The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein–protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis

Rural Participation in the Territorial Development Processes

Recibido 21 de mayo de 2012 • Corregido 02 de octubre de 2012 • Aceptado 07 de noviembre de 2012Este documento es un espacio de reflexión acerca de la necesidad y la importancia de asumir el compromiso de crear un puente entre la participación social y la construcción de capacidades ciudadanas. El diálogo permanente del saber experto y el saber local debe alimentar los procesos de aprendizajes pertinentes y relevantes desde el contexto rural de la región centroamericana y hacia esta. La coherencia y persistencia de estos procesos permitirá promover el bienestar humano, a partir de los cambios experimentados en la ruralidad. En el territorio centroamericano existen numerosas iniciativas que, para concretar sus propuestas, requieren de la participación social e institucional efectiva. La educación, en sus diversas manifestaciones y con sus variados recursos, tiene una gran responsabilidad en posibilitar el aprovechamiento de estas por parte de la ciudadanía.This paper discusses the urgency of creating a bridge between social participation and civic capacity building.  The permanent dialogue between expert and local knowledge should sustain significant, relevant learning processes from/to the rural areas of the Central American region.  Consistency and persistence of these processes will enhance human welfare based on the changes experienced in the rural areas.  Numerous Central American initiatives require effective social and institutional participation to be implemented.  Education, in its different forms and through its different resources, has the crucial responsibility of helping citizens to take advantage of those initiatives

Participación de la población rural en los procesos territoriales de desarrollo

Este documento es un espacio de reflexión acerca de la necesidad y la importancia de asumir el compromiso de crear un puente entre la participación social y la construcción de capacidades ciudadanas. El diálogo permanente del saber experto y el saber local debe alimentar los procesos de aprendizajes pertinentes y relevantes desde el contexto rural de la región centroamericana y hacia esta. La coherencia y persistencia de estos procesos permitirá promover el bienestar humano, a partir de los cambios experimentados en la ruralidad. En el territorio centroamericano existen numerosas iniciativas que, para concretar sus propuestas, requieren de la participación social e institucional efectiva. La educación, en sus diversas manifestaciones y con sus variados recursos, tiene una gran responsabilidad en posibilitar el aprovechamiento de estas por parte de la ciudadanía

Novel beta-lactam derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme

Non-Covalent Inhibitors of the 20S Proteasome

Peptidomimetics have been commonly used as lead compounds to design inhibitors with high affinity and specificity for a particular enzyme. The discovery that a 2-aminobenzylstatine derivative originally designed to target an aspartyl protease was able to inhibit specifically and non-covalently the chymotrypsin-like activity of the 20S proteasome represented a unique starting point for our medicinal chemistry endeavor for this target. Utilizing a structure-based design approach, we have been able to improve the potency of this new class of proteasome inhibitors without affecting its in vitro selectivity profile

Las escuelas de campo del MAP-CATIE pr?ctica y lecciones aprendidas en la gesti?n del conocimiento y la creaci?n de capacidades locales para el desarrollo rural sostenible

CATIE (Centro Agron?mico Tropical de Investigaci?n y Ense?anza

Podocyte EphB4 signaling helps recovery from glomerular injury

Eph receptor tyrosine kinases and their ligands (ephrins) have a pivotal role in the homeostasis of many adult organs and are widely expressed in the kidney. Glomerular diseases beginning with mesangiolysis can recover, with podocytes having a critical role in this healing process. We studied here the role of Eph signaling in glomerular disease recovery following mesangiolytic Thy1.1 nephritis in rats. EphB4 and ephrinBs were expressed in healthy glomerular podocytes and were upregulated during Thy1.1 nephritis, with EphB4 strongly phosphorylated around day 9. Treatment with NPV-BHG712, an inhibitor of EphB4 phosphorylation, did not cause glomerular changes in control animals. Nephritic animals treated with vehicle did not have morphological evidence of podocyte injury or loss; however, application of this inhibitor to nephritic rats induced glomerular microaneurysms, podocyte damage, and loss. Prolonged NPV-BHG712 treatment resulted in increased albuminuria and dysregulated mesangial recovery. Additionally, NPV-BHG712 inhibited capillary repair by intussusceptive angiogenesis (an alternative to sprouting angiogenesis), indicating a previously unrecognized role of podocytes in regulating intussusceptive vessel splitting. Thus, our results identify EphB4 signaling as a pathway allowing podocytes to survive transient capillary collapse during glomerular disease