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1.
Vet Q ; 40(1): 1-15, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31858882

RESUMO

Background: Displaced abomasum (DA) is a condition of dairy cows that severely impacts animal welfare and causes huge economic losses.Objective: To assess the metabolic status of the disease using metabolomics in serum, urine and liver samples aimed at both water soluble and lipid soluble fractions.Methods: Fifty Holstein multiparous cows with DA (42 left, 8 right) and 20 clinically healthy Holstein multiparous cows were used. Left DA was associated with concomitant ketosis in 19 animals and right in two. NMR-based metabolomics approach and hematological and biochemical analyses were performed. Statistical analysis was carried out on 1H-NMR data after they have been normalized using PQN method.Results: Contrary to generated PCA score plots the OPLS-supervised method revealed differences between healthy animals and diseased ones based on serum water-soluble samples. While water and lipid soluble metabolites decreased in serum samples, fatty acid fractions and cholesterol were increased in liver samples in DA affected cows. The metabolomic and chemical profiles clearly revealed that cows with DA (especially with LDA) were at risk of ketosis and fatty liver. Serum hippuric acid concentration was significantly higher in healthy cows in comparison with LDA, whereas serum glycine concentration was reported higher for healthy when compared to RDA affected animals.Conclusion: A biochemical network and pathway mapping revealed 'valine, leucine and isoleucine biosynthesis' and 'phenylalanine, tyrosine and tryptophan biosynthesis' as the most probable altered metabolic pathway in DA condition. Serum was advocated as the optimal biological matrix for the 1H-NMR analysis.


Assuntos
Doenças dos Bovinos/sangue , Doenças dos Bovinos/fisiopatologia , Gastropatias/veterinária , Abomaso/diagnóstico por imagem , Animais , Biomarcadores/sangue , Biomarcadores/urina , Bovinos , Doenças dos Bovinos/diagnóstico por imagem , Doenças dos Bovinos/urina , Indústria de Laticínios , Feminino , Hipuratos/sangue , Lipídeos/sangue , Fígado , Espectroscopia de Ressonância Magnética , Metaboloma , Gastropatias/sangue , Gastropatias/diagnóstico por imagem , Gastropatias/fisiopatologia
2.
ACS Appl Mater Interfaces ; 11(47): 43843-43856, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31663727

RESUMO

Protein-bound uremic toxins (PBUTs) can cause noxious effects in patients suffering from renal failure as a result of inhibiting the transport of proteins and inducing their structural modification. They are difficult to remove through standard hemodialysis (HD) treatment. Herein, we report an organic bioelectronic HD device system for the effective removal of PBUTs through electrically triggered dissociation of protein-toxin complexes. To prepare this system, we employed electrospinning to fabricate electrically conductive quaternary composite nanofiber mats-comprising multiwalled carbon nanotubes (MWCNTs), poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS), poly(ethylene oxide) (PEO), and (3-glycidyloxypropyl)trimethoxysilane (GOPS)-on conventional polyethersulfone (PES) dialysis membranes. These composite nanofiber platforms exhibited (i) long-term water resistance (due to cross-linking among PSS, PEO, and GOPS), (ii) high adhesion strength on the PES membrane (due to GOPS functioning as an adhesion promoter), (iii) enhanced electrical properties [due to the MWCNTs and PEDOT:PSS promoting effective electrical stimulation (ES) operation in devices containing bioelectronic interfaces (BEI)], and (iv) good anticoagulant ability and negligible hemolysis of red blood cells. We employed this organic BEI electronic system as a novel single-membrane HD device to study the removal efficiency of four kinds of uremic toxins [p-cresol (PC), indoxyl sulfate, and hippuric acid as PBUTs; creatinine as a non-PBUT] as well as the effects of ES on lowering the protein binding ratio. Our organic BEI devices provided a high rate of removal of PC with low protein loss after 4 h of a simulated dialysis process. It also functioned with low complement activation, low contact activation levels, and lower amounts of platelet adsorption, suggesting great suitability for use in developing next-generation bioelectronic medicines for HD.


