536 research outputs found
Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design
Natural compounds, such as plant and fruit extracts have shown neuroprotective effect against neurodegenerative diseases. It has been reported that several natural compounds binding to transthyretin (TTR) can be useful in amyloidosis prevention. TTR is a transporter protein that under physiological condition carries thyroxine (T4) and retinol in plasma and in cerebrospinal fluid (CSF); it also has a neuroprotective role against Alzheimer’s disease (AD). However, TTR also is an amyloidogenic protein responsible for familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The TTR amyloidogenic potential is speeded up by several point mutations. One therapeutic strategy against TTR amyloidosis is the stabilisation of the native tetramer by natural compounds and small molecules. In this review, we examine the natural products that, starting from 2012 to present, have been studied as a stabiliser of TTR tetramer. In particular, we discussed the chemical and structural features which will be helpful for future drug design of new TTR stabilisers
The positive side of the Alzheimer's disease amyloid cross-interactions: The case of the Aβ 1-42 peptide with tau, TTR, CysC, and ApoA1
Alzheimer's disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions
Antioxidant quercetin 3-O-glycosylated plant flavonols contribute to Transthyretin stabilization
Plants are rich in secondary metabolites, which are often useful as a relevant source of nutraceuticals. Quercetin (QUE) is a flavonol aglycone able to bind Transthyretin (TTR), a plasma protein that under pathological conditions can lose its native structure leading to fibrils formation and amyloid diseases onset. Here, the dual nature of five quercetin 3-O-glycosylated flavonol derivatives, isolated from different plant species, such as possible binders of TTR and antioxidants, was investigated. The crystal structure of 3-O-β-D-galactopyranoside in complex with TTR was solved, suggesting that not only quercetin but also its metabolites can contribute to stabilizing the TTR tetramer
Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis
Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal
Ultrasound tissue characterization detectspreclinical myocardial structural changes inchildren affected by Duchenne muscular dystrophy
AbstractObjectivesOur goal was to identify early changes in myocardial physical properties in children with Duchenne muscular dystrophy (DMDch).BackgroundDuchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, which triggers complex molecular and biological events in skeletal and cardiac muscle tissues. Although about 30% of patients display overt signs of cardiomyopathy in the late stage of the disease, it is unknown whether changes in myocardial physical properties can be detected in the early (preclinical) stages of the disease.MethodsWe performed an ultrasonic tissue characterization (UTC) analysis of myocardium in DMDch with normal systolic myocardial function and no signs of cardiomyopathy. Both the cyclic variation of integrated backscatter (cvIBS) and the calibrated integrated backscatter (cIBS) were assessed in 8 myocardial regions of 20 DMDch, age 7 ± 2 years (range 4 to 10 years), and in 20 age-matched healthy controls.ResultsWe found large differences in the UTC data between DMDch and controls; the mean value of cvIBS was 4.4 ± 1.5 dB versus 8.8 ± 0.8 dB, whereas the mean value of cIBS was 36.4 ± 7.1 dB versus 26.9 ± 2.0 dB (p < 10−6for both). In DMDch, all eight sampled segments showed cIBS mean values to be significantly higher and cvIBS mean values to be significantly lower than those in the controls. Finally, interindividual differences were greater in DMDch than in controls for both parameters.ConclusionsThe myocardium in DMDch displays UTC features different from those in healthy controls. These results show that lack of dystrophin is commonly associated with changes in myocardial features well before the onset of changes of systolic function and overt cardiomyopathy
Peptidotriazolamers Inhibit A beta(1-42) Oligomerization and Cross a Blood-Brain-Barrier Model
In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid beta (A beta) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation "hot spots" (KLVFF20)-L-16 and G(39)VVIA(42) in A beta(1-42). We found that peptidotriazolamers act as modulators of the A beta(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early A beta oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.Peer reviewe
Designed glycopeptidomimetics disrupt protein−protein interactions mediating amyloid β‑peptide aggregation and restore neuroblastoma cell viability
How anti-Alzheimer’s drug candidates that reduce amyloid 1−42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1−42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1−42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1−42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1−42 aggregation
Application of the principles of activity theory to veterinary education
This work is dedicated to justify the application of the structural principles of the activity theory, to the training of competent veterinarians and zootechnicians. First, the application of activity theory as a tool to study or undertake any type of human activity is justified. Second, needs are posited as instigators of any human activity. And, third, the application of the principles of unity of consciousness and activity, object orientation, mediation and hierarchical structure of activity, to veterinary education, is demonstrated and exemplified.Este trabajo está dedicado a justificar la aplicación de los principios estructurales de la teoría de la actividad, a la formación de veterinarios y zootecnistas competentes. En primer lugar, se justifica la aplicación de la teoría de la actividad como herramienta para estudiar o emprender cualquier tipo de actividad humana. En segundo lugar, se postula a las necesidades como incitadoras de cualquier actividad humana. Y, en tercer lugar, se demuestra y ejemplifica la aplicación de los principios de unidad de conciencia y actividad, orientación a objetos, mediación y estructura jerárquica de la actividad, a la educación veterinaria
Validation in the Cross-Cultural Adaptation of the Korean Version of the Oswestry Disability Index
Disability questionnaires are used for clinical assessment, outcome measurement, and research methodology. Any disability measurement must be adapted culturally for comparability of data, when the patients, who are measured, use different languages. This study aimed to conduct cross-cultural adaptation in translating the original (English) version of the Oswestry Disability Index (ODI) into Korean, and then to assess the reliability of the Korean versions of the Oswestry Disability Index (KODI). We used methodology to obtain semantic, idiomatic, experimental, and conceptual equivalences for the process of cross-cultural adaptation. The KODI were tested in 116 patients with chronic low back pain. The internal consistency and reliability for the KODI reached 0.9168 (Cronbach's alpha). The test-retest reliability was assessed with 32 patients (who were not included in the assessment of Cronbach's alpha) over a time interval of 4 days. Test-retest correlation reliability was 0.9332. The entire process and the results of this study were reported to the developer (Dr. Fairbank JC), who appraised the KODI. There is little evidence of differential item functioning in KODI. The results suggest that the KODI is internally consistent and reliable. Therefore, the KODI can be recommended as a low back pain assessment tool in Korea
Prevalence of spinocellulart ataxia type 2 mutation among ittalian Parkinsonian patients
We evaluated the prevalence of the SCA2 mutation
among 224 Italian patients affected by typical Parkinsonism,
including 145 sporadic and 79 familial forms. Pink1, Parkin,
and LRRK2 gene mutations had been excluded previously.
Molecular testing for the CAG expansion at the SCA 2 locus
was performed on leukocyte DNA. Cloning and sequencing of
the expanded allele was performed in patients positive for the
SCA2 expansion. A 38 CAG expansion was detected in 1 of 79
families studied. The proband, a male age 67, and his sister, age
69, were both affected by a benign form of L-dopa–responsive
Parkinsonism not associated with cerebellar signs. The inheritance
was autosomal dominant. The CAG expansion was stable
through meiotic transmission: sequence analysis showed that
the CAG stretch was interrupted by 3 CAA. Our study shows
that CAG expansion at the SCA 2 locus may represent a genetic
cause of familial L-dopa–responsive Parkinsonism among Italian
patients. The stability of the pathological CAG expansion
detected in this family was related to the presence of CAA
interruptions. These findings, together with literature data, suggest
that the molecular intrinsic structure of the expanded allele
may modulate the phenotypic expression of the SCA2
mutatio
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