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At least 1,783 records · Page 99Linked to original sources
PubMed2004

YM-254890 analogues, novel cyclic depsipeptides with Galpha(q/11) inhibitory activity from Chromobacterium sp. QS3666.

The structure elucidation and biological activity of novel YM-254890 (1) analogues and semi-synthetic derivatives are described. Three natural analogues, YM-254891 (2), YM-254892 (3), and YM-280193 (4), were isolated from the fermentation broth of Chromobacterium sp. QS3666, and two hydrogenated derivatives, YM-385780 (5) and YM-385781 (6), were synthesized from YM-254890. Their structures were determined by one- and two-dimensional NMR studies and mass spectrometry. Among these compounds, two natural analogues 2-3 which possessed acyl groups at beta-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Galpha(q/11) inhibitory activity to that of 1. This indicates that the acyl beta-HyLeu residue plays an important role in activity and also that the alpha,beta-unsaturated carbonyl group of the N-MeDha residue is not critical to activity. The other hydrogenated derivative 5 had significantly less activity, which could be attributed to conformational differences.

Adenosine Diphosphate↗
PubMed2005

Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.

Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 angstroms resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic "autoinhibited" or "tethered" inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation.

Antibodies, Monoclonal↗
PubMed2004

Bacterial subversion of lipid rafts.

Bacteria rely on numerous basic cellular functions of their target cells to reach successful infection. The recent discovery that the plasma membrane contains specialized microdomains, called lipid rafts, with many specific functions but in particular with the ability to concentrate signaling molecules, has therefore attracted the attention of cellular microbiologists. Since then an increasing number of bacteria and their products have been shown to interact with lipid rafts to promote infection or intoxication. Here we review why certain bacteria and/or their products are attracted toward these lipid microdomains.

Animals↗
PubMed2005

Asymmetric distribution of EGFR receptor during mitosis generates diverse CNS progenitor cells.

It has been debated whether asymmetric distribution of cell surface receptors during mitosis could generate asymmetric cell divisions by yielding daughters with different environmental responsiveness and, thus, different fates. We have found that in mouse embryonic forebrain ventricular and subventricular zones, the EGFR can distribute asymmetrically during mitosis in vivo and in vitro. This occurs during divisions yielding two Nestin+ progenitor cells, via an actin-dependent mechanism. The resulting sibling progenitor cells respond differently to EGFR ligand in terms of migration and proliferation. Moreover, they express different phenotypic markers: the EGFRhigh daughter usually has radial glial/astrocytic markers, while its EGFRlow sister lacks them, indicating fate divergence. Lineage trees of cultured cortical glioblasts reveal repeated EGFR asymmetric distribution, and asymmetric divisions underlie formation of oligodendrocytes and astrocytes in clones. These data suggest that asymmetric EGFR distribution contributes to forebrain development by creating progenitors with different proliferative, migratory, and differentiation responses to ligand.

Actins↗
PubMed2004

Activity of thrombocytes as a marker of sufficient intensity of LDL-apheresis in familial hypercholesterolaemia.

Extracorporal elimination is used for selective removal of LDL-cholesterol in severe hypercholesterolaemias. Tests are still going on to find more reliable markers which would sufficiently determine the intensity of the therapy immediately after completion of the procedure, in order to attenuate atherosclerosis activity. According to some literature data such a marker may be platelet aggregability. However, this marker carried out by standard methods has shown to be unreliable. The method was modified (by using various ADP dilutions for aggregation stimulation) and only then changes in aggregation could be observed immediately after completion of the procedure, namely, if there is a rapid drop in cholesterol concentration (of 6 mmol/l or more). Presently, this modification seems to be a suitable marker to determine the intensity of therapy.

Adenosine Diphosphate↗
PubMed1994

Analysis of receptor clustering on cell surfaces by imaging fluorescent particles.

Fluorescently labeled low density lipoproteins (LDL) and influenza virus particles were bound to the surface of human fibroblasts and imaged with a cooled slow-scan CCD camera attached to a fluorescence microscope. Particles were also imaged after attachment to polylysine-coated microscope slides. The digital images were analyzed by fitting data points in the region of fluorescent spots by a two-dimensional Gaussian function, thus obtaining a measure of spot intensity with correction for local background. The intensity distributions for particles bound to polylysine slides were mainly accounted for by particle size distributions as determined by electron microscopy. In the case of LDL, the intensity distributions for particles bound to fibroblasts were considerably broadened, indicative of clustering. The on-cell intensity distributions were deconvolved into 1-particle, 2-particle, 3-particle, etc. components using the data obtained with LDL bound to polylysine-coated slides as an empirical measure of the single particle intensity distribution. This procedure yielded a reasonably accurate measure of the proportion of single particles, but large errors were encountered in the proportions of larger cluster sizes. The possibility of studying the dynamics of clustering was investigated by binding LDL to cells at 4 degrees C and observing changes in the intensity distribution with time after warming to 20 degrees C.

