Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Factors influencing the recovery of organic nitrogen from fresh human urine dosed with organic/inorganic acids and concentrated by evaporation in ambient conditions.

To feed the world without transgressing regional and planetary boundaries for nitrogen and phosphorus, one promising strategy is to return nutrients present in domestic wastewater to farmland. This study tested a novel approach for producing bio-based solid fertilisers by concentrating source-separated human urine through acidification and dehydration. Thermodynamic simulations and laboratory experiments were conducted to evaluate changes in chemistry of real fresh urine dosed and dehydrated using two different organic and inorganic acids. The results showed that an acid dose of 1.36 g H2SO4 L-1, 2.86 g H3PO4 L-1, 2.53 g C2H2O4·2H2O L-1 and 5.9 g C6H8O7 L-1 was sufficient to maintain pH ≤3.0 and prevent enzymatic ureolysis in urine during dehydration. Unlike alkaline dehydration using Ca(OH)2 where calcite formation limits the nutrient content of fertiliser products (e.g. <15 % nitrogen), there is greater value proposition in acid dehydration of urine, as the products contain 17.9-21.2 % nitrogen, 1.1-3.6 % phosphorus, 4.2-5.6 % potassium and 15.4-19.4 % carbon. While the treatment recovered all phosphorus, recovery of nitrogen in the solid products was 74 % (±4 %). Follow-up experiments revealed that hydrolytic breakdown of urea to ammonia, chemically or enzymatically, was not the reason for the nitrogen losses. Instead, we posit that urea breaks down to ammonium cyanate, which then reacts with amino and sulfhydryl groups of amino acids excreted in urine. Overall, the organic acids evaluated in this study are promising for decentralised urine treatment, as they are naturally present in food and therefore already excreted in human urine.

Optimization and kinetic modeling of phosphate recovery as struvite by electrocoagulation from source-separated urine.

Phosphorus recovery is indispensable due to the rapid depletion of its natural reserves and excessive utility in agriculture. Though human urine has high nutrient content including phosphate, nitrogen and potassium; direct use as a fertilizer is restricted due to hygienic, environmental, social and ethical issues. To overcome these limitations, the nutrients are precipitated by the external addition of magnesium (Mg) to form a slow-releasing fertilizer called struvite. The present study aims to maximize phosphate recovery through optimizing struvite production by an emerging electrocoagulation technique. A maximum of 95% phosphate recovery was achieved using inter-electrode distance of 0.5 cm, 2 A current from undiluted urine using Mg-Mg electrodes in a reaction time of 30 min. Further, kinetic modeling of phosphate recovery through electrocoagulation was conducted to comprehend the intended mechanism through the order of kinetics. The results revealed that the data best correlated with first-order kinetics with a correlation coefficient of 0.95. Electrocoagulation improved the supernatant quality by reducing the ion concentrations other than phosphate (30-50%), salinity (40-45%), and microbial population (99%). Qualitative assessment of the precipitate through sophisticated analysis further confirmed the presence of struvite crystals.

Studies on the mechanism of Panax Ginseng in the treatment of deficiency of vital energy dementia rats based on urine metabolomics.

Panax Ginseng (PG) has been used to strengthen memory and physique for thousands of years, because its main components ginsenosides (GS) and ginseng polysaccharides (GP) play a major role, but its mechanism is not clear. In this study, a rat model of dementia with vital energy deficiency (DED) was established through intraperitoneal injection with D-galactose and AlCl3 and combined with exhaustive swimming. Pharmacological studies and the urine metabolomics based on ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were employed for evaluation the efficacy of PG and exploring this treatment mechanism. Through urine metabolic profiling, it can be seen that DED rats after PG administration are close to normal group (NG) rats, and PG can regulate the in vivo status of DED rats which tend to NG. The results of behavioral, biochemical indicators and immunohistochemistry further verified the above results, and the mechanism of action of each component is refined. Ultimately, we believe that the mechanism of PG in the treatment of DED is that ginsenosides (GS) intervenes in phenylalanine tryptophan and tyrosine metabolism, stimulates dopamine production, inhibits Aß deposition and neuroinflammation; and that ginseng polysaccharides (GP) provides energy to strengthen the TCA cycle and improve immune capacity.

The influence of tart cherries (Prunus Cerasus) on vascular function and the urinary metabolome: a randomised placebo-controlled pilot study.

