Biomedical subjects

Francisco J Moreno

Publications and source records attributed to Francisco J Moreno.

13 recordsLinked to original sources

PubMed2006

In vitro tau fibrillization: mapping protein regions.

We have investigated the propensity to form fibrillar aggregates of a variety of fragments and variants of the tau protein under the influence of a tau fibrillization inducer: coenzyme Q(0). To better identify fibrillization hotspots, we compare the polymerization propensity of tau fragments containing the sequence of putative hotspots with that of tau variants with that same sequence deleted. We also investigate the effects of biologically occurring modifications such as phosphorylation and deamidation. We found that residues 305 to 335 are essential for in vitro tau fibrillization. Residues 306 to 311 facilitate in vitro assembly, but are not sufficient to mimic the in vivo fibrillization of tau. Furthermore, the propensity of the 306-311 sequence to form fibrils is highly decreased by chemical modifications of tyrosine 310 that are commonly found in vivo.

Alzheimer Disease↗

PubMed2006

Characteristics of the binding of thioflavin S to tau paired helical filaments.

Binding of histological benzothiazole dye thioflavin S (ThS) to protein aggregates has been related with the presence of amyloid beta sheet structure in those protein aggregates. Paired helical filaments (PHF) from Alzheimer's disease (AD) patients, (whose main component is the microtubule associated protein, tau) bind to thioflavins. By using a novel immunofluorescence method, the binding of ThS to isolated tau filaments was tested. Also, the characteristics of this binding of ThS to PHF or to the in vitro assembled tau filaments, have been analyzed. Our results suggests that ThS binds to PHF with a higher affinity than to the straight filaments (SF), also found in AD.

Alzheimer Disease↗

PubMed2005

SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 inhibitors.

The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an SAR study about TDZD, different structural modifications in the heterocyclic ring aimed to test the influence of each heteroatom on the biological study are here reported here. Various compounds such as hydantoins, dithiazolidindiones, rhodanines, maleimides, and triazoles were synthesized and screened as GSK-3 inhibitors. After an extensive SAR study among these different heterocyclic families, TDZDs have been revealed as a privileged scaffold for the selective inhibition of GSK-3. A CoMFA analysis was also performed highlighting the molecular electrostatic field interaction in the interaction of TDZDs with GSK-3. Moreover, first mapping studies indicate two binding modes which in turn might imply relevant differences in the mechanism that underly the inhibitory activity of TDZDs.

Binding Sites↗

PubMed2005

Neurotoxic dopamine quinone facilitates the assembly of tau into fibrillar polymers.

Aberrant aggregation of microtubule associated protein tau is the main characteristic of different disorders known as tauopathies. Different compounds have been described to facilitate tau aberrant aggregation. In this work, we demonstrate that oxidized products of dopamine (neurotoxic dopamine quinone), a neurotransmitter involved in Parkinson's disease, promote tau polymerization. Curiously, neurons expressing dopamine (substantia nigra) show a low content of tau protein and seldom have tau aggregation in tauopathies. In non-dopaminergic neurons, quinone oxidation products may be involved in tau polymerization. These results support a link between oxidative damage and the onset of tauopathies.

Animals↗

PubMed2005

Visual behavior and perception of trajectories of moving objects with visual occlusion.

Experienced athletes in sports with moving objects have shown greater skill when using visual information to anticipate the direction of a moving object than nonexperienced athletes of those sports. Studies have shown that expert athletes are more effective than novices in occlusion situations in the first stages of the sports sequence. In this study, 12 athletes with different competitive experience in sports with moving objects viewed a sequence of tennis ball launches with and without visual occlusion, launched by a ball-shooting machine toward different areas with respect to the participant's position. The relation among visual behavior, occlusion time, and the precision of the task is reviewed. The spot where the balls bounced was analysed by a digital camera and visual behavior by an Eye Tracking System. Analysis showed that the nonexperienced athletes made significantly more errors and were more variable in visual occlusion conditions. Participants had a stable visual search strategy.