Assuntos
Nanotubos de Carbono/química , Proteínas/química , Diálise Renal/instrumentação , Toxinas Biológicas/química , Uremia/terapia , Adsorção , Cresóis/sangue , Cresóis/química , Eletrônica/instrumentação , Hipuratos/sangue , Hipuratos/química , Humanos , Indicã/sangue , Indicã/química , Polímeros/química , Toxinas Biológicas/sangue , Uremia/sangue
3.
J Pharm Biomed Anal ; 174: 618-624, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276982

RESUMO

Gut-derived uremic toxins contribute to the uremic syndrome and are gaining attention as potentially modifiable cardiovascular disease risk factors in patients with underlying chronic kidney disease. A simple, rapid, robust, accurate and precise ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of a panel of four gut-derived uremic toxins in human serum. The panel was comprised of kynurenic acid, hippuric acid, indoxyl sulfate, and p-cresol sulfate. Serum samples were protein precipitated with acetonitrile containing deuterated internal standards. Chromatographic separation of analytes was accomplished with an Acquity BEH C18 (2.1 × 100 mm, 1.7 µm) column by isocratic elution at a flow rate of 0.3 mL/min with a mobile phase composed of solvent A (10 mM ammonium formate; pH 4.3) and solvent B (acetonitrile) (85:15, v/v). Analytes were detected using heated electrospray ionization and selected reaction monitoring. The total run-time was 4 min. Standard curves were linear and correlation coefficients (r) were ≥0.997 for concentration ranges of 0.01-0.5 µg/mL for kynurenic acid, 0.25-80 µg/mL for p-cresol sulfate, and 0.2-80 µg/mL for hippuric acid and indoxyl sulfate. Intra- and inter-day accuracy and precision were within 19.3% for the LLOQs and ≤10.9% for all other quality controls. Matrix effect from serum was <15% and recovery was ≥81.3% for all analytes. The method utilizes a short run-time, simple/inexpensive sample processing, has passed FDA validation recommendations, and was successfully applied to study patients with kidney disease.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Nefropatias/sangue , Espectrometria de Massas em Tandem/métodos , Uremia/diagnóstico , Cresóis/sangue , Hipuratos/sangue , Humanos , Concentração de Íons de Hidrogênio , Indicã/sangue , Nefropatias/diagnóstico , Ácido Cinurênico/sangue , Controle de Qualidade , Reprodutibilidade dos Testes , Fatores de Risco , Solventes/química , Ésteres do Ácido Sulfúrico/sangue , Fatores de Tempo
4.
Neurotoxicology ; 73: 85-91, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30826344

RESUMO

Patients receiving hemodialysis (HD) have a higher risk of cognitive impairment and dementia than the general population. The accumulation of uremic toxins in the brain causes uremic encephalopathy, however, limited data exists to elucidate the effect of protein-bound uremic toxins on cognitive function. Here we investigate the effect of indole-3 acetic acid (IAA) and hippuric acid (HA), two different protein-bound uremic toxins from amino acid derivatives, on cognitive function by Silico and in a clinical study. Prevalent HD patients were enrolled in two independent hospitals. Serum IAA and HA were measured using mass spectrometry. Cognitive performance was measured using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Cognitive Abilities Screening Instrument (CASI) by trained psychologists. Using silico data to predict the effect of blood-brain barrier penetration was performed. The silico data demonstrated that IAA and HA had positive blood-brain barrier penetration ability. Amongst the 230 HD patients, serum IAA was associated with poor MMSE score (ß= -0.90, 95% CI -1.61 to -0.19) and poor CASI score (ß= -3.29, 95% CI -5.69 to -0.88) in stepwise multiple linear regression analysis. In logistic regression model, Serum IAA was also associated with cognitive impairment based on MMSE definition (OR, 1.96, 95% CI 1.10, 3.5) and CASI definition (OR, 2.09, 95% CI 1.21, 3.61). There was no correlation between Serum HA levels and cognitive function status. In conclusion, IAA, not HA, was associated with cognitive impairment in HD patients. Further large scale and prospective studies are needed to confirm our findings.


