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In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene ( XDH ), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh (− / −) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh (− / −) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene ( Slc23a4 ), which is a pseudogene in humans. Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice was lower than that of patients with type 1 xanthinuria. Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh (− / −) mice survive to adulthood.

Background Allopurinol, one of the drugs routinely used to treat canine leishmaniosis (CanL), is an inhibitor of the enzyme xanthine oxidase, which plays a fundamental role in purine metabolism. Its inhibitory action on this enzyme leads to a state of hyperxanthinuria, favouring the development of xanthine crystals and/or uroliths. However, not all dogs with CanL treated with allopurinol develop xanthinuria and/or xanthine uroliths, and there is not much information on the possible risk factors that contribute to this event. This study aims to evaluate potential predisposing factors associated with the development of xanthinuria in dogs with a previous diagnosis of CanL that were treated with allopurinol. Methods A multicentric, retrospective, observational study was conducted and included dogs with CanL undergoing allopurinol therapy. Dogs that developed xanthinuria (Xgroup) and those without xanthinuria (NXgroup) were selected from cases admitted to three referral hospitals between 2011 and 2022. Medical records were reviewed, and clinical and laboratorial variables were compared between groups. Descriptive statistics, contingency tables and non-parametric tests were used ( P  < 0.05). Results In total, 90 dogs were selected, 45 for each group. Only age and serum alpha-1 globulin concentration were significantly different between groups at day 0. Dogs from Xgroup were younger (median 4 years; interquartile range (IQR) 2–7) than those from NXgroup (median 6 years; IQR 4–9; P  = 0.002). At the time of CanL diagnosis, a higher percentage of dogs from NXgroup had decreased serum alpha-1 globulin concentrations (38.9% versus 13.3% in Xgroup, respectively; P  = 0.020). In Xgroup, the median time to xanthinuria development after starting allopurinol was 150 days (IQR 31–455). Conclusions These results suggest that closer monitoring of young dogs (< 4 years) and those with normal alpha-1 globulin levels at diagnosis is recommended to ascertain the possible development of xanthinuria at an early stage, allowing for early application of measures to reduce the likelihood of its development. Graphical Abstract

 A novel hybrid with three-dimensional (3D) hierarchical CuS@Pd core-shell cauliflowers decorated on nitrogen-doped reduced graphene oxide (CuS@Pd/N–RGO) has been prepared by a facile wet-chemical route without utilizing any template molecules and surfactants. The characterization results reveal that the 3D flower-like structure of CuS “core” is composed of interconnecting nanoplates, which is conductive to the loading of Pd nanoparticles’ “shell” and results in the robust interaction between the core and shell for the formation of CuS@Pd cauliflowers. Anchoring such appealing CuS@Pd cauliflowers on the two-dimensional N–RGO can efficaciously inhibit the aggregation of CuS@Pd cauliflowers and accelerate the kinetics of xanthine oxidation. Benefiting from the multi-functional properties and unique morphology, the sensor constructed by CuS@Pd/N–RGO exhibits excellent performance for non-enzymatic detection of xanthine including a wide detection range of 0.7–200.0 μM (0.94 V vs. SCE), a low detection limit of 28 nM (S/ N  = 3), high reproducibility (relative standard deviation (RSD) = 4.1%), and commendable stability (retained 90% of the initial electrochemical responses after storage for 30 days), which is amongst the best of various electrochemical sensors reported for xanthine assays till date. Reliable and satisfying recoveries (95–105%, RSD ≤ 4.1%) are achieved for xanthine detection in real samples. The inspiring results make the uniquely structural CuS@Pd/N–RGO greatly promising in non-enzymatic electrochemical sensing applications. Graphical abstract A high-performance non-enzymatic xanthine sensor has been constructed by the three-dimensional hierarchical CuS@Pd core-shell cauliflowers decorated on nitrogen-doped reduced graphene oxide.

Coffee contains various bioactives implicated with human health and disease risk. To accurately assess the effects of overall consumption upon health and disease, individual intake must be measured in large epidemiological studies. Metabolomics has emerged as a powerful approach to discover biomarkers of intake for a large range of foods. Here we report the profiling of the urinary metabolome of cohort study subjects to search for new biomarkers of coffee intake. Using repeated 24-hour dietary records and a food frequency questionnaire, 20 high coffee consumers (183-540 mL/d) and 19 low consumers were selected from the French SU.VI.MAX2 cohort. Morning spot urine samples from each subject were profiled by high-resolution mass spectrometry. Partial least-square discriminant analysis of multidimensional liquid chromatography-mass spectrometry data clearly distinguished high consumers from low via 132 significant (p-value<0.05) discriminating features. Ion clusters whose intensities were most elevated in the high consumers were annotated using online and in-house databases and their identities checked using commercial standards and MS-MS fragmentation. The best discriminants, and thus potential markers of coffee consumption, were the glucuronide of the diterpenoid atractyligenin, the diketopiperazine cyclo(isoleucyl-prolyl), and the alkaloid trigonelline. Some caffeine metabolites, such as 1-methylxanthine, were also among the discriminants, however caffeine may be consumed from other sources and its metabolism is subject to inter-individual variation. Receiver operating characteristics curve analysis showed that the biomarkers identified could be used effectively in combination for increased sensitivity and specificity. Once validated in other cohorts or intervention studies, these specific single or combined biomarkers will become a valuable alternative to assessment of coffee intake by dietary survey and finally lead to a better understanding of the health implications of coffee consumption.

