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Direct Interference (direct + interference)
Selected AbstractsDiscovery of novel mechanisms and molecular targets for the inhibition of activated thrombin activatable fibrinolysis inhibitorJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2008K. HILLMAYER Summary.,Background:,Thrombin activatable fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis and an attractive target to develop profibrinolytic drugs. Objective:,To analyze the (inhibitory) properties of five monoclonal antibodies (mAbs) directed towards rat TAFI (i.e. MA-RT13B2, MA-RT30D8, MA-RT36A3F5, MA-RT36B2 and MA-RT82F12). Methods and results:,Direct interference of the mAb with rat activated TAFI (TAFIa) activity was assayed using a chromogenic activity assay. This revealed reductions of 79% ± 1%, 54% ± 4%, and 19% ± 2% in activity in the presence of a 16-fold molar excess of MA-RT13B2, MA-RT36A3F5, and MA-RT82F12, respectively whereas MA-RT30D8 and MA-RT36B2 had no direct inhibitory effect. Additionally, MA-RT13B2 and MA-RT36A3F5 reduced rat TAFIa half-life by 56% ± 2% and 61% ± 3%. Tissue-type plasminogen activator mediated in vitro clot lysis was determined using rat plasma. Compared to potato tuber carboxypeptidase inhibitor, MA-RT13B2, MA-RT30D8, MA-RT36A3F5, and MA-RT82F12 reduced clot lysis times by 86% ± 14%, 100% ± 5%, 100% ± 10%, and 100% ± 11%, respectively. During epitope mapping, Arg227 and Ser251 were identified as major residues interacting with MA-RT13B2. Arg188 and His192 contribute to the interaction with MA-RT36A3F5. Arg227, Ser249, Ser251, and Tyr260 are involved in the binding of MA-RT30D8 and MA-RT82F12 with rat TAFI(a). The following mechanisms of inhibition have been deduced: MA-RT13B2 and MA-RT36A3F5 have a destabilizing effect on rat TAFIa whereas MA-RT30D8 and MA-RT82F12 partially block the access to the active site of TAFIa or interact with the binding of TAFIa to the blood clot. Conclusions:,The described inhibitory mAb towards rat TAFIa will facilitate TAFI research in murine models. Additionally, we reveal novel molecular targets for the direct inhibition of TAFIa through different mechanisms. [source] Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Sascha Rutz Abstract The Notch pathway is involved in cell differentiation processes in various organs and at several developmental stages. The importance of Notch for early T lymphocyte development is well established. Recently, Notch has been implicated in directing naive T helper cell differentiation towards the Th1, Th2 or regulatory T cell lineages. However, the molecular events underlying these processes are poorly understood. We show that the Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jagged1 induce a dose-dependent inhibition of early activation markers CD69 and CD25, as well as inhibition of proliferation after anti-CD3 stimulation of purified CD4+ T cells. Similarly, the rapid activation of transcription factors NF-AT, AP-1 and NF-,B is suppressed. In contrast, triggering of Notch by Delta-like4 enhances T cell activation and proliferation. The observed effects are dependent on simultaneous cross-linking of TCR and Notch but independent of ,-secretase-mediated cleavage of Notch. These data suggest direct interference between Notch and early TCR signal transduction events, independent of the classical Notch pathway via release of the Notch intracellular domain. A Notch-mediated alteration of TCR signaling strength may contribute to the recently described modulation of naïve T cell differentiation by Notch ligands. [source] Exploring the link between microorganisms and oral cancer: A systematic review of the literatureHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2009Samuel J. Hooper PhD Abstract The majority of cases of oral cancer have been related to tobacco use and heavy alcohol consumption. However, the incidence of oral cavity carcinoma appears to be increasing in many parts of the world in a manner that it is difficult to explain with traditional risk factors alone. Meanwhile, interest in the possible relationships between microorganisms and the different stages of cancer development has been rising and numerous mechanisms by which bacteria and yeast may initiate or promote carcinogenesis are currently under investigation. In particular, a persuasive body of evidence suggests a possible etiological role involving the metabolism and production of carcinogenic products, such as acetaldehyde. Other suggested mechanisms include the induction of chronic inflammation and direct interference with eukaryotic cell cycle and signaling pathways. This review aims to summarize the known associations between microbial infection and cancer and draw attention to how they may relate to oral carcinoma. