Structure–function studies for the panacea, valproic acid

2009 ◽  
Vol 37 (5) ◽  
pp. 1126-1132 ◽  
Author(s):  
Nicole Terbach ◽  
Robin S.B. Williams
Keyword(s):  
Valproic Acid ◽  
Short Chain Fatty Acid ◽  
Structural Characteristics ◽  
Short Review ◽  
Hiv Treatment ◽  
Signalling Pathways ◽  
Structural Constraints ◽  
Therapeutic Action ◽  
Cellular Effects ◽  
Related Compounds

The anticonvulsant properties of VPA (valproic acid), a branched short-chain fatty acid, were serendipitously discovered in 1963. Since then, therapeutic roles of VPA have increased to include bipolar disorder and migraine prophylaxis, and have more recently been proposed in cancer, Alzheimer's disease and HIV treatment. These numerous therapeutic roles elevate VPA to near ‘panacea’ level. Surprisingly, the mechanisms of action of VPA in the treatment of many of these disorders remain unclear, although it has been shown to alter a wide variety of signalling pathways and a small number of direct targets. To analyse the mechanism of action of VPA, a number of studies have defined the structural characteristics of VPA-related compounds giving rise to distinct therapeutic and cellular effects, including adverse effects such as teratogenicity and hepatotoxicity. These studies raise the possibility of identifying target-specific novel compounds, providing better therapeutic action or reduced side effects. This short review will describe potential therapeutic pathways targeted by VPA, and highlight studies showing structural constraints necessary for these effects.

scholarly journals Tumour necrosis factor signalling in health and disease

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 111 ◽  
Author(s):  
Jonathan Holbrook ◽  
Samuel Lara-Reyna ◽  
Heledd Jarosz-Griffiths ◽  
Michael F. McDermott
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Short Review ◽  
Vital Role ◽  
Signalling Pathways ◽  
Cellular Effects ◽  
Disease States ◽  
Downstream Effects ◽  
Health And Disease ◽  
Necrosis Factor

The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involvement as well as cellular activation with subsequent proliferation and programmed cell death or necrosis. As might be expected with such a broad spectrum of cellular effects and complex signalling pathways, TNF has also been implicated in a number of disease states, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Since the time of its discovery over 40 years ago, TNF ligand and its receptors, TNF receptor (TNFR) 1 and 2, have been categorised into two complementary superfamilies, namely TNF (TNFSF) and TNFR (TNFRSF), and 19 ligands and 29 receptors have been identified to date. There have been significant advances in our understanding of TNF signalling pathways in the last decade, and this short review aims to elucidate some of the most recent advances involving TNF signalling in health and disease.

Role of the Structural Characteristics of Dendrimers in the Manifestation of the Antiamyloid Properties

INEOS OPEN ◽  
2020 ◽  
Vol 3 ◽  
Author(s):  
S. A. Sorokina ◽  
◽  
Yu. Yu. Stroilova ◽  
V. I. Muronets ◽  
Z. B. Shifrina ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Structural Characteristics ◽  
Short Review ◽  
External Factors ◽  
Amyloid Aggregation ◽  
Amyloid Proteins ◽  
Molecular Parameters ◽  
Amyloid Aggregates ◽  
Aggregation Processes

Among the compounds able to efficiently inhibit the amyloid aggregation of proteins and decompose the amyloid aggregates that cause neurodegenerative diseases, of particular interest are dendrimers, which represent individual macromolecules with the hypercrosslinked architectures and given molecular parameters. This short review outlines the peculiarities of the antiamyloid activity of dendrimers and discusses the effect of dendrimer structures and external factors on their antiamyloid properties. The potential of application of dendrimers in further investigations on the aggregation processes of amyloid proteins as the compounds that exhibit the remarkable antiamyloid activity is evaluated.

scholarly journals Molecular and Therapeutic Potential and Toxicity of Valproic Acid

2010 ◽  
Vol 2010 ◽  
pp. 1-18 ◽  
Author(s):  
Sébastien Chateauvieux ◽  
Franck Morceau ◽  
Mario Dicato ◽  
Marc Diederich
Keyword(s):  
Valproic Acid ◽  
Clinical Trials ◽  
Side Effects ◽  
Histone Deacetylase Inhibitors ◽  
Short Chain Fatty Acid ◽  
Therapeutic Potential ◽  
Mood Stabilizer ◽  
Chain Fatty Acid ◽  
Histone Deacetylation ◽  
Transcription Sites

Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties.

scholarly journals Structural Modeling of Glutathiones Containing Selenium and Tellurium

