metabolites, was analyzed using established spectroscopic and chromatographic methods. The extracts showed considerable variation in protein (45.39 to 114.58 mg/g dw) and free amino acid content (46.51 to 111.10 mg/g dw), as well as differences in elemental composition. Principal component analysis revealed distinct clustering patterns, with several samples displaying metabolite profiles comparable to the Cucurbita pepo var. styriaca variety currently recommended by the European Pharmacopoeia (Ph. Eur.) and the Committee on Herbal Medicinal Products (HMPC). These findings open the possibility of using other CP varieties as alternative sources for extract preparation and offer novel insights into the composition of less explored hydrophilic extracts derived from CP seeds. Full article

Autism spectrum disorder (ASD) is increasingly associated with microbial and metabolic disturbances, including the altered production of gut-derived uremic toxins. We investigated urinary concentrations of five representative uremic toxins—indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)—in 161 children with ASD and 71 healthy controls. Toxins were measured using LC-MS/MS and were normalized to creatinine. Subgroup analyses were performed by sex, age group (2–5.9 vs. 6–17 years), and autism severity based on the Childhood Autism Rating Scale (CARS). In addition to individual concentrations, we calculated the total toxin burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, and IS/ADMA). While individual toxin levels did not differ significantly between groups, stratified analyses revealed that PCS was higher in girls and in severe cases of ASD, whereas IS and TMAO were reduced in younger and more severely affected children. The functional ratios shifted consistently with severity—IS/PCS declined from 1.69 in controls to 0.99 in severe cases of ASD, while PCS/TMAO increased from 12.2 to 20.5. These patterns suggest a phenolic-dominant microbial signature and an altered host–microbial metabolic balance in ASD. Functional toxin profiling may offer a more sensitive approach to characterizing metabolic disturbances in ASD than concentration analysis alone. Full article

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders. Full article

Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids. Full article

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring. Full article

Background/Objectives: Herbal extracts from Betula alba (birch) are traditionally used for their purported diuretic effects, but scientific evidence supporting these claims remains limited. In this pilot study, we evaluated the short-term effects of a standardized B. alba leaf extract in healthy adult rats using an untargeted urinary metabolomics approach based on UPLC-QTOF. Methods: Two doses, 25 or 50 mg/kg, of a standardized B. alba extract were orally administered to rats. The extract contains hyperoside (0.53%), quercetin glucuronide (0.36%), myricetin glucoside (0.32%), and chlorogenic acid (0.28%) as its main constituents. After 3 days of treatment, the 24 h urine output was measured. Results: While no statistically significant changes were observed in the 24 h urine volume or the urinary Na⁺ and K⁺ excretion, multivariate metabolomic analysis revealed treatment-induced alterations in the urinary metabolic profile. Notably, the levels of two glucocorticoids, i.e., corticosterone and 11-dehydrocorticosterone, were increased in treated animals, suggesting that the extract may influence corticosteroid metabolism or excretion, potentially impacting antidiuretic hormone signaling. Elevated bile-related compounds, including bile acids and bilin, and glucuronidated metabolites were also observed, indicating changes in bile acid metabolism, hepatic detoxification, and possibly gut microbiota activity. Conclusions: Although this study did not confirm a diuretic effect of B. alba extract, the observed metabolic shifts suggest broader systemic bioactivities that warrant further investigation. Overall, the results indicate that the approach based on urinary metabolomics may be valuable in uncovering the mechanisms of action and evaluating the bioactivity of herbal extracts with purported diuretic properties. Full article

Background: The gut microbiome is a key modulator of the gut–brain axis and may contribute to the pathophysiology of both gastrointestinal and systemic disorders. This study aimed to evaluate gut microbiota composition and tryptophan/phenylalanine metabolism in women with unclassified irritable bowel syndrome (IBS-U), with or without coexisting chronic fatigue syndrome (CFS). Methods: Eighty women were enrolled and divided into two groups: IBS-U without CFS (Group I, n = 40) and IBS-U with coexisting CFS (Group II, n = 40). Microbial composition and diversity were assessed using the GA-map™ Dysbiosis Test, including the dysbiosis index (DI) and Shannon Diversity Index (SDI). Hydrogen and methane levels were measured in breath samples. Urinary concentrations of selected microbial and neuroactive metabolites—homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), quinolinic acid (QA), hydroxyphenylacetic acid (HPA), and 3-indoxyl sulfate (3-IS)—were quantified using LC-MS/MS. Fatigue severity was assessed using the Chalder Fatigue Questionnaire (CFQ-11) and the fatigue severity scale (FSS). Results: Compared to Group I, patients with IBS-CFS showed significantly greater microbial diversity, higher breath methane levels, and elevated urinary concentrations of QA, XA, 3-IS, and HVA, alongside lower concentrations of 5-HIAA and KYN. Fatigue severity was positively correlated with urinary XA and QA levels. Conclusions: Women with IBS and coexisting CFS exhibit distinct gut microbiota and tryptophan metabolite profiles compared to those without fatigue. The observed metabolite–symptom associations, particularly involving neuroactive kynurenine derivatives, warrant further investigation. These preliminary findings should be interpreted as hypothesis-generating and require validation through high-resolution microbiome analyses, functional pathway profiling, and longitudinal or interventional studies to clarify causality and clinical significance. Full article