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [source] Hepatitis B and C virus coinfection: A novel model system reveals the absence of direct viral interference,HEPATOLOGY, Issue 1 2009Pantxika Bellecave Coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) has been associated with severe liver disease and frequent progression to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests reciprocal replicative suppression of the two viruses, or viral interference. However, interactions between HBV and HCV have been difficult to study due to the lack of appropriate model systems. We have established a novel model system to investigate interactions between HBV and HCV. Stable Huh-7 cell lines inducibly replicating HBV were transfected with selectable HCV replicons or infected with cell culture,derived HCV. In this system, both viruses were found to replicate in the same cell without overt interference. Specific inhibition of one virus did not affect the replication and gene expression of the other. Furthermore, cells harboring replicating HBV could be infected with cell culture,derived HCV, arguing against superinfection exclusion. Finally, cells harboring replicating HBV supported efficient production of infectious HCV. Conclusion: HBV and HCV can replicate in the same cell without evidence for direct interference in vitro. Therefore, the viral interference observed in coinfected patients is probably due to indirect mechanisms mediated by innate and/or adaptive host immune responses. These findings provide new insights into the pathogenesis of HBV,HCV coinfection and may contribute to its clinical management in the future. (HEPATOLOGY 2009.) [source] Bias-free results in the spectrophotometric determination of chemical oxygen demand in bleached textile mill effluentsJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 9 2002Francesc Torrades Abstract A calibration methodology that enables validation of the analytical procedure used in those cases where no placebo or standard reference material is available is applied here. The total Youden blank is used to eliminate the constant error component, and analytical measurements in the presence of the matrix at two different levels of the test portion, in order to avoid its interactive interference, are made. Moreover, the results obtained in the determination of chemical oxygen demand following a closed reflux spectrophotometric method are compared with those obtained when a definitive analytical method is applied, in order to show the absence of direct interference from the matrix. © 2002 Society of Chemical Industry [source] How does acantholysis occur in pemphigus vulgaris: a critical reviewJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2006Alessandro Lanza Background:, Pemphigus vulgaris is a life-threatening autoimmune blistering disease targeting skin and mucous membranes, characterized by disruption of keratinocytes' adhesion termed acantholysis. Today multiple classes of targets are considered to play a role in the genesis of the acantholysis; of these, the classical pemphigus antigens, desmosomal cadherins (desmoglein 1 and 3) are the best characterized and considered as the most important. Additional antigens include the novel epithelial acetylcholine receptors (,9 and pemphaxin). Thus, acantholysis in pemphigus seems to result from a cooperative action of antibodies to different keratinocyte self-antigens, but the mechanisms by which epithelial cleft occurs are not yet clearly understood. In fact, the binding of the autoantibodies to these targets generates a plethora of biological effects due, on one hand, to their direct interference with adhesive function and, on the other, to more complex events involving intracellular pathways that modify proteases activity or calcium metabolism, leading to loss of cell,cell adhesion. [source] Soluble nickel inhibits HIF-prolyl-hydroxylases creating persistent hypoxic signaling in A549 cellsMOLECULAR CARCINOGENESIS, Issue 7 2006Todd L. Davidson Abstract Soluble nickel compounds are carcinogenic to humans although the mechanism by which they cause cancer remains unclear. One major consequence of exposure to nickel is the stabilization of hypoxia inducible factor-1, (HIF-1,), a protein known to be overexpressed in a variety of cancers. In this study, we report a persistent stabilization of HIF-1, by nickel chloride up to 72 h after the removal of nickel from the culture media. In addition, we show that the HIF-prolyl hydroxylases (PHD's) are inhibited when cells are exposed to nickel and that they remain repressed for up to 72 h after nickel is removed. We then show that nickel can inhibit purified HIF-PHD's 2 in vitro, through direct interference with the enzyme. Through theoretical calculations, we also demonstrate that nickel may be able to replace the iron in the active site of this enzyme, providing a plausible mechanism for the persistent inhibition of HIF-PHD's by nickel. The data presented suggest that nickel can interfere with HIF-PHD directly and does not inhibit the enzyme by simply depleting cellular factors, such as iron or ascorbic acid. Understanding the mechanisms by which nickel can inhibit HIF-PHD's and stabilize HIF-1, may be important in the treatment of cancer and ischemic diseases. © 2006 Wiley-Liss, Inc. [source] | ||||||||||