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Pharmacological Applications (pharmacological + application)
Selected AbstractsEARLY ACTIVATION OF INTERNAL MEDIAL SMOOTH MUSCLE CELLS IN THE RABBIT AORTA AFTER MECHANICAL INJURY: RELATIONSHIP WITH INTIMAL THICKENING AND PHARMACOLOGICAL APPLICATIONSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006Huguette Louis SUMMARY 1Smooth muscle cells (SMC) participate in both inflammatory and dedifferentiation processes during atherosclerosis, as well as during mechanical injury following angioplasty. In the latter, we studied medial SMC differentiation and inflammation processes implicated early after de-endothelialization in relation to mechanical stresses. We hypothesized that activation of a subpopulation of SMC within the media plays a crucial role in the early phase of neointimal formation. 2For this purpose, we used a rabbit model of balloon injury to study activation and differentiation of medial SMC in the early time after denudation and just before neointima thickening. Inflammation was evaluated by the expression of vascular cell adhesion molecule (VCAM)-1, integrin a4b1 and nuclear factor (NF)-kB. Myosin isoforms and 2P1A2 antigen, a membrane protein expressed by rabbit dedifferentiated SMC, were used as markers of differentiation. 3On day 2 after de-endothelialization, VCAM-1, a4b1 and NF-kB were coexpressed by a well-defined subpopulation of SMC of the internal part of the media, in the vicinity of the blood stream. At the same time, the majority of SMC throughout the media expressed non-muscle myosin heavy chain-B (nm-MHC-B) and 2P1A2 antigen. On day 7, when intimal thickening appeared, SMC of the media were no longer activated, whereas some intimal SMC expressed the activation markers. Thus, after de-endothelialization, early dedifferentiation occurs in most of the medial SMC, whereas activation concerned only a subpopulation of SMC located in the internal media. Using the T-type voltage-operated calcium channel blocker mibefradil (0.1,1 mmol/L) in SMC culture, we showed that this agent exhibited an antiproliferative effect in a dose-dependant manner only on undifferentiated cells. 4In conclusion, the results suggest that the activated SMC represent cells that are potentially able to migrate and participate in the intimal thickening process. Thus, the medial SMC inflammatory process, without any contribution of inflammatory cells, may represent a major mechanism underlying the development of intimal thickening following mechanical stress. In humans, inhibition of T-type calcium channels may be a tool to prevent the early proliferation step leading to neointimal formation. [source] Diurnal regulation of the gastrin-releasing peptide receptor in the mouse circadian clockEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Ilia N. Karatsoreos Abstract In mammals, circadian rhythms are generated by the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN neurons are heterogeneous and can be classified according to their function, anatomical connections, morphology and/or peptidergic identity. We focus here on gastrin-releasing peptide- (GRP) and on GRP receptor- (GRPr) expressing cells of the SCN. Pharmacological application of GRP in vivo or in vitro can shift the phase of circadian rhythms, and GRPr-deficient mice show blunted photic phase shifting. Given the in vivo and in vitro effects of GRP on circadian behavior and on SCN neuronal activity, we investigated whether the GRPr might be under circadian and/or diurnal control. Using in situ hybridization and autoradiographic receptor binding, we localized the GRPr in the mouse SCN and determined that GRP binding varies with time of day in animals housed in a light,dark cycle but not in conditions of constant darkness. The latter results were confirmed with Western blots of SCN tissue. Together, the present findings reveal that changes in GRPr are light driven and not endogenously organized. Diurnal variation in GRPr activity probably underlies intra-SCN signaling important for entrainment and phase shifting. [source] Review: An overview about the structure,function relationship of marine sulfated homopolysaccharides with regular chemical structures,BIOPOLYMERS, Issue 8 2009Vitor H. Pomin Abstract Efforts in both structural and biological studies of sulfated polysaccharides from marine organisms have increased significantly over the last 10 years. Marine invertebrates have been demonstrated to be a source of glycans with particularly well-defined chemical structures, although ordered structural patterns can also be found occasionally in algal sources such as red seaweeds. Clear and regular structural features are essential for a good understanding of the biological activities of these marine homopolysaccharides of which sulfated fucans and sulfated galactans are the most studied. Herein, the main structural features (sugar type, sulfation and glycosylation sites, and orientational binding preferences) of both sulfated fucans and galactans are individually reviewed with regard to their specific contributions to two frequently described biological functions: the acrosome reaction (a physiological event of sea-urchin fertilization), and the anticoagulant and antithrombotic activities (an alternative and highly desirable pharmacological application). © 2009 Wiley Periodicals, Inc. Biopolymers 91: 601,609, 2009. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Two Novel Antioxidative Stilbene Tetramers from Parthenocissus laetevirensHELVETICA CHIMICA ACTA, Issue 7 2009Shan He Abstract Laetevirenols F (1) and G (2), two novel stilbene tetramers with an unprecedented skeleton, were isolated from Parthenocissus laetevirens. Their structures were elucidated by spectroscopic analysis, including 1D- and 2D-NMR experiments, and their possible biogenetic pathway was discussed. In addition, both compounds were determined to be potent singlet-oxygen quenchers by electron paramagnetic resonance (EPR) experiments, which highlights their potential pharmacological applications in singlet oxygen mediated diseases. [source] Promiscuous Zinc-Dependent Acylase-Mediated One-Pot Synthesis of Monosaccharide-Containing Pyrimidine Derivatives in Organic MediumADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2009Qi Wu Abstract A facile one-pot synthesis route to monosaccharide-containing pyrimidine derivatives was developed by combining the two types of catalytic activities of one enzyme in an organic medium, i.e., the Michael addition/acylation activities of zinc-dependent D -aminoacylase (DA) from Escherichia coli. First, the stepwise approach was investigated. DA showed higher activity towards the Michael addition than acylation in this reaction system. The enzymatic Michael additions of pyrimidines to vinyl acrylate proceeded very rapidly and the initial reaction rates for the Michael addition of pyrimidines to vinyl acrylate were 7.2,16.5,mM,min,1. The catalytic specificity of aminoacylases toward Michael addition was demonstrated by the combination of different control experiments. Then, the two steps could be performed in one pot and a single aminoacylase catalyzed one-pot biotransformation was constructed. Using this strategy, a series of saccharide-pyrimidine complexes with potentially biological and pharmacological applications was prepared efficiently. This high Michael addition activity of zinc-dependent aminoacylases and the novel single aminoacylase-catalyzed one-pot synthesis combining two catalytic activities in vitro is of practical significance in expanding the application of enzymes and in the evolution of new biocatalysts. [source] Fragmentation patterns of new esterified and unesterified aromatic 1-hydroxymethylene-1, 1-bisphosphonic acids by ESI-MSnJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 8 2008Julie Hardouin Abstract 1-Hydroxymethylene-1,1-bisphosphonic acids (HMBPs) are compounds that have interesting pharmacological applications. Unfortunately few studies exist on their analyses by mass spectrometry (MS). In this work, we have analyzed new aromatic HMBPs and their prodrugs with electrospray tandem mass spectrometry (ESI-MSn). We describe, for the first time, a complete study of fragmentation patterns, in both positive and negative-ion modes. In positive mode, the cation dissociations are mainly elimination of water and phosphorus fragments. In negative mode, losses of ROH (RH, C6H5, CH3OC6H5) and HPO2 were observed. The results have revealed specific structural fingerprints for the screening of these compounds in complex biological mixtures. Copyright © 2008 John Wiley & Sons, Ltd. [source] Therapeutic potential of sulfamides as enzyme inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 6 2006Jean-Yves Winum Abstract Sulfamide, a quite simple molecule incorporating the sulfonamide functionality, widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications, may give rise to at least five types of derivatives, by substituting one to four hydrogen atoms present in it, which show specific biological activities. Recently, some of these compounds started to be exploited for the design of many types of therapeutic agents. Among the enzymes for which sulfamide-based inhibitors were designed, are the carbonic anhydrases (CAs), a large number of proteases belonging to the aspartic protease (HIV-1 protease, ,-secretase), serine protease (elastase, chymase, tryptase, and thrombin among others), and metalloprotease (carboxypeptidase A (CPA) and matrix metalloproteinases (MMP)) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays important roles for the binding of the inhibitor to the active site cavity, either by directly coordinating to a metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors, interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HNSO2NH motif, which substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-chemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized moiety when attached to an organic scaffold. This interesting motif is thus of great value for the design of pharmacological agents with a lot of applications. © 2006 Wiley Periodicals, Inc. Med Res Rev [source] Study of bisphosphonates by matrix-assisted laser desorption/ionization mass spectrometry , influence of alkali atoms on fragmentation patternsRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 9 2009Erwann Guénin 1-Hydroxymethylene-1,1-bisphosphonic acids (or bisphosphonates) are compounds that have interesting pharmacological applications. However, few mass spectrometric investigations have been carried out to determine their fragmentation patterns. Herein, we evaluated different matrices for the study by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) of the formation and fragmentation of the protonated, the cationized (MNa+ and MK+) and the deprotonated bisphosphonates. Some in-source fragmentations were observed both in positive and in negative ion modes. The fragmentation patterns obtained in post-source decay mode are also discussed. In contrast to previous electrospray ionization/multi-stage mass spectrometry (ESI-MSn) studies, some new fragmentation pathways were deduced and the effects of alkali ions on the fragmentation patterns were shown. The results summarized here completed the data previously recorded by ESI-MSn and could be used for the characterization of bisphosphonates as alkali complexes in biological mixtures. Copyright © 2009 John Wiley & Sons, Ltd. [source] How to easily replace the independent atom model , the example of bergenin, a potential anti-HIV agent of traditional Asian medicineACTA CRYSTALLOGRAPHICA SECTION B, Issue 6 2009Birger Dittrich Bergenin, which has been isolated from a variety of tropical plants, has several pharmacological applications in traditional Asian medicine. Its electron-density distribution was obtained from a room-temperature low-resolution X-ray data set measured with point detection making use of multipole populations from the invariom library. Two refinement models were considered. In a first step, positional parameters and ADPs were refined with fixed library multipoles (model E1). This model was suitable to be input into a second refinement of multipoles (model E2), which converged smoothly although based on Cu,K, room-temperature data. Quantitative results of a topological analysis of the electron density from both models were compared with Hartree,Fock and density-functional calculations. With respect to the independent atom model (IAM) more information can be extracted from invariom modelling, including the electrostatic potential and hydrogen-bond energies, which are highly useful, especially for biologically active compounds. The reliability of the applied invariom formalism was assessed by a comparison of bond-topological properties of sucrose, for which high-resolution multipole and invariom densities were available. Since a conventional X-ray diffraction experiment using basic equipment was combined with the easy-to-use invariom formalism, the procedure described here for bergenin illustrates how it can be routinely applied in pharmacological research. [source] Structure of a highly stable mutant of human fibroblast growth factor 1ACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2009Anna Szlachcic Fibroblast growth factors (FGFs) are involved in diverse cellular processes such as cell migration, angiogenesis, osteogenesis, wound healing and embryonic and foetal development. Human acidic fibroblast growth factor (FGF-1) is the only member of the FGF family that binds with high affinity to all four FGF receptors and thus is considered to be the human mitogen with the broadest specificity. However, pharmacological applications of FGF-1 are limited owing to its low stability. It has previously been reported that the introduction of single mutations can significantly improve the stability of FGF-1 and its resistance to proteolytic degradation. Here, the structure of the Q40P/S47I/H93G triple mutant of FGF-1, which exhibits much higher stability, a prolonged half-life and enhanced mitogenic activity, is presented. Compared with the wild-type structure, three localized conformational changes in the stable triple mutant were observed, which is in agreement with the perfect energetic additivity of the single mutations described in a previous study. The huge change in FGF-1 stability (the denaturation temperature increased by 21.5,K, equivalent to ,,Gden = 24.3,kJ,mol,1) seems to result from the formation of a short 310 -helix (position 40), an improvement in the propensity of amino acids to form ,-sheets (position 47) and the rearrangement of a local hydrogen-bond network (positions 47 and 93). [source] Swertia (Gentianaceae): Chemical and Pharmacological AspectsCHEMISTRY & BIODIVERSITY, Issue 11 2004Goutam Brahmachari A compilation of the constituents isolated from Swertia species covering the literature up to December 2003 is presented. The botanical classification and ethno-pharmacology of Swertia plants, as well as the biological activities and pharmacological applications of both distinct phytochemicals and medicinally acitve plant materials (formulations, extracts, etc.) are discussed in detail. [source] | |||||||||||||||||||