Assuntos
Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/etiologia , Ácidos Indolacéticos/sangue , Falência Renal Crônica/terapia , Diálise Renal , Uremia/terapia , Idoso , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Hipuratos/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Medição de Risco , Fatores de Risco , Taiwan , Resultado do Tratamento , Uremia/sangue , Uremia/complicações , Uremia/diagnóstico
5.
Artif Organs ; 43(5): 490-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30375673

RESUMO

Protein-bound uremic toxins (PBUTs) accumulate at high plasma levels and cause various deleterious effects in end-stage renal disease patients because their removal by conventional hemodialysis is severely limited by their low free-fraction levels in plasma. Here, we assessed the extent to which solute removal can be increased by adding liposomes to the dialysate. The uptake of liposomes by direct incubation in vitro showed an obvious dose-response relationship for p-cresyl sulfate (PCS) and indoxyl sulfate (IS) but not for hippuric acid (HA). The percent removal of both PCS and IS but not of HA was gradually increased with the increased concentration of liposomes in a rapid equilibrium dialysis setup. In vitro closed circulation showed that adding liposomes to the dialysate markedly increased the dialysances of PBUTs without greatly altering that of urea and creatinine. In vivo experiments in uremic rats demonstrated that adding liposomes to the dialysate resulted in higher reduction ratios (RRs) and more total solute removal (TSR) for several PBUTs compared to the conventional dialysate, which was approximately similar to the addition of bovine serum albumin to the dialysate. These findings highlight that as an adjunct to conventional hemodialysis, addition of liposomes to the dialysate could significantly improve the removal of protein-bound uremic solutes without greatly altering the removal of small, water-soluble solutes.


Assuntos
Soluções para Diálise/química , Lipossomos/química , Diálise Renal/métodos , Toxinas Biológicas/isolamento & purificação , Uremia/sangue , Uremia/terapia , Animais , Cresóis/sangue , Cresóis/isolamento & purificação , Desenho de Equipamento , Hipuratos/sangue , Hipuratos/isolamento & purificação , Indicã/sangue , Indicã/isolamento & purificação , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Ratos Sprague-Dawley , Diálise Renal/instrumentação , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/isolamento & purificação , Toxinas Biológicas/sangue , Uremia/etiologia
6.
Toxins (Basel) ; 10(12)2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563136

RESUMO

Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.


Assuntos
Cardiopatias , Insuficiência Renal Crônica , Toxinas Biológicas/sangue , Uremia , Adulto , Pressão Arterial , Débito Cardíaco , Cresóis/sangue , Exercício Físico , Glucuronídeos/sangue , Cardiopatias/sangue , Cardiopatias/fisiopatologia , Frequência Cardíaca , Hipuratos/sangue , Humanos , Indicã/sangue , Ácidos Indolacéticos/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Ésteres do Ácido Sulfúrico/sangue , Uremia/sangue , Uremia/fisiopatologia
7.
J Am Soc Nephrol ; 29(7): 1992-1999, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728422

RESUMO

Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis.Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p-cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis.Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/Vurea, patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p-cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations.Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.


Assuntos
Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Cresóis/sangue , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Indicã/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica , Ésteres do Ácido Sulfúrico/sangue , Ureia/sangue
8.
Clin Chim Acta ; 484: 47-51, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29758204

RESUMO

BACKGROUND: Left ventricular hypertrophy (LVH) is one of the most common cardiac abnormalities in patients with end-stage renal disease. Hippuric acid (HA), a harmful uremic toxin, is known to be elevated in patients with uremia, and serum HA levels are associated with neurological symptoms, metabolic acidosis, and accelerated renal damage associated with chronic kidney disease. However, the pathophysiological role of HA in patients with uremia remains unclear. We investigated the association between serum HA levels and echocardiographic measurements in patients undergoing hemodialysis (HD) treatment. METHODS: Eighty consecutive patients treated at a single HD center (44 males, 36 females; mean age 66 y, mean HD duration 6 y) were included in this study. Comprehensive echocardiography was performed after HD. Blood samples were obtained before HD. RESULTS: Pearson's correlation analysis revealed that serum HA levels were positively correlated with diastolic blood pressure, serum creatinine, left ventricular mass index, end diastolic interventricular septal thickness, left ventricular end-diastolic diameter, left ventricular end systolic diameter, end systolic left ventricular posterior wall thickness, and left atrium diameter, and negatively correlated with age. Furthermore, the HD patients with LVH had higher median serum HA levels than those without LVH (34.2 vs. 18.1 µg/ml, p = 0.003). Multiple logistic regression analysis revealed that HA was independently associated with LVH even after adjusting for known biomarkers. Moreover, the receiver operator characteristics curve of HA showed that a HA level of >26.9 µg/ml was associated with LVH. CONCLUSIONS: HA was significantly associated with LVH. HA could be a novel biomarker of left ventricular overload, which is closely associated with an increased risk of death in HD patients.


