Neurodegenerative diseases: A protein misfolding consequence

Protein misfolding and aggregation into amyloid-like structures is related with an increasing number of both non-neuropathic (either localized or systemic) and neurodegenerative human disorders. Decrypting the mechanisms and implications underlying amyloid assemblies has become a central issue in biology and medicine. Compelling evidence show that the formation of amyloid aggregates has a negative impact in cell physiology, entailing the cell dysfunction and finally apoptosis and cell death. The aim of the present review is to illustrate the currently status of the most common and/or debilitating conformational diseases, from Alzheimer to prion diseases.

Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Neurodegenerative diseases: A protein misfolding consequence

Protein misfolding and aggregation into amyloid-like structures is related with an increasing number of both non-neuropathic (either localized or systemic) and neurodegenerative human disorders. Decrypting the mechanisms and implications underlying amyloid assemblies has become a central issue in biology and medicine. Compelling evidence show that the formation of amyloid aggregates has a negative impact in cell physiology, entailing the cell dysfunction and finally apoptosis and cell death. The aim of the present review is to illustrate the currently status of the most common and/or debilitating conformational diseases, from Alzheimer to prion diseases.

Los determinantes sociales del pensamiento: ni anomalismo ni funcionalización

El principal objetivo del presente trabajo es indagar si las habituales tentativas por descifrarel pensamiento desde un punto de vista sociológico, a pesar de su vehemente compromisoantirreduccionista, podrían aceptar en último término la reducción de ideas, argumentos y doctrinasa sus presuntos determinantes sociales. En una primera etapa analizamos el ¿sociologismoanómalo¿ de Martin Kusch, señalamos algunas de sus lagunas, y establecemos que la panopliaconceptual en losofía de la mente es fértilmente aplicable al ámbito racional-social. A continuaciónconsideramos el funcionalismo reduccionista de Jaegwon Kim, nos centramos en latesis de que los estados intencionales de la mente, al contrario de lo que ocurre con los qualia,son causalmente funcionalizables, e intentamos establecer sus posibles repercusiones en la interpretaciónsocial del pensamiento. La aplicación de la metodología funcionalista al horizonteracional-social, de todos modos, parece venir desmentida por la evidencia, ya que las propiedadesdel pensamiento equiparables a los qualia son de hecho eminentemente funcionalizablesen la medida que fundamentan la efectividad social de los recursos gurativos y retóricos. Enun sentido análogo, la obra de Hans Blumenberg demuestra que los inescrutables ingredientes gurativos de todo pensamiento que él denomina ¿metáforas absolutas¿ son tan decisivos paracualquier proceso abstractivo que los conceptos nunca llegan a agotar su alcance determinador.Con lo cual los conceptos y las ideas más generales, antes considerados del todo funcionalizables,ahora dependen de algunas metáforas básicas, aun cuando por analogía con los qualia selas creía inmunes a toda funcionalización. Por tanto parece que la reducción no puede resolverlas di cultades que plantean los presuntos ¿determinantes sociales del pensamiento¿. Al mismotiempo, y con rmando así algunos emergentismos, los aspectos causal-funcionales del ámbitoracional-social dan la impresión de ser inconciliables con la enigmática estructura causal queponen de mani esto las aproximaciones losó cas al problema mente-cuerpo.

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.