Montmorency tart cherries (MC) have been found to modulate indices of vascular function with interventions of varying duration. The objective of this preliminary study was to identify the chronic effects of MC supplementation on vascular function and the potential for urinary metabolomics to provide mechanistic evidence. We performed a placebo-controlled, double-blind, randomised study on 23 healthy individuals (18M, 7F) that consumed 30 ml MC or a placebo twice daily for 28 days. Whole body measures of vascular function and spot urine collections were taken at baseline and after supplementation. There were no significant changes to vascular function including blood pressure and arterial stiffness. Urinary metabolite profiling highlighted significant changes (P < 0⋅001) with putative discriminatory metabolites related to tryptophan and histidine metabolism. Overall, MC supplementation for 28 days does not improve indices of vascular function but changes to the urinary metabolome could be suggestive of potential mechanisms.

Characterization of Metabolites in Plasma, Urine and Feces of Healthy Participants after Taking Brahmi Essence for Twelve Weeks Using LC-ESI-QTOF-MS Metabolomic Approach.

Brahmi essence, developed from Bacopa monnieri (L.) Wettst. standardized extract and mulberry juice, was proven to improve the memory speed of healthy participants aged 55-80 years old, following a 12-week dietary program. However, the metabolites have not yet been reported. Our objective was to characterize the altered metabolites in the plasma, urine, and feces of healthy volunteers after consumption of Brahmi essence for 12 weeks, using the LC-MS metabolomics approach. The altered metabolites were selected from OPLS-DA S-plots; 15 metabolites in the plasma, 7 in the urine, and 17 in the feces samples were tentatively identified by comparison with an online database and literature. The metabolites in the plasma samples were in the classes of amino acids, acylcarnitine, and phospholipids. Benzeneactamide-4-O-sulphate and 3-hydroxyhippuric acid were found in urine samples. The metabolites in the class of amino acids, together with jujubogenin and pseudojujubogenin, were identified in the fecal samples. The aminoacyl-tRNA, aromatic amino acids, and branched-chain amino acid biosynthetic pathways were mainly related to the identified metabolites in all three samples. It could be implied that those metabolites and their pathways might be linked with the effect of Brahmi essence on memory speed.

Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults.

Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO3-) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m2) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO3- (HN: 2 × 70 mL BJ/day) (2) medium-NO3- (MN: 70 mL BJ/day), (3) low-NO3- (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO3--depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO3- intake, and by measuring NO3- and NO2- concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO3- dose and the increase in plasma and urinary NO3- concentration (R2 = 0.71, P < 0.001 and R2 = 0.46 P < 0.001, respectively), but relationships between NO3- dose and changes in salivary NO3- and NO2- were non-linear (R2 = 0.35, P = 0.002 and R2 = 0.23, P = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults.

Gut Microbial and Metabolic Profiling Reveal the Lingering Effects of Infantile Iron Deficiency Unless Treated with Iron.

SCOPE: Iron deficiency (ID) compromises the health of infants worldwide. Although readily treated with iron, concerns remain about the persistence of some effects. Metabolic and gut microbial consequences of infantile ID were investigated in juvenile monkeys after natural recovery (pID) from iron deficiency or post-treatment with iron dextran and B vitamins (pID+Fe). METHODS AND RESULTS: Metabolomic profiling of urine and plasma is conducted with 1 H nuclear magnetic resonance (NMR) spectroscopy. Gut microbiota are characterized from rectal swabs by amplicon sequencing of the 16S rRNA gene. Urinary metabolic profiles of pID monkeys significantly differed from pID+Fe and continuously iron-sufficient controls (IS) with higher maltose and lower amounts of microbial-derived metabolites. Persistent differences in energy metabolism are apparent from the plasma metabolic phenotypes with greater reliance on anaerobic glycolysis in pID monkeys. Microbial profiling indicated higher abundances of Methanobrevibacter, Lachnobacterium, and Ruminococcus in pID monkeys and any history of ID resulted in a lower Prevotella abundance compared to the IS controls. CONCLUSIONS: Lingering metabolic and microbial effects are found after natural recovery from ID. These long-term biochemical derangements are not present in the pID+Fe animals emphasizing the importance of the early detection and treatment of early-life ID to ameliorate its chronic metabolic effects.