Assuntos
Hipuratos/efeitos adversos , Hipertrofia Ventricular Esquerda/terapia , Diálise Renal , Idoso , Biomarcadores/sangue , Ecocardiografia , Feminino , Hipuratos/administração & dosagem , Hipuratos/sangue , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico , Masculino
9.
J Proteome Res ; 17(3): 1120-1128, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29364680

RESUMO

Equine grass sickness (EGS) is a frequently fatal disease of horses, responsible for the death of 1 to 2% of the U.K. horse population annually. The etiology of this disease is currently uncharacterized, although there is evidence it is associated with Clostridium botulinum neurotoxin in the gut. Prevention is currently not possible, and ileal biopsy diagnosis is invasive. The aim of this study was to characterize the fecal microbiota and biofluid metabolic profiles of EGS horses, to further understand the mechanisms underlying this disease, and to identify metabolic biomarkers to aid in diagnosis. Urine, plasma, and feces were collected from horses with EGS, matched controls, and hospital controls. Sequencing the16S rRNA gene of the fecal bacterial population of the study horses found a severe dysbiosis in EGS horses, with an increase in Bacteroidetes and a decrease in Firmicutes bacteria. Metabolic profiling by 1H nuclear magnetic resonance spectroscopy found EGS to be associated with the lower urinary excretion of hippurate and 4-cresyl sulfate and higher excretion of O-acetyl carnitine and trimethylamine-N-oxide. The predictive ability of the complete urinary metabolic signature and using the four discriminatory urinary metabolites to classify horses by disease status was assessed using a second (test) set of horses. The urinary metabolome and a combination of the four candidate biomarkers showed promise in aiding the identification of horses with EGS. Characterization of the metabolic shifts associated with EGS offers the potential of a noninvasive test to aid premortem diagnosis.


Assuntos
Acetilcarnitina/urina , Cresóis/urina , Disbiose/diagnóstico , Hipuratos/urina , Doenças dos Cavalos/diagnóstico , Metilaminas/urina , Ésteres do Ácido Sulfúrico/urina , Acetilcarnitina/sangue , Animais , Bacteroidetes/classificação , Bacteroidetes/isolamento & purificação , Biomarcadores/sangue , Biomarcadores/urina , Clostridium botulinum/metabolismo , Clostridium botulinum/patogenicidade , Cresóis/sangue , Disbiose/sangue , Disbiose/microbiologia , Disbiose/urina , Fezes/microbiologia , Firmicutes/classificação , Firmicutes/isolamento & purificação , Microbioma Gastrointestinal , Hipuratos/sangue , Doenças dos Cavalos/sangue , Doenças dos Cavalos/microbiologia , Doenças dos Cavalos/urina , Cavalos , Espectroscopia de Ressonância Magnética , Metilaminas/sangue , RNA Ribossômico 16S/genética , Ésteres do Ácido Sulfúrico/sangue
10.
Sci Rep ; 7(1): 14914, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097715

RESUMO

The number of patients with chronic kidney disease increases while the number of available donor organs stays at approximately the same level. Unavoidable accumulation of the uremic toxins and cytokines for these patients comes as the result of malfunctioning kidneys and their high levels in the blood result in high morbidity and mortality. Unfortunately, the existing methods, like hemodialysis and hemofiltration, provide only partial removal of uremic toxins and/or cytokines from patients' blood. Consequently, there is an increasing need for the development of the extracorporeal treatments which will enable removal of broad spectrum of uremic toxins that are usually removed by healthy kidneys. Therefore, in this work we developed and tested ordered mesoporous carbons as new sorbents with dual porosity (micro/meso) that provide selective and efficient removal of a broad range of uremic toxins from human plasma. The new sorbents, CMK-3 are developed by nanocasting methods and have two distinct pore domains, i.e. micropores and mesopores, therefore show high adsorption capacity towards small water soluble toxins (creatinine), protein-bound molecules (indoxyl sulfate and hippuric acid), middle molecules (ß-2-microglobulin) and cytokines of different size (IL-6 and IL-8). Our results show that small amounts of CMK-3 could provide selective and complete blood purification.


Assuntos
Carbono/química , Citocinas/isolamento & purificação , Desintoxicação por Sorção/métodos , Toxinas Biológicas/isolamento & purificação , Uremia/terapia , Adsorção , Citocinas/sangue , Hipuratos/sangue , Hipuratos/isolamento & purificação , Humanos , Indicã/sangue , Indicã/isolamento & purificação , Porosidade , Toxinas Biológicas/sangue , Uremia/sangue , Microglobulina beta-2/sangue , Microglobulina beta-2/isolamento & purificação
11.
Clin J Am Soc Nephrol ; 12(11): 1787-1794, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-28971980

RESUMO

BACKGROUND AND OBJECTIVES: Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Metabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (n=687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (n=166), and replication was performed in Study A, a substudy of MDRD with higher GFR (n=423). RESULTS: Overall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrulline, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (P<0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, and hippurate) were replicated in Study A (P<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes. CONCLUSIONS: Metabolomic profiling identified several metabolites strongly associated with cause of CKD.


Assuntos
Glomerulonefrite/sangue , Metaboloma/fisiologia , Doenças Renais Policísticas/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Adulto , Citrulina/análogos & derivados , Citrulina/sangue , Desoxiglucose/sangue , Feminino , Glomerulonefrite/complicações , Guanosina/análogos & derivados , Guanosina/sangue , Hipuratos/sangue , Ácido Homovanílico/sangue , Humanos , Ácido Cinurênico/sangue , Masculino , Pessoa de Meia-Idade , Ácidos Palmíticos/sangue , Doenças Renais Policísticas/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Sci Rep ; 7(1): 13670, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29057986

RESUMO

Reduced gut microbiome diversity is associated with multiple disorders including metabolic syndrome (MetS) features, though metabolomic markers have not been investigated. Our objective was to identify blood metabolite markers of gut microbiome diversity, and explore their relationship with dietary intake and MetS. We examined associations between Shannon diversity and 292 metabolites profiled by the untargeted metabolomics provider Metabolon Inc. in 1529 females from TwinsUK using linear regressions adjusting for confounders and multiple testing (Bonferroni: P < 1.71 × 10-4). We replicated the top results in an independent sample of 420 individuals as well as discordant identical twin pairs and explored associations with self-reported intakes of 20 food groups. Longitudinal changes in circulating levels of the top metabolite, were examined for their association with food intake at baseline and with MetS at endpoint. Five metabolites were associated with microbiome diversity and replicated in the independent sample. Higher intakes of fruit and whole grains were associated with higher levels of hippurate cross-sectionally and longitudinally. An increasing hippurate trend was associated with reduced odds of having MetS (OR: 0.795[0.082]; P = 0.026). These data add further weight to the key role of the microbiome as a potential mediator of the impact of dietary intake on metabolic status and health.


Assuntos
Biodiversidade , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Hipuratos/sangue , Biomarcadores/sangue , Estudos Transversais , Dieta , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/microbiologia , Metaboloma , Metabolômica , Pessoa de Meia-Idade
13.
Kidney Int ; 92(6): 1484-1492, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28739139

RESUMO

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.


Assuntos
Doenças Cardiovasculares/sangue , Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Diálise Renal/estatística & dados numéricos , Fatores de Risco , Albumina Sérica/análise , Uremia/sangue , Uremia/complicações
14.
Bull Environ Contam Toxicol ; 99(2): 258-263, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28646397

RESUMO

Human biomonitoring (HBM) is an appreciated tool used to evaluate human exposure to environmental, occupational or lifestyle chemicals. Therefore, the aim of this study was to evaluate the exposure levels for environmental chemicals in urine and blood samples of children from San Luis Potosí, Mexico (SLP). This study identifies environmental chemicals of concern such as: arsenic (45.0 ± 15.0 µg/g creatinine), lead (5.40 ± 2.80 µg/dL), t,t-muconic acid (266 ± 220 µg/g creatinine), 1-hydroxypyrene (0.25 ± 0.15 µmol/mol creatinine), PBDEs (28.0 ± 15.0 ng/g lipid), and PCBs (33.0 ± 16.0 ng/g lipid). On the other hand, low mercury (1.25 ± 1.00 µg/L), hippuric acid (0.38 ± 0.15 µg/g creatinine) and total DDT (130 ± 35 ng/g lipid) exposure levels were found. This preliminary study showed the tool's utility, as the general findings revealed chemicals of concern. Moreover, this screening exhibited the need for HBM in the general population of SLP.


