Chembiochem : a European journal of chemical biology
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The C22 and C26 trehalose monoesters, each containing a single acyl chain, were synthesised in good overall yields and found to activate macrophages in a Mincle-dependent manner. The activities of the monoesters paralleled those of their diester counterparts, and both mono- and diesters could activate the immune response in the absence of priming. This is the first time that trehalose monoesters have been found to activate macrophages, and these studies thus provide an important framework for the rational design of other Mincle agonists.
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Myo-inositol trispyrophosphate (ITPP), a synthetic allosteric effector of hemoglobin, increases the regulated oxygen-releasing capacity of red blood cells (RBCs), leading to suppression of hypoxia-inducible factor 1α (HIF-1α) and to down-regulation of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF). As a consequence, tumor growth is markedly affected. The effect of weekly intravenous injection of ITPP on an orthotopic, syngenic rat hepatocellular carcinoma (HCC) model was compared to that for untreated animals and animals subjected to conventional Doxorubicin chemotherapy. ⋯ Under these conditions, HIF-1α activity was strongly decreased, VEGF expression was down-regulated, and apoptosis was induced in HCC and surrounding liver cells, as indicated by Caspase-3 expression. ITPP did not affect hematologic parameters during treatment. The observations of in vivo tumor eradication suggest a significant clinical potential for ITPP in cancer therapy.
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The compartmentalization of kinases and phosphatases plays an important role in the specificity of second-messenger-mediated signaling events. Localization of the cAMP-dependent protein kinase is mediated by interaction of its regulatory subunit (PKA-R) with the versatile family of A-kinase-anchoring proteins (AKAPs). Most AKAPs bind avidly to PKA-RII, while some have dual specificity for both PKA-RI and PKA-RII; however, no mammalian PKA-RI-specific AKAPs have thus far been assigned. ⋯ Immunolocalization studies revealed that recombinant SPHKAP is expressed in the cytoplasm, where PKA-RIalpha also mainly resides. Alignment of SPHKAPs' amphipathic helix with peptide models of PKA-RI- or PKA-RII-specific anchoring domains shows that it has largely only PKA-RIalpha characteristics. Being the first mammalian PKA-RI-specific AKAP with cytosolic localization, SPHKAP is a very promising model for studying the function of the less explored cytosolic PKA-RI signaling nodes.
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Three types of opioid receptors-mu, delta, and kappa-belong to the rhodopsin subfamily in the G protein-coupled receptor superfamily. With the recent characterization of the high-resolution X-ray crystal structure of bovine rhodopsin, considerable attention has been focused on molecular modeling of these transmembrane proteins. In this study, a homology model of the mu opioid receptor was constructed based on the X-ray crystal structure of bovine rhodopsin. ⋯ The opioid ligand naltrexone was docked into the optimized model, and the critical amino acid residues for binding were identified. The mu opioid receptor homology model optimized in a complete membrane-aqueous system should provide a good starting point for further characterization of the binding modes for opioid ligands. Furthermore, the method developed herein will be applicable to molecular model building to other opioid receptors as well as other GPCRs.