Ethnopharmacological investigations of the leaves of Cecropia pachystachya Trécul (Urticaceae): A native Brazilian tree species.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia pachystachya Trécul (Urticaceae) is a medicinal plant popularly known as 'embaúba'. In Brazil, the leaves of this species are used for the treatment of various kidney and cardiovascular diseases. However, there are no detailed studies on the renal and cardiovascular activities of this species. No studies on the anatomy or the quality control of this herbal drug is available thus far. AIM: This study was aimed to investigate the ethnopharmacological properties of the leaves of C. pachystachya. MATERIAL AND METHODS: The leaves of C. pachystachya were analyzed by light and scanning electron microscopy for pharmacobotanical and anatomical characterization. The ethanol-soluble fraction of C. pachystachya leaf extract (ESCP) was characterized by high-performance liquid chromatograph equipped with diode array detector and mass spectrometry (HPLC-DAD-MS). The acute oral toxicity of ESCP on female Wistar rats was assessed. The acute and prolonged diuresis and antioxidant effects of ESCP (30, 100, and 300 mg/kg) were evaluated in male Wistar rats. In addition, the hypotensive effects of the ESCP as well as the vasodilatory activity in isolated and perfused mesenteric vascular beds were investigated. RESULTS: The anatomical markers obtained in this study can help in the identification of C. pachystachya, as well as to distinguish it from the other 'embaúbas'. The metabolites found in the ESCP were phenolic compounds, mainly C- and O-glycosylated flavonoids. The ESCP did not exhibit any toxic effects at a dose of 2000 mg/kg. Significant diuretic activities were observed at the doses of 30, 100, and 300 mg/kg. In addition, a significant modulating activity of the tissue redox state was observed after prolonged treatment. On the other hand, no hypotensive or vasodilator activity was observed. CONCLUSION: The key findings of the present study can contribute to the taxonomy, species identification and quality control of C. pachystachya. Chemical studies have shown the presence of glycosylated flavonoids, phenylpropanoid derivative and proanthocyanidins. The pharmacological studies showed significant diuretic and antioxidant effects of C. pachystachya leaf extract, indicating a possible validation of its popular medicinal use.

Prospective Evaluation of Daily and Weekly Urine pH Variations Along With Diet Intake in Postmenopausal Women With Recurrent Urinary Tract Infections.

OBJECTIVES: Acidic urine pH may be protective against recurrent urinary tract infections (RUTIs). After reviewing the literature, we primarily analyzed urine pH fluctuations and secondarily compared them with diet in older women with RUTIs. METHODS: After IRB approval, postmenopausal women with documented RUTIs were enrolled. Participants were given preformatted charts to record urinalysis reagent strips (Medimpex) findings 4 times per day and concomitant food/beverage intake (food diary). Urine cultures at baseline ensured no infection during measurement period. Nutrient content reported in food diaries was analyzed by an experienced registered dietitian and compared with parallel fluctuations in urine pH. RESULTS: Of 26 women with median age of 72 years (55-86 years), the first 3 days of diet and urine pH recordings found that 17 (65%) of 26 exhibited urine pH variation greater than 1 unit, with an overall median of 6 (5-9). Comparing dietary analysis and urine pH changes, beta-carotene (P = 0.017) and total dietary sugar intake (P = 0.036) were associated with a decrease in urine pH, whereas monounsaturated fatty acids (MFA, 22:1, P = 0.023) and protein (P = 0.028) were associated with an increase in urine pH. CONCLUSIONS: In this real-life, observational study, 65% of older women with RUTIs exhibited notable changes in urine pH, with decreased urine pH associated with nutrients found in orange and yellow vegetables and several major food groups. A longitudinal study is needed to determine if changing an individual's diet and/or adding supplements could decrease the urine pH, thus affecting the rate of RUTIs.

Random urine drug testing among patients receiving opioid therapy for cancer pain.