Background/Objectives: Trimethylamine (TMA), produced by gut microbiota, and its derivative trimethylamine N-oxide (TMAO) are both associated with cardiometabolic diseases. While the effects of high-fat diets (HFDs) and high-disaccharide diets (HDDs) on gut microbiota in the context of obesity have been well studied, their impact on TMA/TMAO production, particularly alongside physiological caloric intake, remains obscure. This study investigates how standard HFDs and HDDs alongside physiological caloric intake influence gut microbiota composition and TMA/TMAO production in rats. Methods: Sprague Dawley rats were fed one of three diets a standard diet, an HFD, or an HDD for 12 weeks, with chow availability adjusted by age to maintain physiological caloric intake. Gut bacterial diversity was analyzed using 16S rRNA gene sequencing, and metabolites were quantified via High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) in urine and plasma. Results: The HFD group had significantly higher urinary levels of TMA and TMAO compared to the control and HDD groups. Gut bacterial diversity in the HFD group was markedly reduced, displaying the lowest species richness and phylogenetic diversity among all the groups. Notably, Pasteurellaceae (within the order Pasteurellales) and S24-7 (within the order Bacteroidales) were positively correlated with TMAO levels. The demonstrated HDD group increased microbial diversity compared to both the control and HFD groups. Conclusions: A high-fat diet during controlled and physiological caloric intake increases TMA/TMAO production and reduces gut microbial diversity. This underscores the role of diet composition, beyond caloric excess, in shaping gut microbiota and the related cardiometabolic biomarkers. Full article

Background: Informal electronic waste (e-waste) recycling practices release a complex mixture of pollutants, particularly heavy metals, into the environment. Chronic exposure to these contaminants has been linked to a range of health risks, but the molecular underpinnings remain poorly understood. In this study, we investigated the alterations in metabolic profiles due to e-waste exposure and linked these metabolites to systemic biological effects. Methods: We applied untargeted high-resolution metabolomics using dual-column LC-MS/MS and a multi-step analysis workflow combining MS1 feature detection, MS2 annotation, and chemical ontology classification, to characterize urinary metabolic alterations in 91 e-waste workers and 51 community controls associated with the Agbogbloshie site (Accra, Ghana). The impacts of heavy metal exposure in e-waste workers were assessed by establishing linear regression and four-parameter logistic (4PL) models between heavy metal levels and metabolite concentrations. Results: Significant metal-associated metabolomic changes were identified. Both linear and nonlinear models revealed distinct sets of exposure-responsive compounds, highlighting diverse biological responses. Ontology-informed annotation revealed systemic effects on lipid metabolism, oxidative stress pathways, and xenobiotic biotransformation. This study demonstrates how integrating chemical ontology and nonlinear modeling facilitates exposome interpretation in complex environments and provides a scalable template for environmental biomarker discovery. Conclusions: Integrating dose–response modeling and chemical ontology analysis enables robust interpretation of exposomics datasets when direct compound identification is limited. Our findings indicate that e-waste exposure induces systemic metabolic alterations that can underlie health risks and diseases. Full article

Background: Chronic non-communicable diseases (NCDs) are a major global health challenge, with unhealthy diets contributing significantly to their burden. Metabolomics data offer new possibilities for identifying nutritional biomarkers, as demonstrated in short-term intervention studies. This study investigated associations between habitual dietary intake and urinary metabolites, a not well-studied area. Methods: Data were available from 496 participants of the population-based MEIA study. Linear and median regression models examined associations between habitual dietary intake and metabolites, adjusted for possible confounders. K-means clustering identified urinary metabolite clusters, and multinomial regression models were applied to analyze associations between food intake and metabolite clusters. Results: Using linear regression models, previously reported associations could be replicated, including citrus intake with proline betaine, protein intake with urea, and fiber intake with hippurate. Novel findings include positive associations of poultry intake with taurine, indoxyl sulfate, 1-methylnicotinamide, and trimethylamine-N-oxide. Milk substitutes were positively associated with urinary uracil, pseudouridine, 4-hydroxyhippurate, and 3-hydroxyhippurate, and inversely associated with quinic acid. Dietary fiber intake showed a positive association with 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and a negative association with indoxyl sulfate. We identified sucrose and taurine as key metabolites differentiating metabolite clusters. Multinomial regression analysis confirmed significantly different dietary associations across clusters, particularly for fruits, processed meat, poultry, and alcoholic beverages. Conclusions: This study highlights established and novel food–metabolite associations, demonstrating the potential of urinary metabolomics for use as nutritional biomarkers in individuals from the general population. Full article

