RESUMEN
The announcement by Kasahara and Kato of a new redox-cofactor vitamin for mammals, pyrroloquinoline quinone (PQQ), was based on their claim that an enzyme, predicted to be involved in mouse lysine metabolism, is a PQQ-dependent dehydrogenase. However, this claim was dependent on a sequence analysis using databases that inappropriately label beta-propeller sequences as PQQ-binding motifs. What the evidence actually suggests is that the enzyme is an interesting novel protein that has a seven-bladed beta-propeller structure, but there is nothing to indicate that it is a PQQ-dependent dehydrogenase.
Asunto(s)
Coenzimas/metabolismo , Cofactor PQQ/metabolismo , Proteínas/química , Proteínas/metabolismo , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/metabolismo , Aldehído Oxidorreductasas/química , Aldehído Oxidorreductasas/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Evolución Molecular , L-Aminoadipato-Semialdehído Deshidrogenasa , Lisina/metabolismo , Ratones , Modelos Moleculares , Reproducibilidad de los ResultadosRESUMEN
Systemic inflammation induces cytokine synthesis within the central nervous system. This results in sickness behaviour and may exacerbate ongoing neuroinflammatory disease. The precise mechanisms underlying the relay of signal from the periphery to the central nervous system are not entirely understood. CD163-positive macrophages occupy a unique position at the blood-brain barrier and upregulate prostaglandin-synthesizing enzymes in response to systemic inflammation. This finding suggests that they might play a role in signalling inflammation to the central nervous system. However, here we demonstrate that de novo brain cytokine transcription during systemic endotoxaemia may be prostaglandin-independent. We therefore set out to interrogate more directly the role of CD163-positive macrophages in immune-to-brain signalling. Intracerebroventricular injections of clodronate liposomes were used to selectively deplete CD163-positive macrophages. We show that de novo brain cytokine synthesis during systemic endotoxaemia persists in the absence of CD163-positive macrophages. Cerebral endothelial cells outnumber CD163-positive macrophages and are arguably better situated to signal circulating inflammatory stimuli to the brain.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Corteza Cerebral/citología , Citocinas/metabolismo , Regulación de la Expresión Génica/inmunología , Macrófagos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Temperatura Corporal/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Ácido Clodrónico/farmacología , Citocinas/genética , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Inyecciones Intraventriculares/métodos , Liposomas/administración & dosificación , Macrófagos/efectos de los fármacos , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.