RESUMEN
Human islet amyloid peptide (hIAPP1-37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1-37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1-37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1-37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A-F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.
Asunto(s)
Amiloide/química , Diabetes Mellitus/tratamiento farmacológico , Descubrimiento de Drogas , Polipéptido Amiloide de los Islotes Pancreáticos/química , Terapia Molecular Dirigida , Animales , Supervivencia Celular/efectos de los fármacos , Cerebelo/patología , Curcumina/química , Curcumina/uso terapéutico , Diabetes Mellitus/patología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/toxicidad , Polipéptido Amiloide de los Islotes Pancreáticos/ultraestructura , Cinética , Ratones , Simulación del Acoplamiento Molecular , Agregado de Proteínas , Pliegue de Proteína , Multimerización de Proteína , Ratas WistarRESUMEN
En el siglo XXI, el reto para la medicina es utilizar nuevamente términos, como filantropía y filotecnia, para la práctica clínica contemporánea, ya que estos términos se adaptan a nuestro actual entendimiento de que la medicina basada en valores y la medicina basada en evidencias deben ir siempre de la mano. Nuestro propósito es proponer un método integral de deliberación ética que implique una visión holística de los dilemas éticos en la práctica clínica de la pediatría.
A challenge for 21st century medicine is to rediscover the value of philanthropy and philotechnia in contemporary clinical practice because both are terms that adapt to our more current understanding of how value-based medicine and evidence-based medicine must always go "hand in hand." Our proposal is to offer an integral ethical deliberation method that implies a holistic view of the ethical dilemmas in pediatric clinical practice.