RESUMO
Chronic heart failure (CHF) as a long-term disease is highly prevalent in elder people worldwide. Early diagnosis and treatments are crucial for preventing the development of CHF. Herein, we aimed to identify novel diagnostic biomarker, therapeutic target and drug for CHF. Untargeted metabolomic analysis has been used to characterize the different metabolomic profile between CHF patients and healthy people. Meanwhile, the targeted metabolomic study demonstrated the elevation of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) in the serum of CHF patients and coronary artery ligation-induced CHF mice. Subsequently, we firstly observed that elevation of CMPF impaired cardiac function and aggravated myocardial injury by enhancing fatty acid oxidation (FAO). Interestingly, inhibition of responsible transporters organic anion transporter 1/3 (OAT1/3) has been found to decrease the CMPF level, and suppress FAO-related key protein expressions including peroxisome proliferator-activated receptor alpha, peroxisome proliferative activated receptor-α, carnitine palmitoyl transferase 1, and malonyl CoA decarboxylase in coronary artery ligation-induced CHF mice. Meanwhile, the inhibitor of OAT1/3 presented an excellent improvement in cardiac function and histological injury. Based on the above findings, molecular docking was adopted to screen the potential therapeutic drug targeting OAT1/3, and ruscogenin (RUS) exhibited a great binding affinity with OAT1 and OAT3. Next, it was verified that RUS could remarkedly decrease the expression of OAT1/3 and CMPF levels in heart tissue of CHF mice, as well as suppress the expression of FAO-related proteins. What's more, RUS can effectively improve cardiac function, myocardial fibrosis and morphological damage. Collectively, this study provided a potential metabolic marker CMPF and novel target OAT1/3 for CHF, which were demonstrated to be involved in FAO. And RUS was identified as a potential anti-FAO drug for CHF by regulating OAT1/3.
Assuntos
Doença da Artéria Coronariana , Insuficiência Cardíaca , Isquemia Miocárdica , Humanos , Camundongos , Animais , Idoso , Simulação de Acoplamento Molecular , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Doença Crônica , Ácidos GraxosRESUMO
Aim: 4-pyridoxic acid (PDA) has been proposed as an endogenous biomarker for renal organic anion transporter 1/3 (OAT1/3) inhibition. Clinical data are needed to support the proposal. Materials & methods: A hydrophilic interaction chromatography (HILIC)-LC/MS/MS assay was developed and characterized to support clinical drug-drug interaction (DDI) studies. Results: A HILIC-LC/MS/MS assay was successfully developed. PDA was measured in two clinical DDI studies; one where no significant OAT1/3 inhibition was observed and a second where a known inhibitor of the transporter was dosed. In both clinical studies, PDA plasma concentrations correlate to OAT1/3 function. Conclusion: The analysis of study samples from two clinical DDI studies using a HILIC-LC/MS/MS assay contributes further evidence that PDA is an endogenous biomarker for OAT1/3 inhibition.
Assuntos
Biomarcadores/metabolismo , Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Ácido Piridóxico/metabolismo , Espectrometria de Massas em Tandem/métodos , HumanosRESUMO
To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CLR post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.
Assuntos
Rim/metabolismo , Modelos Biológicos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Eliminação Renal/fisiologia , Adolescente , Amoxicilina/administração & dosagem , Amoxicilina/farmacocinética , Variação Biológica da População , Cefazolina/administração & dosagem , Cefazolina/farmacocinética , Criança , Pré-Escolar , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/farmacocinética , Interações Medicamentosas , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Piperacilina/administração & dosagem , Piperacilina/farmacocinéticaRESUMO
The regulation of renal transporters such as organic anion transporter (OATs) is a new target for treatment of acute renal failure. The purpose of this study was to investigate whether the effect of puerarin (Pur) on renal damage induced by methotrexate (MTX) is related to the expression of renal Oat1/3 in vivo and in vitro, and to explore the related mechanisms. Effect of Pur on the renal damage caused by MTX was evaluated by assessment of the changes of endogenous metabolites, toxins and H&E staining. Furthermore, Real-time PCR and western blot methods were taken to evaluate the modulation of Oat1/3 in rats. Then, the regulation of Oat1/3 by B-cell CLL/lymphoma (BCL)6 was explored by siRNA assay using NRK-52E cells in vitro. Pur reduced levels of endogenous metabolites and toxins, like creatinine, urea nitrogen and indoxyl sulfate in plasma in MTX-treated rats. Moreover, plasma concentration of MTX was significantly decreased, while the cumulative urinary excretion of MTX and the uptake of MTX by kidney slices were strongly increased after administration of multiple-dose of Pur via up-regulation of renal Oat1/3 expression. Knockdown of BCL6 by siRNA abrogated the Pur-induced Oat1/3 expression in NRK-52E cells. Pur improved MTX-induced renal toxicity through promotion of renal excretion of toxins by up-regulating renal Oat1/3 via BCL6. Pur was beneficial for the improvement of MTX-induced renal toxicity.