Tyburski, J. B., Patterson, A. D., Krausz, K. W., Slavík, J., Fornace, A. J. Jr., Gonzalez, F. J. and Idle, J. R. Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice. Radiat. Res. 172, 42-57 (2009). Gamma-radiation exposure of humans is a major public health concern as the threat of terrorism and potential hostile use of radiological devices increases worldwide. We report here the effects of sublethal γ-radiation exposure on the mouse urinary metabolome determined using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry-based metabolomics. Five urinary biomarkers of sublethal radiation exposure that were statistically significantly elevated during the first 24 h after exposure to doses ranging from 1 to 3 Gy were unequivocally identified by tandem mass spectrometry. These are deaminated purine and pyrimidine derivatives, namely, thymidine, 2′-deoxyuridine, 2′-deoxyxanthosine, xanthine and xanthosine. Furthermore, the aminopyrimidine 2′-deoxycytidine appeared to display reduced urinary excretion at 2 and 3 Gy. The elevated biomarkers displayed a time-dependent excretion, peaking in urine at 8–12 h but returning to baseline by 36 h after exposure. It is proposed that 2′-deoxyuridine and 2′-deoxyxanthosine arise as a result of γ irradiation by nitrosative deamination of 2′-deoxycytidine and 2′-deoxyguanosine, respectively, and that this further leads to increased synthesis of thymidine, xanthine and xanthosine. The urinary excretion of deaminated purines and pyrimidines, at the expense of aminopurines and aminopyrimidines, appears to form the core of the urinary radiation metabolomic signature of mice exposed to sublethal doses of ionizing radiation.

Objectives Individual activities of N-acetyltransferase 2 (NAT2) and of xanthine oxidase (XO) can be assessed using ratios of urinary caffeine metabolites. We investigated how ratios changed over time and which urine collection interval would be the best for NAT2 and XO activity assessments. Methods On two occasions separated by 14 days, 16 healthy male Caucasians collected urine before and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16 and 16-24 h after a dose of 150 mg caffeine given in the framework of a phenotyping cocktail study. The metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1X), and 1-methylurate (1U) were quantified with LC-MS/MS. The molar ratio (AFMU + AAMU)/(1X + 1U + AFMU + AAMU) was used as a NAT2 metric, while the ratio 1U/(1X + 1U) served as XO metric. Results The NAT2 ratios were stable in the intervals 4-24 h after caffeine dosing. Mean intra-individual coefficients of variation were 11-23% starting 4 h post-dose, while inter-individual variability reached 37-75%. The XO ratios increased gradually by 14% from the 2-4 to the 16-24 h interval. The mean intra- and inter-individual coefficients of variation of XO activity were 3-18 and 7-10% respectively. No significant differences between study occasions were observed. Conclusions Any sampling interval at least 4 h after caffeine dosing is suitable for NAT2 and XO activity assessments. XO activities can only be compared between volunteers and studies if the same urine collection schedule has been respected. The low intraindividual variability allows for sample sizes of 16 and 6 participants in crossover interaction studies of NAT2 and XO activity respectively.