BACKGROUND: There is limited information regarding the true frequency of nonmedical opioid use (NMOU) among patients receiving opioid therapy for cancer pain. Data to guide patient selection for urine drug testing (UDT) as well as the timing and frequency of ordering UDT are insufficient. This study examined the frequency of abnormal UDT among patients with cancer who underwent random UDT and their characteristics. METHODS: Demographic and clinical information for patients with cancer who underwent random UDT were retrospectively reviewed and compared with a historical cohort that underwent targeted UDT. Random UDT was ordered regardless of a patient's risk potential for NMOU. Targeted UDT was ordered on the basis of a physician's estimation of a patient's risk for NMOU. RESULTS: In all, 552 of 573 eligible patients (96%) underwent random UDT. Among these patients, 130 (24%) had 1 or more abnormal results; 38 of the 88 patients (43%) who underwent targeted UDT had 1 or more abnormal results. When marijuana was excluded, 15% of the random group and 37% of the targeted group had abnormal UDT findings (P < .001). It took a shorter time from the initial consultation to detect 1 or more abnormalities with the random test than the targeted test (median, 130 vs 274 days; P = .02). Abnormal random UDT was independently associated with younger age (P < .0001), male sex (P = .03), Cut Down, Annoyed, Guilty, and Eye Opener-Adapted to Include Drugs positivity (P = .001), and higher Edmonton Symptom Assessment System anxiety (P = .01). CONCLUSIONS: Approximately 1 in 4 patients receiving opioids for cancer pain at a supportive care clinic who underwent random UDT had 1 or more abnormalities. Random UDT detected abnormalities earlier than the targeted test. These findings suggest that random UDT is justified among patients with cancer pain.

Nonantibiotic treatments for urinary cystitis: an update.

PURPOSE OF REVIEW: Urinary tract infections (UTIs) are one of most common infections in everyday clinical practice. Given the increase in antimicrobial therapy resistance, there has been an increased interest in nonantibiotic treatment options for common infections. RECENT FINDINGS: A review of the recent literature including on nonantibiotic options for management of UTIs, symptoms of cystitis and prevention of recurrent UTIs. SUMMARY: The article provides an overview on alternative therapy to antibiotics in the treatment of cystitis and recurrent UTI prophylaxis, including alkalinization of urine, cranberry products, probiotics, NSAIDS, D-mannose, herbal medicine, methenamine hippurate, oral immunostimulants (immunotherapy), topical oestrogens, vitamins and acupuncture. The last few years of intense research has focused on an effort to find evidence to corroborate potentially efficacious non antibiotic treatments. However, alternative treatments for UTIs have not brought conclusive evidence that antibiotic usage can be replaced completely by nonantibiotic options. The reason for this is largely due to a lack of good-quality randomized controlled trials on this subject.

Streptozotocin-induced diabetic cardiomyopathy in rats: ameliorative effect of PIPERINE via Bcl2, Bax/Bcl2, and caspase-3 pathways.