Biophysical Phenomena↗
PubMed1995

Intracellular mediators regulate CD2 lateral diffusion and cytoplasmic Ca2+ mobilization upon CD2-mediated T cell activation.

CD2 is a T cell surface glycoprotein that participates in T cell adhesion and activation. These processes are dynamically interrelated, in that T cell activation regulates the strength of CD2-mediated T cell adhesion. The lateral redistribution of CD2 and its ligand CD58 (LFA-3) in T cell and target membranes, respectively, has also been shown to affect cellular adhesion strength. We have used the fluorescence photobleaching recovery technique to measure the lateral mobility of CD2 in plasma membranes of resting and activated Jurkat T leukemia cells. CD2-mediated T cell activation caused lateral immobilization of 90% of cell surface CD2 molecules. Depleting cells of cytoplasmic Ca2+, loading cells with dibutyric cAMP, and disrupting cellular microfilaments each partially reversed the effect of CD2-mediated activation on the lateral mobility of CD2. These intracellular mediators apparently influence the same signal transduction pathways, because the effects of the mediators on CD2 lateral mobility were not additive. In separate experiments, activation-associated cytoplasmic Ca2+ mobilization was found to require microfilament integrity and to be negatively regulated by cAMP. By directly or indirectly controlling CD2 lateral diffusion and cell surface distribution, cytoplasmic Ca2+ mobilization may have an important regulatory role in CD2 mediated T cell adhesion.

Actin Cytoskeleton↗
PubMed2002

E-selectin and ICAM-1 are incorporated into detergent-insoluble membrane domains following clustering in endothelial cells.

Here we present data supporting the role of lipid rafts in endothelial cells during leukocyte adhesion. Following adhesion of THP-1 cells or antibody-mediated clustering, both E-selectin and intercellular adhesion molecule-1 (ICAM-1) partitioned into the detergent-insoluble portion of the endothelial cellular lysate. Sucrose gradient centrifugation revealed the partitioning of clustered E-selectin and ICAM-1 with the low-density fraction where they co-fractionated with src family kinases, markers of lipid rafts. Depleting the plasma membrane of cholesterol inhibited clustering of adhesion molecules following their antibody-induced crosslinking and inhibited their association with src kinases. Thus, our data suggest that E-selectin and ICAM-1 associate with lipid rafts in human endothelial cells following leukocyte adhesion.

Antibodies↗
PubMed2000

Dependence of T cell activation on area of contact and density of a ligand-coated surface.

An apparatus which allows precise control of the time of initiation and the area of contact of cells with immobilized ligands has been developed. Cells are trapped in an asymmetric film that can be quantitatively thinned, forcing the cells into close contact with ligands adsorbed on the base of the apparatus. Using microbeads to indicate the film height, the amount of thinning can be controlled to within 1 microm, producing known contact areas between cells and the ligand-coated surface. This system was used with anti-CD3-coated surfaces of different densities to examine the effect of ligand density on T cell activation, while keeping the number of ligands presented to the cells constant. T cell activation was observed individually in each cell as intracellular calcium mobilization. In these experiments both the percent of T cell activation and the rate of calcium rise were found to depend only on the number of anti-CD3 molecules presented and not on their density. This implies that the spacing between molecules is not important in the range studied, and suggests that receptor clustering to levels higher than dimers may not be necessary for induction of calcium mobilization by anti-CD3.

Animals↗
PubMedDate not supplied

Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) alter peripheral handling of serotonin, leading to potential side effects. Further, the majority of the body's serotonin is found outside the central nervous system. Peripheral serotonin is important in platelet aggregation and the modulation of vascular tone. SSRIs block platelet uptake and pulmonary endothelial metabolism of serotonin, and use of these agents may conceivably result in bleeding and vasospastic complications.

Endothelium↗
PubMed2002

In vitro effect of a thrombin inhibition peptide selected by phage display technology.

A repeated selection of phages from a cyclic heptapeptide phage display library resulted in the enrichment of phages that bind to human alpha-thrombin. One clone of the binding phages that competed with PPACK for binding to thrombin and that had the best binding characteristics was chosen. The amino acid sequence of the peptide displayed on this phage was determined and a peptide with the sequence, Cys-Asn-Arg-Pro-Phe-Ile-Pro-Thr-Cys was synthesised. This peptide, thrombin-inhibiting peptide (TIP), is a full competitive inhibitor of thrombin with an inhibition constant (K(i)) of 0.4974 mM. It lengthened the thrombin time and inhibited thrombin-induced platelet activation and the platelet release reaction, both in a dose-dependent manner. It also reduced platelet adhesion onto a human microvascular endothelial matrix in the parallel plate flow chamber under both arterial and venous shear conditions. Thus, we have selected and synthesised a cyclic heptapeptide that competes with PPACK to bind to thrombin and that can be developed as a direct antithrombin.

Bacteriophages↗