Inhibition of interleukin-6 signaling by galiellalactone.

A search for inhibitors of the IL-6-mediated signal transduction in HepG2 cells using secreted alkaline phosphatase (SEAP) as reporter gene resulted in the isolation of galiellalactone (1) from fermentations of the ascomycete strain A111-95. Galiellalactone inhibits the IL-6-induced SEAP expression with IC(50) values of 250-500 nM by blocking the binding of the activated Stat3 dimers to their DNA binding sites without inhibiting the tyrosine and serine phosphorylation of the Stat3 transcription factor. Due to its selective activity, galiellalactone may serve as a lead compound for the development of new therapeutic agents for diseases originating from the inappropriate expression of IL-6 and as molecular tool to dissect the JAK/STAT pathways.

Inhibition of interleukin-6 signaling and Stat3 activation by a new class of bioactive cyclopentenone derivatives.

The IL-6-dependent activation of the JAK/STAT pathway plays a central role in the induction of the acute phase response in the liver. In a search for new inhibitors of the IL-6-mediated signal transduction in HepG2 cells using secreted alkaline phosphatase (SEAP) as reporter gene, four novel cyclopentenones, 2-(1-chloropropenyl)-4,5-dihydroxycyclopent-2-enone (CPDHC, 1), 4, 5-dihydroxy-2-propenylcyclopent-2-enone (DHPC, 2), 5-hydroxy-2, 3-dimethylcyclopent-2-enone (HDC, 3), and 4-methyl-5-methylenecyclopent-3-en-1,2-diol (MMCD, 4) were isolated from fermentations of the ascomycete strain A23-98. CPDHC (1) inhibits the IL-6-induced SEAP expression with IC(50) values of 4.

Structure of the cytoplasmic domain of p23 in solution: implications for the formation of COPI vesicles.

Coatomer, the coat protein complex of coat protein (COPI) vesicles, is involved in the budding of these vesicles. Its interaction with the cytoplasmic domains of some p24-family members, type I transmembrane proteins of the Golgi, has been shown to induce a conformational change of coatomer that initiates polymerization of the complex. From stoichiometrical data it is likely that interaction of coatomer with the small tail domains involves an oligomeric form of the p24 proteins.

The structure of human parathyroid hormone-related protein(1-34) in near-physiological solution.

Parathyroid hormone-related protein plays a major role in the pathogenesis of humoral hypercalcemia of malignancy. Under normal physiological conditions, parathyroid hormone-related protein is produced in a wide variety of tissues and acts in an autocrine or paracrine fashion. Parathyroid hormone-related protein and parathyroid hormone bind to and activate the same G-protein-coupled receptor.