Adult↗

PubMed2004

Effect of quinones on microtubule polymerization: a link between oxidative stress and cytoskeletal alterations in Alzheimer's disease.

Increases in the concentration of quinones, such as benzoquinone, in pathological processes mediated by oxidative imbalance play a role in the disorganization and disassembly of the microtubule network in both non-neural and neural cells. In this study, we show that the effects on microtubules appear to be a direct result of the action of the quinones on tubulin, the main component of microtubules, since tubulin modification by quinones, including benzoquinone and juglone, leads to aggregation into dimers and other oligomers. Therefore, quinones and quinone-mediated effects provide a mechanistic link between oxidative stress, microtubule disruption, neuronal dysfunction and death, i.e., key salient feature of Alzheimer's disease.

3T3 Cells↗

PubMed2004

Phosphorylation modulates the alpha-helical structure and polymerization of a peptide from the third tau microtubule-binding repeat.

Paired helical filaments (PHFs) isolated from patients with Alzheimer's disease (AD) mainly consist of the microtubule-associated protein tau in a hyperphosphorylated form. It has been found that PHFs are the first example of pathological protein aggregation associated with formation of alpha-helices [Biochemistry (2002) 41, 7150-5]. In an effort to investigate the interplay between phosphorylation and the putative role of short regions of alpha-helix in the polymerization of tau, we have focused on the region of tau encompassing residues 317 to 335. This region is able to form protein fibrils in vitro and has two serines that are often found phosphorylated in PHFs. Using trifluoroethanol as an indicator of the alpha-helix, we find that the stability of the alpha-helix conformation is enhanced by phosphorylation. Circular dichroism data show that the phosphorylated peptide in water presents a content in alpha-helix similar to the unphosphorylated peptide at 40% of trifluoroethanol. Phosphorylation also stimulates the effect of juglone in promoting the in vitro polymerization. Furthermore, Fourier transformed infrared spectroscopy of samples of phosphorylated peptide polymerized with juglone renders a spectrum with maxima at approximately 1665 and approximately 1675 cm(-1), which are suggestive of a mixture of turns and alpha-helix conformations. Our results provide a direct mechanistic connection between phosphorylation and polymerization in tau. The connection between phosphorylation and polymerization appears to involve formation of alpha-helix structure.

Amino Acid Sequence↗

PubMed2004

Quinones facilitate the self-assembly of the phosphorylated tubulin binding region of tau into fibrillar polymers.

The fragment of tau containing the first and third tubulin-binding motifs, involved in self-assembly of tau, was phosphorylated by protein kinase A (PKA). In the presence of hydroxynonenal (HNE) or in the presence of quinones such as juglone, 2,3-dimethoxy-5-methyl-1,4-benzoquinone (coenzyme Q(0) or DMM), or menadione, the polymerization of this phosphorylated tau fragment is catalyzed, whereas polymerization of the unmodified fragment takes place in a lesser extent. The quinones coenzyme Q(0) and menadione are found in every cell, including neural cells, and may interact with tau protein to facilitate its assembly into filamentous structures. These tau filaments, assembled in the presence of quinones, have a fibrillar morphology very similar to that of paired helical filaments present in the brains of patients with Alzheimer's disease.

Amino Acid Motifs↗

PubMed2003

Thienyl and phenyl alpha-halomethyl ketones: new inhibitors of glycogen synthase kinase (GSK-3beta) from a library of compound searching.

Glycogen synthase kinase (GSK-3beta) plays a crucial role in Alzheimer's disease (AD). Its inhibition is a valid approach to the treatment of AD. In this initial letter, some thienyl and phenyl alpha-halomethyl ketones are described as new non-ATP competitive inhibitors of GSK-3beta. They are considered as lead compounds for designing and synthesizing new series, to carry out SAR studies, clear up the mechanism of action, and, in general, evaluate their therapeutical usefulness.

Adenosine Triphosphate↗

PubMed2003

Contextual interference in learning precision skills.