Background: Environmental tobacco smoke (ETS) exposes adolescents to various environmental toxins, potentially affecting their developmental health. However, limited research exists on the associations between ETS exposure and the bodily burdens of environmental chemicals on adolescents. This study aimed to investigate the relationship between ETS exposure and the concentration of various environmental chemicals in adolescents, utilizing urinary cotinine as an objective biomarker. Methods: Data from 828 adolescents aged 12–17 years participating in the Korean National Environmental Health Survey (KoNEHS) were analyzed. ETS exposure was assessed via self-reported questionnaires and confirmed by urinary cotinine measurements. Levels of 33 environmental chemicals, including heavy metals, polycyclic aromatic hydrocarbons (PAHs), phthalates, phenols, volatile organic compounds (VOCs), and per- and polyfluoroalkyl substances (PFASs), were measured. Statistical analyses were conducted after adjusting for covariates. Results: Adolescents exposed to ETS showed significantly higher urinary cotinine and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) concentrations than non-exposed adolescents. Additionally, significant positive correlations were observed between urinary cotinine levels and metabolites of PAHs (NAP, OHFlu), phenols (BPA, BPS), phthalates (MMP), and VOCs (t,t-MA) after adjustments. However, ETS exposure was not significantly associated with heavy metal concentrations. Conclusions: This study described the association between ETS exposure and environmental chemicals. A trend has been identified between ETS exposure in adolescents and increased bodily concentrations of various environmental chemicals, including PAHs, phenols, phthalates, and VOCs. As adolescence is a critical developmental period of vulnerability to environmental toxins, reducing ETS exposure to protect adolescents’ health and prevent potential lifelong health effects should be emphasized. This study was based on a cross-sectional design, and some confounding factors and measurement limitations may exist. Therefore, caution is needed in interpreting causality, and further research is recommended to determine more precise causality and long-term health effects. Full article

Given the widespread environmental presence of thioxanthones (TXs), a class of commonly used photoinitiators, great concerns have been raised regarding their potential human exposure and associated health risks. However, a comprehensive understanding of the total burden of human exposure to these compounds remains limited. To address this gap, the current study collected urine samples from 211 healthy adults in Taizhou City, China, and, for the first time, analyzed the presence of TXs and their metabolites in human urine. The findings revealed that 2-ITX (2-isopropylthioxanthone) and DETX (2,4-diethylthioxanthone) were more frequently detected than other TXs, displaying the detection frequencies of 82% and 79%, respectively, in human urine. Measured mean levels of 2-ITX and DETX were 0.66 ng/mL and 0.51 ng/mL, respectively, in human urine. Female participants (0.67 ± 0.24 ng/mL) demonstrated higher (p < 0.01) urinary concentrations of DETX than male participants (0.42 ± 0.19 ng/mL). Human urinary levels of 2-isopropy1-10-oxothioxanthen-9-one (p = 0.011), 2-diisopropy1-10,10-dioxothioxanthen-9-one (p < 0.01), and DETX (p = 0.011) were negatively correlated with the age of individual participants. The calculated mean daily exposure value of 2-ITX (240 ng/kg bw/day) was much (p < 0.01) higher than that of DETX (151 ng/kg bw/day) for the participants. This study offers foundational information on human exposure to TXs, contributing to future environmental health research and the development of human exposure management strategies. Full article

Erica species native to the Mediterranean basin are the principal Ericas that have found use in traditional medicine. Examples include treatments for urinary tract disorders, inflammatory conditions, gastrointestinal ailments and weight loss. This review critically evaluates the ethnobotanical usage, phytochemical profiles and pharmacological potential of the Mediterranean Erica species, including Erica arborea L., Erica multiflora L. and Erica manipuliflora Salisb. A wide spectrum of bioactive secondary metabolites has been identified across these species, notably pentacyclic triterpenes (e.g., lupeol, ursolic acid and oleanolic acid) and polyphenolics (e.g., myricetin and quercetin glycosides). Extracts of these species have demonstrated antioxidant, anti-inflammatory, analgesic, antimicrobial and diuretic activities in vitro and/or in vivo, providing pharmacological support for traditional uses. Phytochemical profiles vary by species, plant part, geography and extraction technique. Filsuvez^®, comprising pentacyclic triterpenes from birch bark, has clinical approval for the treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa. The undoubted reservoir of pentacyclic triterpenes and flavonoid glycosides in Mediterranean Erica species warrants further comprehensive mechanistic studies, toxicological evaluations and clinical validation. Full article