Key proteins in the polyamine-trypanothione pathway as drug targets against Trypanosoma cruzi.

In trypanosomatids, redox homeostasis is centered on trypanothione (N(1),N(8)-bis(glutathionyl)spermidine, T(SH)2), a low molecular weight thiol that is distinctive for this taxonomic family and not present in the mammalian host. Thus, the study of the metabolism of T(SH)2 is interesting as a potential therapeutic target. In this review, we summarize the existing evidence about the metabolism of thiols in Trypanosoma cruzi, focused on those proteins that can be considered the best candidates for selective therapy. Herein, we examine the biosynthetic pathway of T(SH)2, identifying three key points that are susceptible to attack pharmacologically: the activity of the trypanothione reductase (TR), the function of glutamate-cysteine ligase (GCL) and polyamine transport in T. cruzi. TR has been widely studied and is a good example for the development of the medicinal chemistry of antichagasic compounds. Conversely, GCL and the polyamine uptake system are high flow points in the reductive metabolism of the parasite. However, very little is known at the molecular level about these two systems. Therefore, their potential as targets for drug development is discussed, and it is suggested that research should focus on the production of alternative drugs for Chagas' disease treatment.

Dual-mode "co-conformational" switching in catenanes incorporating bipyridinium and dialkylammonium recognition sites.

Three [2]catenanes and three [3]catenanes incorporating one or two pi-electron-rich macrocyclic polyethers and one pi-electron-deficient polycationic cyclophane have been synthesized in yields ranging from 4 to 38%. The pi-electron-rich macrocyclic components possess either two 1,4-dioxybenzene or two 1.5-dioxynaphthalene recognition sites. The pi-electron-deficient cyclophane components incorporate two bipyridinium and either one or two dialkylammonium recognition sites. The template-directed syntheses of these catenanes rely on i) pi...pi stacking interactions between the dioxyarene and bipyridinium recognition sites, ii) C-H...O hydrogen bonds between some of the bipyridinium hydrogen atoms and some of the polyether oxygen atoms, and iii) C-H...pi interactions between some of the dioxyarene hydrogen atoms and the aromatic spacers separating the bipyridinium units. The six catenanes were characterized by mass spectrometry and by both 1H and 13C NMR spectroscopy. The absorption spectra and the electrochemical properties of the catenanes have been investigated and compared with those exhibited by the component macrocycles and by related known catenanes. Broad and weak absorption bands in the visible region, originating from charge-transfer (CT) interactions between electron-donor and electron-acceptor units, have been observed. Such charge-transfer interactions are responsible for the quenching of the potentially fluorescent excited states of the aromatic units of the macrocyclic polyether components. The redox behavior of these novel compounds has been investigated and correlations among the observed redox potentials are illustrated and discussed. The catenanes undergo co-conformational switching upon one-electron reduction of the two bipyridinium units. One of them--in its reduced form--can be also switched by acid/base inputs and exhibits AND logic behavior. The co-conformational rearrangements induced by the redox and acid/base stimulations lend themselves to exploitation in the development of molecular-level machines and logic gates.

Efecto del tiempo sobre la determinación de pH y gases en sangre de cordón umbilical / Effect of time on umbilical cord pH and blood gas determinations

El análisis de pH y gases en sangre de cordón umbilical es un procedimiento aceptado por la mayoría de las maternidades, no ya por ser una prueba objetiva para valorar el bienestar fetal; sino también de ayuda para disminuir los riesgos de denuncias contra el obstetra. En este trabajo valoramos si son útiles las cifras obtenidas tras un tiempo de latencia en la obtención de las muestras. Hemos extraído sangre arterial y venosa de cordón umbilical, inmediatamente después del nacimiento y a los treinta minutos, para analizar el pH, PO2 y PCO2; en 50 recién nacidos. No hemos encontrado diferencias significativas en los valores medios, salvo en las cifras de PCO2 arterial. Concluimos que el retraso en treinta minutos en la toma de muestras de sangre; arterial y venosa del cordón umbilical, no invalida los resultados para uso clínico. (AU)

Determinación de pH y gases en sangre de cordón umbilical: efecto del tiempo / The measurement of pH and gases in umbilical cord blood: the effect of time

El análisis de pH y gases en sangre de cordón umbilical es un procedimiento aceptado por la mayoría de las maternidades, no ya por ser una prueba objetiva para valorar el bienestar fetal, sino también porque ayuda a disminuir los riesgos de denuncias contra el obstetra. En este trabajo valoramos si son útiles las cifras obtenidas tras un tiempo de latencia en la obtención de las muestras. Hemos extraído sangre arterial y venosa de cordón umbilical, inmediatamente después del nacimiento y a los 15 min, para analizar el pH, PO2 y PCO2, en 50 recién nacidos. No hemos encontrado diferencias significativas en los valores medios. Concluimos que el retraso en 15 min en la toma de muestras de sangre arterial y venosa del cordón umbilical no invalida los resultados para uso clínico (AU)

Isolation and characterization of two distinct gonadotropins from the pituitary gland of Mediterranean yellowtail, Seriola dumerilii (Risso, 1810).

Two gonadotropins, GTH I and GTH II, were isolated and chemically characterized from the pituitary of Mediterranean yellowtail. They were extracted with 35% ethanol-10% ammonium acetate, separated by ion-exchange chromatography on a DE-52 column, and purified by reversed-phase high-performance liquid chromatography on Asahipak C4P-50 and subsequently by gel filtration chromatography on Superdex 75. The molecular weights were estimated at 47 kDa for GTH I and 29 kDa for GTH II by SDS-PAGE and at 49 kDa for GTH I and 42 kDa for GTH II by gel filtration. GTH II was completely dissociated, while GTH I was partially dissociated into alpha- and beta-subunits by treatment with 0.1% trifluoroacetic acid. The complete amino acid sequences of GTH alpha-, GTH I beta-, and GTH II beta-subunits were determined. The GTH alpha-subunit consisted of 91 amino acid residues. The GTH I beta and GTH II beta consisted of 105 and 115 amino acid residues, respectively, and had a 28% sequence identity to each other. They had the highest sequence identity with the respective gonadotropin subunits of bonito, tuna, and striped bass: 81-83% for GTH alpha, 67-71% for GTH I beta, and 91-93% for GTH II beta. The sequence identity of the GTH alpha-subunit with those of other teleosts and human and bovine LH and FSH was 57-67%. The GTH I beta-subunit showed a low sequence identity with other known fish GTH I beta s (36-51%) and was more similar to human and bovine FSH beta s (34% identity) than to human and bovine LH beta s (29% identity). The sequence identity of the GTH II beta-subunit with those of other teleosts was higher (60-73%), being more similar to LH beta s (43% identity) than FSH beta s (38% identity). Thus, two distinct gonadotropins, GTH I and GTH II, homologous to mammalian FSH and LH, respectively, are synthetized by M. yellowtail pituitary glands.