Mecanismos Bioquímicos y Moleculares de la Neurodegeneración en la Enfermedad de Alzheimer

La enfermedad de Alzheimer se caracteriza por la presencia de placas amiloideas, hiperfosforilación de la proteína TAU e incremento de la inflamación cerebral. El uso de modelos animales de experimentación, como APP/PS1 (proteína precursora de amiloide/presenilina 1), permite observar los cambios producidos tanto a nivel de bioquímico como de biología molecular. Las células encargadas de intervenir en el proceso inflamatorio cerebral son los astrocitos y la microglía. Los resultados de esta tesis nos indican que los cambios en las quimiocinas y los receptores de quimiocinas son importantes debido a la implicación que podrían tener en la inflamación relacionada con la enfermedad de Alzheimer. Además, podrían ser una de las posibles causas para el desarrollo de este trastorno. Se produce daño en la barrera hematoencefálica, con un aumento de la quimiotaxis. Por otra parte, el movimiento de las moléculas a través de las membranas celulares podría ser posiblemente mayor en ratones transgénicos en comparación con los ratones de tipo salvaje, lo que sugeriría que podría existir una pérdida de energía en los ratones transgénicos si los comparamos con los ratones de tipo salvaje. Esto viene evidenciado por los resultados obtenidos respecto a los cambios detectados en la proteína ABCF1 que presentan mayor expresión en el ratón transgénico que en el ratón de tipo salvaje. Los niveles de quimiocinas y citoquinas, junto con sus receptores cambian en el ratón APP/PS1 con respecto al ratón de tipo salvaje. Este hecho podría llevar a nuevos tratamientos en la EA, con la posibilidad de actuar de manera más específica controlando todos los procesos fisiológicos ligados a la acción de estos mediadores en nuestro organismo.Alzheimer's disease is characterized by the presence of amyloid plaques, hyperphosphorylation of the TAU protein, and increased brain inflammation. The use of experimental animal models, such as APP/PS1 (amyloid precursor protein/presenilin 1), makes it possible to observe the changes produced both at the biochemical and molecular biology level. The cells responsible for intervening in the cerebral inflammatory process are astrocytes and microglia. The results of this thesis indicate that changes in chemokines and chemokine receptors are important due to the implication they could have in inflammation related to Alzheimer's disease. In addition, they could be one of the possible causes for the development of this disorder. Damage to the blood-brain barrier occurs, with increased chemotaxis. On the other hand, the movement of molecules across cell membranes could possibly be higher in transgenic mice compared to wild-type mice, which would suggest that there could be a loss of energy in transgenic mice compared to wild-type mice. wild type mice. This is evidenced by the results obtained regarding the changes detected in the ABCF1 protein that present greater expression in the transgenic mouse than in the wild-type mouse. The levels of chemokines and cytokines, along with their receptors, change in the APP/PS1 mouse relative to the wild-type mouse. This fact could lead to new treatments in AD, with the possibility of acting more specifically by controlling all the physiological processes linked to the action of these mediators in our body

Functions of Astrocytes under Normal Conditions and after a Brain Disease

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10−8 M), Rn (10−6 M), and Ins + Rn (10−8 M and 10−6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone

Deposition of Zinc–Cerium Coatings from Deep Eutectic Ionic Liquids

This work studies the electrodeposition of zinc and cerium species on carbon steel substrates from choline chloride-based ionic liquid bath in order to develop a protective coating with anti-corrosion, sacrificial, and self-repairing properties. Hull cell tests were used to study the influence of the current density on composition of the coatings and their morphology. Surface morphology, chemical composition and oxidation state of the obtained coatings were examined by scanning electron microscopy (SEM), Energy Dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS), respectively. Furthermore, electrochemical characterization and corrosion tests were performed in order to evaluate the corrosion properties of the electrodeposited Zn–Ce coatings. The cathodic deposition of Zn–Ce was achieved for the first time using the deep eutectic solvent choline chloride-urea as an electrolyte. Cerium was incorporated in the coating as oxide or mixed oxide within the Zn metal matrix. The composition and morphology of the electrodeposited coating were dependent on the applied current density. Electrochemical corrosion tests showed similar corrosion rates for all the coatings. Nevertheless on scratched tests with a ratio area of 15:1, for Zn-Ce coatings cerium oxide somehow migrates from the coating to the high pH cathodic areas developed on the surface of the bare steel substrate. Further study is still necessary to improve the corrosion protection of the Zn–Ce coating for carbon steel.The authors wish to express their gratitude for funding from the PIE-CSIC project 2009601084 “Electrolytic deposition of corrosion resistant coatings using ionic liquids”Peer reviewe

Electrospun Poly(acrylic acid-co-4-styrene sulfonate) as Potential Drug-Eluting Scaffolds for Targeted Chemotherapeutic Delivery Systems on Gastric (AGS) and Breast (MDA-Mb-231) Cancer Cell Lines

Potential drug-eluting scaffolds of electrospun poly(acrylic acid-co-styrene sulfonate) P(AA-co-SS) in clonogenic assays using tumorigenic gastric and ovarian cancer cells were tested in vitro. Electrospun polymer nanofiber (EPnF) meshes of PAA and PSSNa homo- and P(AA-co-SS) copolymer composed of 30:70, 50:50, 70:30 acrylic acid (AA) and sodium 4-styrene sulfonate (SSNa) units were performed by electrospinning (ES). The synthesis, structural and morphological characterization of all EPnF meshes were analyzed by optical and electron microscopy (SEM-EDS), infrared spectroscopy (FTIR), contact angle, and X-ray diffraction (XRD) measurements. This study shows that different ratio of AA and SSNa of monomers in P(AA-co-SS) EPnF play a crucial role in clonogenic in vitro assays. We found that 50:50 P(AA-co-SS) EPnF mesh loaded with antineoplastic drugs can be an excellent suppressor of growth-independent anchored capacities in vitro assays and a good subcutaneous drug delivery system for chemotherapeutic medication in vivo model for surgical resection procedures in cancer research

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10−8 M), Rn (10−6 M), and Ins + Rn (10−8 M and 10−6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone