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Antecedentes/Objetivo : Las enfermedades cardiovasculares y la depresión son comunes y, muchas veces, coexistentes empeorando la calidad de vida. Además, existen trastornos de funciones cognitivas omnipresentes en pacientes con insuficiencia cardiaca. Se obser - van deficiencias de distinto nivel de severidad en varios dominios cognitivos. Asimismo, en la depresión existen problemas cognitivos que podrían perjudicar el funcionamiento cotidiano, obstaculizar la adaptación a la enfermedad y empeorar los pronósticos. El objetivo de este trabajo fue evaluar la relación entre calidad de vida, intensificación de trastornos depresivos y trastornos de ciertos aspectos de las funciones ejecutivas y me - moria en pacientes con insuficiencia cardiaca grave y estable. Método : Los estudios se realizaron en un grupo de 50 pacientes con insuficiencia cardiaca grave y estable, y otro de 50 pacientes con enfermedad coronaria, pero sin insuficiencia cardiaca. Resultados : Los resultados de las pruebas cognitivas son notablemente peores en el grupo con insufi - ciencia cardiaca en comparación con el grupo control. Se observó una calidad de vida considerablemente peor y unos resultados significativamente más altos en la prueba BDI- II. No se demostró que los trastornos cognitivos influyeran en el empeoramiento de la calidad de vida. Sin embargo, se observó que los síntomas de depresión influían en la calidad de vida. Conclusiones : El factor que afecta significativamente la calidad de vida es la intensificación de los síntomas depresivos.

Background. The prognostic value of cardiopulmonary exercise testing (CPET) is known, but the predictive value of 6MWT in patients with heart failure (HF) and patients undergoing coronary artery bypass grafting (CABG) is not established yet. Objective. We conducted a systematic review exploring the prognostic value of 6MWT in HF patients undergoing cardiac surgery. The aim was to find out whether the change in the distance walked during follow-up visits was associated with prognosis. Data Source. We searched “PubMed” from January 1990 to December 2012 for any review articles or experimental studies investigating the prognostic value of 6MWT in HF patients and patients undergoing cardiac surgery. Results. 53 studies were included in the review, and they explored the role of 6MWT in cardiology, cardiac surgery, and rehabilitation. The results did not show the relation between the six-minute walk distance and adverse events after CABG. The predictive power of the distance walked for death in HF patients undergoing cardiac surgery was not found. It is not yet proved if the change in the six-minute walk distance is associated with prognosis. The predictive power of the six-minute walk distance for death in HF patients undergoing cardiac surgery remains unclear.

Tryptophan-derived, indolic metabolites possess diverse functions in Arabidopsis innate immunity to microbial pathogen infection. Here, we investigate the functional role and regulatory characteristics of indolic metabolism in Arabidopsis systemic acquired resistance (SAR) triggered by the bacterial pathogen Pseudomonas syringae. Indolic metabolism is broadly activated in both P. syringae-inoculated and distant, non-inoculated leaves. At inoculation sites, camalexin, indol-3-ylmethylamine (I3A), and indole-3-carboxylic acid (ICA) are the major accumulating compounds. Camalexin accumulation is positively affected by MYB122, and the cytochrome P450 genes CYP81F1 and CYP81F2. Local I3A production, by contrast, occurs via indole glucosinolate breakdown by PEN2- dependent and independent pathways. Moreover, exogenous application of the defense hormone salicylic acid stimulates I3A generation at the expense of its precursor indol-3-ylmethylglucosinolate (I3M), and the SAR regulator pipecolic acid primes plants for enhanced P. syringae-induced activation of distinct branches of indolic metabolism. In uninfected systemic tissue, the metabolic response is more specific and associated with enhanced levels of the indolics I3A, ICA, and indole-3-carbaldehyde (ICC). Systemic indole accumulation fully depends on functional CYP79B2/3, PEN2, and MYB34/51/122, and requires functional SAR signaling. Genetic analyses suggest that systemically elevated indoles are dispensable for SAR and associated systemic increases of salicylic acid. However, soil-grown but not hydroponically -cultivated cyp79b2/3 and pen2 plants, both defective in indolic secondary metabolism, exhibit pre-induced immunity, which abrogates their intrinsic ability to induce SAR., (Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.)

The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is a growing impetus to develop more accurate, predictive and relevant in vitro models of renal xenobiotic exposure. As part of the EU-FP7, Predict-IV project, a major aim was to develop models that recapitulate not only normal tissue physiology but also aspects of disease conditions that exist as predisposing risk factors for xenobiotic toxicity. Hypoxia, as a common micro-environmental alteration associated with pathophysiology in renal disease, was investigated for its effect on the toxicity profile of a panel of 14 nephrotoxins, using the human proximal tubular epithelial RPTECT/TERT1 cell line. Changes in ATP, glutathione and resazurin reduction, after 14 days of daily repeat exposure, revealed a number of compounds, including adefovir dipivoxil with enhanced toxicity in hypoxia. We observed intracellular accumulation of adefovir in hypoxia and suggest decreases in the efflux transport proteins MRP4, MRP5, NHERF1 and NHERF3 as a possible explanation. MRP5 and NHERF3 were also down-regulated upon treatment with the HIF-1 activator, dimethyloxalylglycine. Interestingly, adefovir dependent gene expression shifted from alterations in cell cycle gene expression to an inflammatory response in hypoxia. The ability to investigate aspects of disease states and their influence on renal toxin handling is a key advantage of in vitro systems developed here. They also allow for detailed investigations into mechanisms of compound toxicity of potential importance for compromised tissue exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 μM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14days. CsA was quantified in supernatants and cellular lysates by LC-MS/MS for kinetic modeling. There was a rapid cellular uptake and accumulation of CsA, with a non-linear relationship between intracellular and applied concentrations. CsA at 15μM induced mitochondrial disturbances and activation of the Nrf2-oxidative-damage and the unfolded protein-response pathways. All three omic streams provided complementary information, especially pertaining to Nrf2 and ATF4 activation. No stress induction was detected with 5μM CsA; however, both concentrations resulted in a maximal secretion of cyclophilin B. The study demonstrates for the first time that CsA-induced stress is not directly linked to its primary pharmacology. In addition we demonstrate the power of integrated omics for the elucidation of signaling cascades brought about by compound induced cell stress., (Copyright © 2012 Elsevier B.V. All rights reserved.)