The objective of present investigation was to appraise the effects of piperine on STZ-induced diabetic cardiomyopathy in rats. Diabetes was induced in Sprague-Dawley rats with intraperitoneal STZ injection, and the rats were assigned to seven groups. Electrocardiograph, hemodynamic, various biochemical, molecular, and histological parameters were examined. Treatment with piperine significantly (p < 0.05) restored altered myocardial functions, inhibited cardiac marker, and restored electrocardiogram and hemodynamic alterations. The elevated level of cardiac oxido-nitrosative stress and decreased cardiac Na-K-ATPase concentration, after STZ administration, were significantly (p < 0.05) attenuated by piperine treatment. Piperine also considerably (p < 0.05) increased myocardial mitochondrial enzyme activity. STZ-induced alteration in heart ANP, BNP, cTn-I, Bcl2, Bax/Bcl2, and caspase3 mRNA expression was significantly (p < 0.05) restored by piperine treatment. Piperine administration reduced histopathological aberrations induced by STZ. In conclusion, the present investigation suggests that piperine ameliorates STZ-induced diabetic cardiomyopathy via modulation of caspase-3, Bcl2, Bax/Bcl2 pathways. Abbreviations: ACE: Angiotensin-Converting Enzyme; ANOVA: Analysis of Variance; ANP: Atrial Natriuretic Peptide; APAF: Apoptotic Protease-Activating Factor; ARB: Angiotensin Receptor Blockers; ATP: Adenosine Triphosphate; Bax: Bcl-2-associated X protein; Bcl2: B-cell lymphoma 2; BPM: Beats Per Minute; BNP: brain natriuretic peptide; CAD: Caspase-3-Activated DNase; cDNA: Complementary DNA; CK-MB: Creatine Kinase-MB; CPCSEA: Committee for the Purpose of Control And Supervision of Experiments on Animals; cTn-I: cardiac troponin I; DBP: Diastolic Blood Pressure; DCM: Diabetic Cardiomyopathy; DNA: Deoxyribonucleic Acid; DPX: DisterenePhthalate Xylene; ECG: Electrocardiogram; ETC: Electron Transport Chain; GOD-POD: Glucose Oxidase Peroxidase; GSH: Glutathione; IAEC: Institutional Animal Ethics Committee; IL-6: Interleukin-6; IL-1b: Interleukin-1b; LDH: Lactate Dehydrogenase; LV: Left Ventricle; LVEDP: left ventricular end-diastolic Pressure; MABP: Mean Arterial Blood Pressure; MDA: Malondialdehyde; mRNA: Messenger Ribonucleic Acid; MTT: 3- (4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide; NADH: Nicotinamide Adenine Dinucleotide Phosphate; NADPH: Nicotinamide Adenine Dinucleotide Phosphate Hydrogen; NO: nitric oxide; NP: Natriuretic Peptides; OXPHOS: Oxidative Phosphorylation; p.o.: per os; PCR: Polymerase Chain Reaction; RT-PCR: Reverse Transcriptionpolymerase Chain Reaction; PPAR: Peroxisome Proliferator-Activated Receptor Gamma; RAS: Renin-Angiotensin System; RNA: Ribonucleic Acid; ROS: Reactive Oxygen Species; SBP: Systolic Blood Pressure; SDH: Succinate Dehydrogenase; SEM: Standard Error Means; SOD: superoxide dismutase: STZ: Streptozotocin; TNF: Tumor Necrosis Factor Alpha; TnI: Troponin I.

Chemical compounds, antioxidant activity, and in vitro and in silico litholytic effects of Zizyphus lotus extracts.

Background The aim of this study was to evaluate the antioxidant activity and to determine the chemical compounds of organic extracts of fruits and leaves of Zizyphus lotus. The litholytic effect was determined on the basis of the in vitro effect of the aqueous extracts on the formation of crystals of stones. Finally, chemical compounds were investigated to identify their target using an in silico approach. Methods The antioxidant activity was determined with the diphenylpicrylhydrazyl radical trapping method. An aliquot of 2 mL of urine and 100 µL of an infusion of fruit and leaf aqueous extract of Z. lotus at different concentrations were used. The induction of calcium oxalate (CaOx) crystals was done by the addition of oxalic acid at 0.1 mol/L. The effect of aqueous extracts was compared with two inhibitors (citrate and magnesium) used as references. In silico modelization was carried out using SwissTargetPrediction. Results The antioxidant activity test showed that the methanol extract was active with an IC50 of 5 mg/mL. The aqueous extracts of fruits and leaves inhibit the formation of crystals of CaOx. Then, the composition of the methanol extracts of the leaves and fruits in high-performance liquid chromatography showed majority compounds such as quercetin-3-galactoside and hyperin. In silico assays showed that the identified molecules exert their effect by targeting enzymes responsible for calcium regulation, urate regulation, and maintenance of acid-base balance, and that had anti-inflammatory properties. Conclusions The present study showed that Z. lotus may be considered as a functional or nutraceutical food. However, further studies should be carried out in order to extract and purify these compounds to test their effect on urinary lithiasis.

A systematic metabolic pathway identification of Common Gardenia Fruit (Gardeniae Fructus) in mouse bile, plasma, urine and feces by HPLC-Q-TOF-MS/MS.

Gardeniae Fructus was a traditional Chinese medicine (TCM) containing various biological ingredients including iridoids and crocetins, monocyclic monoterpenes, organic acids, and flavonoids. However, few systematic identification studies of the bioactive components in vivo have been reported. Herein, the ingredients and metabolites of Gardeniae Fructus were investigated using high-performance liquid chromatography coupled with high-sensitivity Q-TOF mass spectrometry. A total of 45 prototype compounds in Gardeniae Fructus extract were tentatively identified. After oral administration, 69 of prototypes and metabolites were identified from mice bile, plasma, urine, and feces, in which, 31 compounds were prototypes, and 38 chemicals were metabolites. The in vivo biotransformation pathways of these metabolites were also proposed including phase I (hydrolysis, hydrogenation, oxidation, loss of O, and ketone formation, decarboxylation) and phase II reactions (glycine, cysteine, glutathione, and glutamine, and sulfate conjugation, and glucuronidation). For the first time, our results had revealed systematic metabolic profiles of ingredients in Gardeniae Fructus extract in vivo of mice and replenished novel knowledge into the explanation of effective material and/or toxicological basis of Gardeniae Fructus which deserves further investigation.