Habitual consumption of medium amounts of coffee over the whole life-span is hypothesized to reduce the risk to develop diabetes type 2 (DM2) and Alzheimer’s disease (AD). To identify putative bioactive coffee-derived metabolites, first, pooled urine from coffee drinkers and non-coffee drinkers were screened by UPLC-HDMS. After statistical data analysis, trigonelline, dimethylxanthines and monomethylxanthines, and ferulic acid conjugates were identified as the major metabolites found after coffee consumption. For quantitative analysis of these markers in body fluids, targeted methods based on stable-isotope dilution and UPLC-MS/MS were developed and applied to plasma samples from a coffee intervention study ( n  = 13 volunteers) who consumed a single cup of caffeinated coffee brew after a 10-day washout period. Chlorogenic acid-derived metabolites were found to be separated into two groups showing different pharmacokinetic properties. The first group comprised, e.g., ferulic acid and feruloyl sulfate and showed early appearance in the plasma (∼1 h). The second group contained particularly chlorogenic acid metabolites formed by the intestinal microflora, appearing late and persisting in the plasma (>6 h). Trigonelline appeared early but persisted with calculated half-life times ∼5 h. The plasma levels of caffeine metabolites significantly and progressively increased 2–4 h after coffee consumption and did not reach c max within the time frame of the study. The pharmacokinetic profiles suggest that particularly trigonelline, caffeine, its metabolites, as well as late appearing dihydroferulic acid, feruloylglycine and dihydroferulic acid sulfate formed from chlorogenic acid by the intestinal microflora accumulate in the plasma due to their long half-life times during habitual consumption of several cups of coffee distributed over the day. Since some of these metabolites have been reported to show antioxidant effects in vivo, antioxidant-response-element activating potential, and neuroprotective properties, respectively, some of these key metabolites might account for the inflammation- and DM2/AD risk reducing effects reported for habitual life time consumption of coffee. Figure Identification of coffee key metabolites in human urine using untargeted MS-based profiling and subsequent targeted analyses in plasma using stable isotope dilution assays

Background Psychological co-morbidities in irritable bowel syndrome (IBS) have been widely recognized, whereas less is known regarding the role of gut microbial and host metabolic changes in clinical and psychological symptoms in IBS. Results A total of 70 diarrhoea-predominant IBS (IBS-D) patients and 46 healthy controls were enrolled in this study. Stool and urine samples were collected from both groups for 16S rRNA gene sequencing and metabolomic analysis. The results showed that fecal microbiota in IBS-D featured depleted Faecalibacterium (adjusted P =  0.034), Eubacterium rectale group (adjusted P =  0.048), Subdoligranulum (adjusted P =  0.041) and increased Prevotella (adjusted P =  0.041). O-ureido-L-serine, 3,4-dihydroxybenzenesulfonic acid and (R)-2-Hydroxyglutarate demonstrated lower urinary concentrations in IBS-D patients. We further built correlation matrices between gut microbe abundance, differentiated metabolite quantities and clinical parameters. Dialister manifested negative association with IBS severity ( r  = − 0.285, P  = 0.017), anxiety ( r  = − 0.347, P  = 0.003) and depression level ( r  = − 0.308, P  = 0.010). Roseburia was negatively associated with IBS severity ( r  = − 0.298, P  = 0.012). Twenty metabolites correlated with anxiety or depression levels, including 3,4-dihydroxymandelaldehyde with SAS ( r  = − 0.383, P  = 0.001), 1-methylxanthine with SDS ( r  = − 0.347, P  = 0.004) and 1D-chiro-inositol with SAS ( r  = − 0.336, P  = 0.005). In analysis of microbe-metabolite relationship, 3,4-dihydroxymandelaldehyde and 1-methylxanthine were negatively correlated with relative abundance of Clostridium sensu stricto . Conclusions Our findings demonstrated altered microbial and metabolomic profiles associated with clinically and psychological symptoms in IBS-D patients, which may provide insights for further investigations.

Molybdenum cofactor (MoCo) deficiency is a rare, autosomal-recessive disorder, mainly caused by mutations in MOCS1 (MoCo deficiency type A) or MOCS2 (MoCo deficiency type B) genes; the absence of active MoCo results in a deficiency in all MoCo-dependent enzymes. Patients with MoCo deficiency present with neonatal seizures, feeding difficulties, severe developmental delay, brain atrophy and early childhood death. Although substitution therapy with cyclic pyranopterin monophosphate (cPMP) has been successfully used in both Mocs1 knockout mice and in patients with MoCo deficiency type A, there is currently no Mocs2 knockout mouse and no curative therapy for patients with MoCo deficiency type B. Therefore, we generated and characterized a Mocs2 -null mouse model of MoCo deficiency type B. Expression analyses of Mocs2 revealed a ubiquitous expression pattern; however, at the cellular level, specific cells show prominent Mocs2 expression, e.g., neuronal cells in cortex, hippocampus and brainstem. Phenotypic analyses demonstrated that Mocs2 knockout mice failed to thrive and died within 11 days after birth. None of the tested MoCo-dependent enzymes were active in Mocs2 -deficient mice, leading to elevated concentrations of purines, such as hypoxanthine and xanthine, and non-detectable levels of uric acid in the serum and urine. Moreover, elevated concentrations of S -sulfocysteine were measured in the serum and urine. Increased levels of xanthine resulted in bladder and kidney stone formation, whereas increased concentrations of toxic sulfite triggered neuronal apoptosis. In conclusion, Mocs2 -deficient mice recapitulate the severe phenotype observed in humans and can now serve as a model for preclinical therapeutic approaches for MoCo deficiency type B.