4-amino bis-pyridinium derivatives as novel antileishmanial agents.

The antileishmanial activity of a series of bis-pyridinium derivatives that are analogues of pentamidine have been investigated, and all compounds assayed were found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with 50% effective concentrations (EC50s) lower than 1 µM in most cases. The majority of compounds showed similar behavior in both Leishmania species, being slightly more active against L. major amastigotes. However, compound VGP-106 {1,1'-(biphenyl-4,4'-diylmethylene)bis[4-(4-bromo-N-methylanilino)pyridinium] dibromide} exhibited significantly higher activity against L. donovani amastigotes (EC50, 0.86 ± 0.46 µM) with a lower toxicity in THP-1 cells (EC50, 206.54 ± 9.89 µM). As such, VGP-106 was chosen as a representative compound to further elucidate the mode of action of this family of inhibitors in promastigote forms of L. donovani. We have determined that uptake of VGP-106 in Leishmania is a temperature-independent process, suggesting that the compound crosses the parasite membrane by diffusion. Transmission electron microscopy analysis showed a severe mitochondrial swelling in parasites treated with compound VGP-106, which induces hyperpolarization of the mitochondrial membrane potential and a significant decrease of intracellular free ATP levels due to the inhibition of ATP synthesis. Additionally, we have confirmed that VGP-106 induces mitochondrial ROS production and an increase in intracellular Ca(2+) levels. All these molecular events can activate the apoptotic process in Leishmania; however, propidium iodide assays gave no indication of DNA fragmentation. These results underline the potency of compound VGP-106, which may represent a new avenue for the development of novel antileishmanial compounds.

Sé tú el cambio que quieras ver en la Universidad / You must be the change you want to see in the University

Se discutirán las dos primeras misiones de la Universidad, tales como la docencia y la investigación.Además, las relaciones inter-personales son fundamentales en todo grupo humano y se abordará elpapel del liderazgo en el grupo de investigación de acuerdo con las modernas tendencias del mundoempresarial.La Universidad española se encuentra en una situación excesivamente alejada de la realidad social yeconómica en la que vivimos. El enfoque del Espacio Europeo de Enseñanza Superior puede subsanarestas deficiencias, pero la adaptación conlleva, en mayor o menor grado, una transformación delmodelo educativo actual. Lo que no está claro es que las universidades españolas hayan alcanzado oestén en vías de alcanzar plenamente la nueva configuración de la Declaración de Bolonia. Más bienestán en una situación transitoria, ambigua, en la que permanecen rasgos anteriores con los nuevos.Con respecto al papel carismático del líder dentro de un grupo, merecen ser destacados aspectos talescomo la motivación, delegación y resolución de conflictos, entre los muchos valores que debenadornarlo.La Universidad de Granada es una institución muy grande. El secreto para que funcione esta macroestructuraes que cada uno de sus componentes, dentro de su status, se identifique con sus principios yse comprometa a cumplir con sus funciones, tanto particulares como generales. El secreto del éxito es la ilusión, trabajo y generosidad. Es así y sólo así, cuando el trabajo y la colaboración comprometidade todos sus miembros, dará lugar a una Universidad mejor(AU)

Teaching and research, two missions of the University, will be discussed herein. Moreover, the interpersonalrelationships are fundamental in all human groups and the role of the leadership in theresearch group will be tackled according to the modern tendencies of the business world.The Spanish University has been too distanced from the social and economical reality. The approachof the European higher education system may overcome all these shortcomings, but the adaptationmay lead, to a greater or a lesser degree, to a transformation of the present education system. It is notclear that the Spanish universities have reached or are now being fully reaching the new configurationof the Bologna Declaration. They are rather in a temporary ambiguous situation, in which someprevious features remain with the new ones.In relation to the charismatic role of the leader within a group, aspects such as motivation, delegationof functions and resolution of conflicts warrant the greatest attention among the many values that mustenhance it.The University of Granada is a vast institution. The secret for this macro-structure to work is that itscomponents, each within its own status, be identified with its principles and be committed toobserving its functions, both particular and general. The secret of the success is illusion, work andgenerosity. Only thus, when work and collaboration implicating all its members is a better Universitypossible(AU)