Species Differences of Bile Acid Redox Metabolism: Tertiary Oxidation of Deoxycholate is Conserved in Preclinical Animals.

It was recently disclosed that CYP3A is responsible for the tertiary stereoselective oxidations of deoxycholic acid (DCA), which becomes a continuum mechanism of the host-gut microbial cometabolism of bile acids (BAs) in humans. This work aims to investigate the species differences of BA redox metabolism and clarify whether the tertiary metabolism of DCA is a conserved pathway in preclinical animals. With quantitative determination of the total unconjugated BAs in urine and fecal samples of humans, dogs, rats, and mice, it was confirmed that the tertiary oxidized metabolites of DCA were found in all tested animals, whereas DCA and its oxidized metabolites disappeared in germ-free mice. The in vitro metabolism data of DCA and the other unconjugated BAs in liver microsomes of humans, monkeys, dogs, rats, and mice showed consistencies with the BA-profiling data, confirming that the tertiary oxidation of DCA is a conserved pathway. In liver microsomes of all tested animals, however, the oxidation activities toward DCA were far below the murine-specific 6ß-oxidation activities toward chenodeoxycholic acid (CDCA), ursodeoxycholic acid, and lithocholic acid (LCA), and 7-oxidation activities toward murideoxycholic acid and hyodeoxycholic acid came from the 6-hydroxylation of LCA. These findings provided further explanations for why murine animals have significantly enhanced downstream metabolism of CDCA compared with humans. In conclusion, the species differences of BA redox metabolism disclosed in this work will be useful for the interspecies extrapolation of BA biology and toxicology in translational researches. SIGNIFICANCE STATEMENT: It is important to understand the species differences of bile acid metabolism when deciphering biological and hepatotoxicology findings from preclinical studies. However, the species differences of tertiary bile acids are poorly understood compared with primary and secondary bile acids. This work confirms that the tertiary oxidation of deoxycholic acid is conserved among preclinical animals and provides deeper understanding of how and why the downstream metabolism of chenodeoxycholic acid dominates that of cholic acid in murine animals compared with humans.

Valores de referencia de analitos en orina en la edad pediatrica / Reference values of analytes in urine in the pediatric age / Valores de referência de analitos na urina na idade pediátrica

La deteccion de trastornos metabolicos minerales puede explicar diversas anomalias fisiologicas que exigen para su interpretacion la comparacion con valores de referencia validados. El objetivo de este trabajo fue la determinacion de valores de referencia en la poblacion infantil uruguaya, de los analitos sodio, potasio, calcio, magnesio, fosforo y urato relacionados con la creatinina en muestras de la segunda miccion de la manana en 470 escolares (240 ninas y 230 ninos) con edades comprendidas entre 7 y 12 anos. Las medianas obtenidas fueron: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. A excepcion de los cocientes Na/Crea y K/Crea se encontro una disminucion de la excrecion de estos analitos con la edad, independientemente del sexo. Los valores obtenidos resultaron ser analogos a los de otras poblaciones con tipo de alimentacion similar.

The detection of mineral metabolic disorders can explain several pathologies which require the comparison with reference values for their interpretation. The aim of this study was to determine the reference values of 470 Uruguayan school children with ages between 7 and 12 for sodium, potassium, calcium, magnesium, phosporous and urate and their relationship with creatinine in urine samples of the second urination of the morning. The median obtained were: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. A diminishment of excretion with the age was found, regardless the sex, except for Na/Crea and K/Crea. The values obtained were similar to those of others populations with a similar diet.