Assuntos
Exposição Ambiental/análise , Poluentes Ambientais/metabolismo , Arsênico/sangue , Arsênico/urina , Criança , Exposição Ambiental/estatística & dados numéricos , Monitoramento Ambiental , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Feminino , Éteres Difenil Halogenados/sangue , Éteres Difenil Halogenados/urina , Hipuratos/sangue , Hipuratos/urina , Humanos , Masculino , México , Bifenilos Policlorados/sangue , Bifenilos Policlorados/urina , Pirenos/sangue , Pirenos/urina , Ácido Sórbico/análogos & derivados , Ácido Sórbico/metabolismo
15.
Mol Nutr Food Res ; 61(9)2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28556578

RESUMO

SCOPE: Urinary hippuric acid has been proposed as a biomarker for fruit, vegetable, and polyphenol consumption. We assessed how serum hippuric acid changes after a bilberry-enriched diet (BB; high anthocyanin intake) and another berry diet including strawberries, raspberries, and cloudberries (SRC; lower anthocyanin intake) and how these changes associate with insulin and glucose metabolism. METHODS AND RESULTS: Hippuric acid was measured with LC-QTOF-MS metabolite profiling analysis from fasting serum samples at baseline and after an 8-week intervention in 47 individuals with features of the metabolic syndrome who were randomized to either a BB diet (n = 15), an SRC diet (n = 20) or a control diet (n = 12). Fasting serum hippuric acid increased significantly (3.5-fold, p = 0.001) only in the BB group and correlated with changes in fasting plasma glucose concentration (r = -0.54, p < 0.05) and insulin secretion (r = 0.59, p < 0.05). These associations were confirmed in the Finnish Diabetes Prevention Study (n = 198). CONCLUSION: Fasting serum hippuric acid is increased after consumption of anthocyanin-rich bilberries, and may contribute to the beneficial effect of bilberry consumption through its associations with better glycemic control and ß-cell function.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/prevenção & controle , Jejum/sangue , Hipuratos/sangue , Insulina/metabolismo , Vaccinium myrtillus , Adulto , Feminino , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade
16.
Arch Toxicol ; 91(10): 3439-3454, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28337503

RESUMO

The intestinal microbiota contributes to the metabolism of its host. Adequate identification of the microbiota's impact on the host plasma metabolites is lacking. As antibiotics have a profound effect on the microbial composition and hence on the mammalian-microbiota co-metabolism, we studied the effects of antibiotics on the "functionality of the microbiome"-defined as the production of metabolites absorbed by the host. This metabolomics study presents insights into the mammalian-microbiome co-metabolism of endogenous metabolites. To identify plasma metabolites related to microbiome changes due to antibiotic treatment, we have applied broad-spectrum antibiotics belonging to the class of aminoglycosides (neomycin, gentamicin), fluoroquinolones (moxifloxacin, levofloxacin) and tetracyclines (doxycycline, tetracycline). These were administered orally for 28 days to male rats including blood sampling for metabolic profiling after 7, 14 and 28 days. Fluoroquinolones and tetracyclines can be absorbed from the gut; whereas, aminoglycosides are poorly absorbed. Hippuric acid, indole-3-acetic acid and glycerol were identified as key metabolites affected by antibiotic treatment, beside changes mainly concerning amino acids and carbohydrates. Inter alia, effects on indole-3-propionic acid were found to be unique for aminoglycosides, and on 3-indoxylsulfate for tetracyclines. For each class of antibiotics, specific metabolome patterns could be established in the MetaMap®Tox data base, which contains metabolome data for more than 550 reference compounds. The results suggest that plasma-based metabolic profiling (metabolomics) could be a suitable tool to investigate the effect of antibiotics on the functionality of the microbiome and to obtain insight into the mammalian-microbiome co-metabolism.


Assuntos
Antibacterianos/farmacologia , Sangue/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Animais , Sangue/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Glicerol/sangue , Hipuratos/sangue , Indicã/sangue , Ácidos Indolacéticos/sangue , Metabolômica/métodos , Ratos Wistar , Tetraciclinas/farmacologia
17.
Clin Chem ; 63(4): 915-923, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28188231

RESUMO

BACKGROUND: The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS: We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS: Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%-47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS: Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.


Assuntos
Cresóis/sangue , Glicina/análogos & derivados , Hipuratos/sangue , Indicã/sangue , Túbulos Renais Proximais/metabolismo , Ésteres do Ácido Sulfúrico/sangue , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Feminino , Glicina/sangue , Humanos , Túbulos Renais Proximais/química , Masculino , Espectrometria de Massas em Tandem
18.
Biomarkers ; 22(2): 178-188, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27775443

RESUMO

CONTEXT: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable. OBJECTIVE: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach. METHOD: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs. RESULTS: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation. CONCLUSION: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.