2016 ◽  
Vol 8 (1) ◽  
pp. 102
Author(s):  
Valter A. Nascimento ◽  
Petr Melnikov ◽  
André V. D. Lanoa ◽  
Anderson F. Silva ◽  
Lourdes Z. Z. Consolo
Keyword(s):  
Molecular Mechanics ◽  
Structural Characteristics ◽  
Structural Modeling ◽  
Structural Description ◽  
Ionic Radii ◽  
X Ray ◽  
Bond Angles ◽  
Bond Lengths ◽  
Available Information ◽  
Related Compounds

<p>The comparative structural modeling of reduced and oxidized glutathiones, as well as their derivatives containing selenium and tellurium in chalcogen sites (Ch = Se, Te) has provided detailed information about the bond lengths and bond angles, filling the gap in the structural characteristics of these tri-peptides. The investigation using the molecular mechanics technique with good approximation confirmed the available information on X-ray refinements for the related compounds. It was shown that Ch-H and Ch-C bond lengths grow in parallel with the increasing chalcogen ionic radii. Although the distances C-C, C-O, and C-N are very similar, the geometry of GChChG glutathiones is rich in conformers owing to the possibility of rotation about the bridge Ch-Ch. It is confirmed that the distances Ch-Ch are essentially independent of substituents in most of chalcogen compounds from elemental chalcogens to oxydized glutathiones. The standard program Hyperchem 7.5 has proved to be an appropriate tool for the structural description of less-common bioactive compositions when direct X-ray data are missing.</p>

scholarly journals Valproic Acid Inhibits Proliferation and Reduces Invasiveness in Glioma Stem Cells Through Wnt/β Catenin Signalling Activation

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 522 ◽  
Author(s):  
Gabriele Riva ◽  
Chiara Cilibrasi ◽  
Riccardo Bazzoni ◽  
Massimiliano Cadamuro ◽  
Caterina Negroni ◽  
...  
Keyword(s):  
Stem Cells ◽  
Valproic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Cell Signalling ◽  
Luciferase Reporter ◽  
Signalling Pathways ◽  
Boyden Chamber ◽  
Glioma Stem Cells ◽  
Bioinformatics Analyses ◽  
E Cadherin

Glioblastoma is the most common malignant brain tumour in adults. The failure of current therapies can be ascribed to glioma stem cells (GSCs), which can rapidly repopulate the tumour following the initial treatment. The study of histone deacetylase inhibitors, such as valproic acid (VPA), is becoming an attractive field in cancer research. However, the exact mechanisms underlying its anti-cancer effect remain to be elucidated due to its pleiotropic effects on several cell-signalling pathways. Ingenuity Pathway Analysis (IPA) bioinformatics analysis was performed on genome-wide data regarding GSCs methylome to identify the signalling pathways mainly affected by methylation changes induced by VPA. Real time PCR and luciferase reporter assay were used to better investigate VPA effects on Wnt/β-catenin signalling pathway. VPA effect on GSC proliferation was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and Trypan blue assays. Finally, VPA impact on GSC motility was demonstrated by Boyden chamber assay and further confirmed evaluating the expression levels or localisation, through western blot or immunofluorescence, of Twist1, Snail1, E-Cadherin and N-Cadherin. The bioinformatics analyses performed on GSCs methylome highlighted that Wnt/β-catenin signalling was affected by the methylation changes induced by VPA, which could influence its activation status. In particular, we pointed out a general activation of this pathway after VPA exposure, which was accompanied by an inhibitory potential on GSCs proliferation. Finally, we also proved VPA’s ability to inhibit GSCs invasion through Snail1 and Twist1 downregulation and E-Cadherin relocalisation. VPA treatment may represent a new, interesting therapeutic approach to affect GSC proliferation and motility, but further investigations are certainly needed.

Prospects for stable analogues of phosphohistidine

2013 ◽  
Vol 41 (4) ◽  
pp. 1072-1077 ◽  
Author(s):  
Tom E. McAllister ◽  
Jeffrey J. Hollins ◽  
Michael E. Webb
Keyword(s):  
Amino Acids ◽  
Chemical Synthesis ◽  
Short Review ◽  
Signalling Pathways ◽  
Post Translational Modification ◽  
Almost All

Phosphorylation is a ubiquitous protein post-translational modification, and the importance of phosphorylation of serine, threonine and tyrosine is well established. What is lesser known is that almost all heteroatom-containing amino acids can be phosphorylated and, among these, histidine, aspartate and cysteine have well established roles in bacterial signalling pathways. The first of these, phosphohistidine, is the most unusual in that it is labile under many conditions used to study proteins in vitro and can exist as two different isomers. In the present short review, we highlight the chemical challenges that this modification presents and the manner in which chemical synthesis has been used to identify and mimic the modification in proteins.