A detecção de distúrbios metabólicos minerais pode explicar várias anomalias fisiológicas, que exigem a comparação com valores de referência validados para serem interpretados. O objetivo deste estudo foi determinar valores de referência na população infantil uruguaia, dos analitos sódio, potássio, cálcio, magnésio, fósforo e urato relacionados com a creatinina em amostras da segunda micção da manhã em 470 alunos (240 meninas e 230 meninos) com idades entre 7 e 12 anos. As medianas obtidas foram: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. Com exceção dos quocientes Na/Crea e K/Crea, foi encontrada uma diminuição na excreção destes analitos com a idade independentemente do sexo. Os valores obtidos foram análogos aos de outras populações com um tipo similar de dieta.

Urine metabolome alterations in malnutrition and the impact of glycerol or rumen-protected choline chloride supplementation in advanced pregnant ewes.

The objective of this study was to explore the metabolic profiles of pregnancy malnutrition induced by feed restriction (FR) and the counteracting effects of glycerol and rumen-protected choline chloride supplementation. Two feeding trials were conducted. In the first experiment, twenty pregnant Hu sheep carrying multiple fetuses with a gestation period of 108 d were randomly divided into two groups. The ewes in the control (CON) group were offered 100 % of their nutritional requirements as recommended by the National Research Council (NRC), while the FR group was offered 30 % of feed intake of CON for 15 d. In the second experiment, eighteen pregnant Hu sheep were offered a feed intake comprising 30 % of the NRC-recommended nutritional requirements twice daily. The sheep were randomly divided into three groups: the FR group in the second experiment (FR2), with no supplementation, the glycerol (GLY) group, which received 40 ml of glycerol per d, and the rumen-protected choline chloride (RPC) group, which received 10 g of rumen-protected choline chloride per d for 9 d. In the first experiment, the urine metabolome of sixteen ewes showed significant difference between the CON group and FR group. Compared with the CON group, FR decreased the level of d-glucose, lactic acid, levoglucosan, α-ketoglutarate, phosphohydroxypyruvic acid, glucose 6-phosphate and the methyl donors, while increasing the level of pyruvate, fumaric acid and carnitines in urine. Both the GLY and RPC treatments counteracted some of these changes and modulated the urine metabolome in advanced pregnant ewes suffering from malnutrition.

Maternal paraben exposure triggers childhood overweight development.

Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother-child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.

Effect of a commercial anionic dietary supplement on urinary pH and concentrations of electrolytes and pH in blood of horses.

Aims: To compare urine urinary pH, blood pH and concentration of electrolytes in blood of healthy horses fed an anionic salt supplement to achieve diets with a dietary cation-anion difference (DCAD) of -40 or 0 mEq/kg DM, with horses a fed a diet with a DCAD of 85 mEq/kg DM.Methods: Eight healthy horses received each of three diets in a randomised crossover design. Diets consisted of grass hay and concentrate feed, with a varying amount of an anionic supplement to achieve a DCAD of 85 (control), 0 or -40 mEq/kg DM. They were fed for 14 days each with a washout period of 7 days between. Urine pH was measured daily and blood samples were collected on Days 0, 7 and 14 of each study period for the measurement of pH and concentration of electrolytes.Results: Four horses voluntarily consumed the anionic supplement with their feed, but four horses required oral supplement administration via dose syringe. During the study period mean urine pH was lower in horses fed diets with a DCAD of 0 (6.91; SD 0.04) and -40 (6.83; SD 0.04) mEq/kg DM compared to the control diet (7.30; SD 0.04). Compared with horses fed the control diet, mean urine pH was lower in horses fed the 0 and -40 mEq/kg DM diets on Days 1-12 and 14 (p < 0.05) of the study period. On Day 13 it was only lower in horses fed the -40 mEq/kg DM diet (p < 0.01). Urine pH was similar for horses fed the 0 and -40 mEq/kg DM diets (p = 0.151). The DCAD of the diet had no effect on blood pH, ionised Ca or anion gap. Mean concentrations of bicarbonate in blood were affected by diet (p = 0.049); they were lower when horses were fed the 0 mEq/kg diet relative to the control diet on Day 14.Conclusions and clinical relevance: The anionic supplement reduced urine pH in horses fed diets with a DCAD of 0 or -40 mEq/kg DM compared with 85 mEq/kg DM. However as urinary pH did not fall below pH 6.5, the pH below which calcium carbonate uroliths do not form, this reduction in urine pH is unlikely to be clinically significant. The supplement was variably palatable and showed minimal promise as an effective urinary acidifier at the doses administered in this study.