Ion-Pairing Assemblies of Anion-Responsive π-Electronic Systems Bearing Triazole Moieties Introduced by Click Chemistry.

In this study, the diverse derivatives of dipyrrolyldiketone boron complexes as anion-responsive π-electronic systems were synthesized via the Huisgen cycloaddition of an ethynyl-substituted anion receptor and azide derivatives. The obtained triazole-substituted anion receptors showed effective anion-binding behaviors and ion-pairing assemblies comprising receptor-anion complexes and countercations. Solid-state ion-pairing structures were modulated according to the introduced azide moieties along with coexisting bulky and π-electronic cations.

Flavonoids that mimic human ligands from the whole plants of Euphorbia lunulata.

In our investigation of a cell proliferation-based screening assay using human ligand-dependent cell lines for medicinal herbal extracts, the acetone extract of the whole plants of Euphorbia lunulata (EL) was observed for its proliferation activity for insulin- and interleukin-10 (IL-10)-dependent cell lines. Fractionation of the active extract led to the isolation of one new flavonoid galactoside, quercetin 3-O-(2'',3''-digalloyl)-beta-D-galactopyranoside (1), and four known ones, quercetin 3-O-(2''-galloyl)-beta-D-galactopyranoside (2), hyperin (3), quercetin (4), and gallic acid (5). Compounds 1 and 2 showed insulin-like activity. Compounds 4 and 5 showed IL-10-like activity. This is the first report of these activities of EL, and 1 and 2 will become the seed compounds for the development of a nonpeptidyl insulin substitutional medicine. Compounds 4 and 5 support the pharmacological use of EL, which has been employed as an herbal medicine for the treatment of bronchial asthma.

CIN85 associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosis.

CIN85 is a multidomain protein that associates with receptors carrying tyrosine kinase domains. Here we report that it is also a component of the signaling complex associated with tumor necrosis factor receptor 1 (TNFR1), which lacks a tyrosine kinase domain. This was established by showing that CIN85 was co-precipitated with TNFR1, TRADD, cIAP-1 and TARF1/2, but not with FADD, RIP, caspase-8 or TRAF6. However, CIN85 did not bind directly to the cytoplasmic domain of TNFR1 (TNFR1-CYT) but to Src family kinases, Cbl and the p85alpha subunit of phosphatidylinositol 3-kinase (PI3-K p85alpha). Src bound directly to TNFR1-CYT, but Cbl and PI3-K p85alpha did not. A human cell line ectopically expressing CIN85 was 10 times more susceptible to TNF-alpha-induced apoptosis than control cells, which expressed identical levels of TNFR1 on their surface. However, the susceptibility of these two cell lines to CD95-induced apoptosis was the same. The three SH3 domains of CIN85 were essential for this increased susceptibility to apoptosis and its proline-rich regions were also required for maximal effect. TNF-alpha treatment recruited CIN85 to the TNFR1 signaling complex. Taken together, these results indicate that CIN85 associates with TNFR1 via Src and modulates TNF-alpha-induced apoptosis.

A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor.

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation of bone marrow granulocytic progenitor cells and promotes their differentiation into granulocytes. G-CSF is therefore an important component of immune defense against pathogenic microorganisms: recombinant human G-CSF (rhG-CSF) is used to treat patients with a variety of neutropenias. In the present study, we screened approximately 10 000 small nonpeptidyl compounds and found 3 small compounds that mimic G-CSF in several in vitro and in vivo assays. These compounds induced G-CSF-dependent proliferation, but had no effect on interleukin-3-dependent, interleukin-2-dependent, interleukin-10-dependent, thrombopoietin (TPO)-dependent, or erythropoietin (EPO)-dependent proliferation. Each compound induced the phosphorylation of signal transducers and activators of transcription-3 (STAT3) and mitogen-activated protein kinase (MAPK) in a G-CSF-dependent cell line and in human neutrophils. In addition, these compounds induced hematopoietic colony formation from primary rat bone marrow cells in vitro. When subcutaneously injected into normal rats, they caused an increase in peripheral blood neutrophil counts. Furthermore, when they were administered to cyclophosphamide-induced neutropenic rats, blood neutrophil levels increased and remained elevated up to day 8. We therefore suggest that these small nonpeptidyl compounds mimic the activity of G-CSF and may be useful in the treatment of neutropenic patients.