Assuntos
Biomarcadores/análise , Glicina/análogos & derivados , Hipuratos/análise , Lipidoses/diagnóstico , Animais , Biomarcadores/sangue , Biomarcadores/urina , Monitoramento de Medicamentos/métodos , Glicina/análise , Glicina/sangue , Glicina/urina , Hipuratos/sangue , Hipuratos/urina , Lipidoses/induzido quimicamente , Metabolômica/métodos , Fosfolipídeos , Ratos
19.
Free Radic Biol Med ; 99: 128-138, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27495388

RESUMO

Following ingestion of [2-14C](-)-epicatechin by rats, radioactivity in urine, feces, body fluids and tissues collected over a 72h period, was measured and 14C-metabolites were analyzed by HPLC-MS2 with a radioactivity monitor. In total 78% of the ingested radioactivity was absorbed from the gastrointestinal tract (GIT), and then rapidly eliminated from the circulatory system via renal excretion. A peak plasma concentration occurred 1h after intake corresponding to ~0.7% of intake. Low amounts of radioactivity, <2% of intake, appeared transiently in body tissues. Glucuronidation and methylation of (-)-epicatechin began in the duodenum but occurred more extensively in the jejunum/ileum. Radioactivity reaching the cecum after 6-12h was predominantly in the form of the ring fission metabolites 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and 5-(3',4'-dihydroxyphenyl)-γ-hydroxyvaleric acid along with smaller amounts of their phase II metabolites. Low levels of metabolites were detected in the colon. Of the ingested radioactivity, 19% was voided in feces principally as ring-fission metabolites. The main components in plasma were (-)-epicatechin-5-O-glucuronide and 3'-O-methyl-(-)-epicatechin-5-O-glucuronide with small amounts of (-)-epicatechin, 3'-O-methyl-(-)-epicatechin, 5-(3'-hydroxyphenyl)-γ-hydroxyvaleric acid-4'-glucuronide and hippuric acid also being detected. No oxidized products of (-)-epicatechin were detected. No compelling evidence was obtained for biliary recycling of metabolites. The findings demonstrate substantial differences in the metabolism of (-)-epicatechin by rats and humans. Caution should, therefore, be exercised when using animal models to draw conclusions about effects induced by (-)-epicatechin intake in humans.


Assuntos
Catequina/farmacocinética , Catequina/urina , Metaboloma , Animais , Biotransformação , Radioisótopos de Carbono , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/sangue , Duodeno/metabolismo , Fezes/química , Glucuronídeos/sangue , Hipuratos/sangue , Humanos , Íleo/metabolismo , Jejuno/metabolismo , Lactonas/sangue , Masculino , Metilação , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
20.
J Pharm Sci ; 105(4): 1519-25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27019966

RESUMO

Pharmaceutical oil depots are meant to release active substances at a sustained rate. Most of these depots contain benzyl alcohol (BOH) to facilitate the production and administration. Because BOH changes the solubility of components in both the body fluid and the oil formulation, it is relevant to know the change in the BOH concentration in the oil over time. In this study, volunteers were subcutaneously injected with an oil depot that contained 10% BOH, nandrolone decanoate, and cholecalciferol. The aim of this study was to determine the pharmacokinetic profiles of BOH and its metabolites benzoic acid and hippuric acid simultaneously in serum to estimate the BOH release out of the depot. For this, an HPLC bioassay was developed and adequately validated. Hereafter, the bioassay was applied to serum samples obtained at several time points between 0 and 35 days. BOH appeared immediately in serum after injection. The pharmacokinetic profile revealed that all BOH was depleted from the depot within 52 h after injection. Thus, the partition coefficient of active substances between the oil formulation and the body tissue changes rapidly in the first days after injection but will remain constant hereafter.


Assuntos
Álcool Benzílico/administração & dosagem , Álcool Benzílico/sangue , Preparações de Ação Retardada/química , Óleos/química , Idoso , Ácido Benzoico/sangue , Ácido Benzoico/metabolismo , Álcool Benzílico/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Hipuratos/sangue , Hipuratos/metabolismo , Humanos
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