This research studied the effect of different organisations of practice (blocked and random) on the learning of three different types of throwing. 35 male students practiced three precise throws for 3 wk. Initially the subjects were separated into two groups who trained under different conditions of practice (blocked and random). All subjects improved significantly from initial performance, with both blocked practice and random practice. At the end of acquisition no differences were found between the groups. No significant differences were found on retention tests carried out 48 hr., 4 wk., and 8 wk. after the training period.

Adult↗

PubMed2002

First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease.

Glycogen synthase kinase 3 beta (GSK-3beta) has a central role in Alzheimer's disease (AD). Selective inhibitors which avoid tau hyperphosphorylation may represent an effective therapeutical approach to the AD pharmacotherapy and other neurodegenerative disorders. Here, we describe the synthesis, biological evaluation, and SAR of the small heterocyclic thiadiazolidinones (TDZD) as the first non-ATP competitive inhibitor of GSK-3beta. Their synthesis is based on the reactivity of sulfenyl chlorides. In GSK-3beta assays, TDZD derivatives showed IC(50) values in the micromolar range, whereas in other protein kinases assays they were devoid of any inhibitory activity. SAR studies allowed the identification of the key structural features. Finally, a possible enzymatic binding mode is proposed.

Adenosine Triphosphate↗

PubMed2002

P24, a glycogen synthase kinase 3 (GSK 3) inhibitor.

A heat resistant glycogen synthase kinase 3 (GSK 3) binding protein, p24, that inhibits its kinase activity at a low magnesium concentration (in a way similar to that of lithium) was found in microtubules from adult rat brains. This protein associates with GSK 3 in microtubules and corresponds to one previously described in the literature as p25, although it has a relative molecular weight of 23472. p24 is a poor substrate for GSK 3 but it could be phosphorylated by other protein kinases such as cAMP dependent protein kinase and cdk 5. Since p24 could form complexes with GSK 3, it may not only regulate GSK 3 activity but also it might act as an anchoring protein for the kinase.

Amino Acid Sequence↗

PubMed2002

Mechanisms involved in the attenuation of intestinal toxicity induced by (S)-(+)-ketoprofen in re-fed rats.

In addition to suppression of prostaglandins synthesis a number of factors have been implicated in nonsteroidal antiinflammatory drugs (NSAIDs) enteropathy, including oxygen radical-dependent microvascular injuries, depletion of glutathione, and food. Inflammatory cytokines such as tumor necrosis factor-alpha regulate endothelial adhesion molecules expression and promote vascular neutrophil adherence. Racemic ketoprofen is a potent NSAID with a chiral structure existing in two enantiomeric forms. Its therapeutic effects reside almost exclusively in the (S)-(+) isomer nevertheless the potential contribution to side effects of the (R)-(-) isomer cannot be ignored. The aims of this study were to explore the role of prostaglandins depletion, tumor necrosis factor-alpha production, and glutathione homeostasis in the comparative pathogenesis of intestinal injury induced by racemic-ketoprofen and its enantiomers in re-fed rats. Racemic ketoprofen and (R)-(-)-ketoprofen dose-dependently caused similar and multiple lesions in the mid-jejunum significantly higher than those observed with (S)-(+)-ketoprofen. All the treatments significantly decreased prostaglandins content. A significant increase of tumor necrosis factor-alpha production and decreases in glutathione levels and glutathione reductase activity after treatment of the racemate and (R)-(-)-ketoprofen, were observed whereas the (S)-(+)-isomer did not change these parameters. In conclusion, (S)-(+)-ketoprofen possesses a better intestinal toxicity profile than the racemate and its (R)-(-)-isomer. Despite inhibiting cyclooxygenase activity, the attenuation of (S)-(+)-ketoprofen-induced intestinal toxicity could be correlated with a reduced oxidative damage characterized not only by a lack of changes in glutathione reductase activity and glutathione levels but also by an absence of up-regulation of tumor necrosis factor-alpha production in intestinal mucosa.

Administration, Oral↗