RESUMO
La Salud Mental en el hospital general nos permite trazar lazos interdisciplinarios con otras disciplinas a la vez que se hace visible el padecimiento subjetivo, no solo de los pacientes internados por salud mental, sino también de aquellos que lo están por otras especialidades. Se hace visible un cuerpo no solo biológico sino además libidinal. Este equipo conformado fundamentalmente en contexto de Pandemia, cumple funciones vinculadas a un Segundo Nivel de complejidad, abordando situaciones de Crisis, Urgencia y Emergencia subjetiva desde las duplas Psicólogo y Psiquiatra. En el contexto de una Guardia General, en una franja horaria que va de 08 a 20hs. Luego de ese horario, los pacientes ingresan conforme a la Ley de Salud Mental 26.657 y permanecen para ser evaluados a través de guardia pasiva y/o bien de modo presencial, al día siguiente.
RESUMO
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1. The QTAIM study has allowed us to obtain an excellent correlation between the electronic densities and the experimental data of IC50. Also, using combined techniques (MD simulations and QTAIM calculations) enabled us to describe in detail the molecular interactions that stabilize the different L-R complexes. In addition, our results allowed us to determine what portion of these compounds should be changed in order to increase their affinity with the BACE1. Another interesting result is that a sort of synergism was observed when the effects of these new catalytic site inhibitors were combined with Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH2, which we have recently reported as a modulator of BACE1 acting on its exosite.
Assuntos
Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Pirimidinas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Bioensaio , Domínio Catalítico , Desenho de Fármacos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Quantitativa Estrutura-AtividadeRESUMO
Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showed that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-κB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-κB only in melanoma cells that lack FLNA. In these cells, S1P, but not TNF, promotes IκB kinase (IKK) and p65 phosphorylation, IκBα degradation, p65 nuclear translocation, and NF-κB reporter activity. NF-κB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced the phosphorylation of protein kinase Cδ (PKCδ), and its downregulation reduced S1P-induced the phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-κB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IκBα. Hence, these results support a negative role of FLNA in S1P-mediated NF-κB activation in melanoma cells through modulation of Akt.