EFFICIENT ALGORITHMS AND SOFTWARE FOR DETECTION OF FULL-LENGTH LTR RETROTRANSPOSONS

2006 ◽  
Vol 04 (02) ◽  
pp. 197-216 ◽  
Author(s):  
ANANTHARAMAN KALYANARAMAN ◽  
SRINIVAS ALURU
Keyword(s):  
Genomic Sequence ◽  
Linear Time ◽  
Structural Characteristics ◽  
Full Length ◽  
Yeast Genome ◽  
Structural Constraints ◽  
Ltr Retrotransposons ◽  
High Quality ◽  
Robust Parameter ◽  
And Performance

LTR retrotransposons constitute one of the most abundant classes of repetitive elements in eukaryotic genomes. In this paper, we present a new algorithm for detection of full-length LTR retrotransposons in genomic sequences. The algorithm identifies regions in a genomic sequence that show structural characteristics of LTR retrotransposons. Three key components distinguish our algorithm from that of current software — (i) a novel method that preprocesses the entire genomic sequence in linear time and produces high quality pairs of LTR candidates in run-time that is constant per pair, (ii) a thorough alignment-based evaluation of candidate pairs to ensure high quality prediction, and (iii) a robust parameter set encompassing both structural constraints and quality controls providing users with a high degree of flexibility. We implemented our algorithm into a software program called LTR_par, which can be run on both serial and parallel computers. Validation of our software against the yeast genome indicates superior results in both quality and performance when compared to existing software. Additional validations are presented on rice BACs and chimpanzee genome.

Signalling Pathways and Cellular Effects Activated in Endothelial Cells by Exogenous AIMP1

2010 ◽  
Vol 150 ◽  
pp. 512-512
Author(s):  
V.C. Jackson ◽  
S. Dewilde ◽  
A. Giuliano Albo ◽  
D. Corpillo ◽  
K. Lis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signalling Pathways ◽  
Cellular Effects

scholarly journals Experimental chemotherapy of typhus Anti-rickettsial action of p -sulphonamidobenzamidine and related compounds

1946 ◽  
Vol 133 (870) ◽  
pp. 20-62 ◽  
Keyword(s):  
Biological Activity ◽  
Therapeutic Action ◽  
Experimental Chemotherapy ◽  
Related Compounds

The discovery of the pronounced anti-rickettsial activity of p -sulphonamidobenzamidine on experimental typhus infections in mice has led to a search for compounds of enhanced therapeutic action. A large number of compounds have been prepared in development of the sulphonamido-amidine structure, but anti-rickettsial activity has been found to be confined to about a dozen substances intimately related to p -sulphonamidobenzamidine, only one, namely, p -sulphonamidobenzamidoxime, having a very slightly superior therapeutic action. The significance of the discovery of yet another sulphonamide type with pronounced biological activity is discussed.

scholarly journals Transfer Method of Geometric Tolerance Items Based on Assembly Joints

2021 ◽  
Author(s):  
Ning MA ◽  
Bo YANG ◽  
Jinping LI ◽  
Yanchao LIU ◽  
Dianxi WANG ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
General Structure ◽  
Analysis Tool ◽  
Structural Constraints ◽  
Functional Requirements ◽  
Priority Rules ◽  
Top Down ◽  
Geometric Tolerance ◽  
Transfer Path ◽  
Piston Mechanism

Abstract In order to reduce the uncertainty in the selection of geometric tolerance items, a qualitative method for top-down transfer of geometric tolerance items based on assembly joints is proposed. According to the structural characteristics, the assembly joints are divided into meta-assembly joints and composite assembly joints, and the priority rules for assembly joints are proposed. The transfer path of part-level geometric tolerance items is established according to the functional requirements and structural constraints among parts. On this basis, by adding information about the composition and constraint types of assembly joints between parts and the positioning constraint relationship of the general structure surface in the part, the transfer path of part-level geometric tolerance items is extended to the surface-level transfer path. The structural transformation rules for functional requirements based on structural constraints, the tolerance item generation specifications and datum transfer specifications are established. And based on the above specifications, the mapping relationship between functional requirements, structural constraints and geometric tolerance items is defined. The synchronous transmission of geometric tolerance items along with the product design process are realized which provides an effective analysis tool for the top-down design of geometric tolerance items. Finally, the effectiveness of the method is verified by taking the transmission parts and connection parts in the crankshaft-piston mechanism as an example.

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