Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function.

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

Mecanismo sensor y de adaptación a los niveles de oxígeno y su implicancia en las enfermedades cardiovasculares: a propósito del Premio Nobel de Fisiología-Medicina 2019 / Role of hypoxia-inducible factor-1 (HIF-1) in the adaptacion to oxygen levels: Nobel Prize in physiology-medicine 2019

RESUMEN: El Premio Nobel 2019 en Fisiología-Medicina se confirió a los Profesores Gregg Semenza, William Kaelin y Sir Peter Ratcliffe por sus investigaciones en la maquinaria molecular que regula la expresión de genes sensibles a los cambios en los niveles de oxígeno. La síntesis de eritropoyetina inducida por la disminución de los niveles sanguíneos de oxígeno condujo al estudio del gen de la eritropoyetina y descubrimiento de los elementos de respuesta a hipoxia (HRE) en la región promotora y posteriormente al factor transcripcional inducible por hipoxia tipo 1 (HIF-1). Este factor consta de dos subunidades: HIF-1α, sensible al oxígeno, y HIF-1β, expresada constitutivamente. HIF1 activa la transcripción de genes que codifican enzimas, transportadores y proteínas mitocondriales que disminuyen la utilización de oxígeno al cambiar el metabolismo oxidativo al metabolismo glicolítico y además aquellos involucrados en la angiogénesis y diferenciación celular. Las investigaciones paralelas en la enfermedad von Hippel-Lindau (VHL), un desorden autosómico dominante, permitieron descubrir el mecanismo de degradación de HIF1 en condiciones de normoxia y como se estabiliza bajo hipoxia. El impacto de HIF en clínica radica en el establecimiento de nuevas dianas terapéuticas para combatir la anemia y diversas enfermedades cardiovasculares. HIF promueve la angiogénesis a través de la expresión del factor de crecimiento vascular endotelial (VEGF), agente cardioprotector con potencial para tratar la isquemia/reperfusión, hipertrofia patológica e insuficiencia cardíaca.

ABSTRACT: The Nobel Prize in Physiology-Medicine was awarded to Drs. Gregg Semenza, William Kaelin and Sir Peter Ratcliffe for their research in the molecular machinery that regulates the expression of genes sensitive to the change in oxygen levels. The synthesis of erythropoietin induced by the decrease levels of oxygen in the blood led to investigate the promoter of the erythropoietin gene where the so-called hypoxia response elements (HRE) were described. Semenza et al. described a protein that binds to HREs and called it hypoxia-inducible transcriptional factor (HIF) that regulates gene expression among those involved in angiogenesis, cell differentiation and glycolytic enzymes. HIF presents two oxygen-sensitive subunits HIF-1α and HIF-1β constitutively expressed. In parallel, Kaelin et al. investigated von Hippel-Lindau disease (VHL), an autosomal dominant disorder, discovering a mutation of this protein generated a behavior similar to hypoxia. The impact of HIF-1α lies in the search for new strategies such as hydrolase inhibitors to combat prevalent diseases, including anemia and cardiovascular diseases These compounds promote the expression of vascular endothelial growth factor (VEGF), a cardioprotective agent with potential use in pre- and post-conditioning therapy, cardiac hypertrophy and heart failure.

Technical-environmental optimisation of the activated carbon production of an agroindustrial waste by means response surface and life cycle assessment.

In this study, a simultaneous optimisation of technical and environmental parameters for activated carbon production from soybean shells is presented. A 23 factorial design was developed to explore the performance of the technical responses yield and iodine number, and the single score of ReCiPe endpoint method, which was evaluated by means the life cycle assessment. The independent factors included in the design of experiments were the impregnation ratio, temperature, and time activation. Three quadratic equations were obtained and simultaneously optimised by maximisation of the overall desirability function. The principal results of the individual responses indicate that the iodine number is practically independent of the activation temperature in a range of 450 ºC-650 ºC; the yield is inversely proportional to activation time and exhibits minimum values between 500 ºC-600 ºC; and the environmental response single score presents the lowest value at a temperature and time activation of 450 ºC and 30 min, respectively. The most polluting stage of activated carbon production from soybean shells production is the impregnation stage, mainly for the use of ZnCl2 as activating agent and the energy consumption. The simultaneous optimisation of the three responses indicates that the optimal activated carbon should be produced at 180 min, 650 ºC, and an impregnation ratio of 1 g soybean shell g ZnCl2-1.

Scaling-up parameters for site restoration process using surfactant-enhanced soil washing coupled with wastewater treatment by Fenton and Fenton-like processes.

Estimation of scaling-up parameters for a site restoration process using a surfactant-enhanced soil washing (SESW) process followed by the application of advanced oxidation processes (Fenton and photo-Fenton) was performed. For the SESW, different parameters were varied and the soil washing efficiency for pesticide (2,4-D) removal assessed. The resulting wastewater was treated using the Fenton reaction in the absence and presence of ultraviolet (UV) radiation for pesticide removal. Results showed that agitation speed of 1550 rpm was preferable for the best pesticide removal from contaminated soil. It was possible to wash contaminated soils with different soil concentrations; however the power drawn was higher as the soil concentration increased. Complete removal of the pesticide and the remaining surfactant was achieved using different reaction conditions. The best degradation conditions were for the photo-Fenton process using [Fe(II)] = 0.3 mM; [H2O2] = 4.0 mM where complete 2,4-D and sodium dodecylsulfate (SDS) removal was observed after 8 and 10 minutes of reaction, respectively. Further increase in the hydrogen peroxide or iron salt concentration did not show any improvement in the reaction rate. Kinetic parameters, i.e. reaction rate constant and scaling-up parameters, were determined. It was shown that, by coupling both processes (SESW and AOPs), it is possible the restoration of contaminated sites.