Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation     

Valentina Sepe  Francesco Saverio Di Leva  Claudio D’Amore  Carmen Festa  Simona De Marino  Barbara Renga  Maria Valeria D’Auria  Ettore Novellino  Vittorio Limongelli  Lisette D’Souza  Mahesh Majik  Angela Zampella  Stefano Fiorucci 《Marine drugs》2014,12(6):3091-3115

In recent years many sterols with unusual structures and promising biological profiles have been identified from marine sources. Here we report the isolation of a series of 24-alkylated-hydroxysteroids from the soft coral Sinularia kavarattiensis, acting as pregnane X receptor (PXR) modulators. Starting from this scaffold a number of derivatives were prepared and evaluated for their ability to activate the PXR by assessing transactivation and quantifying gene expression. Our study reveals that ergost-5-en-3β-ol (4) induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target gene CYP3A4. To shed light on the molecular basis of the interaction between these ligands and PXR, we investigated, through docking simulations, the binding mechanism of the most potent compound of the series, 4, to the PXR. Our findings provide useful functional and structural information to guide further investigations and drug design.  相似文献   

Linking albinism and immunity: the secrets of secretory lysosomes   总被引：1，自引：0，他引：1  

Stinchcombe J  Bossi G  Griffiths GM 《Science (New York, N.Y.)》2004,305(5680):55-59

Lysosomes are membrane-bound organelles that are found in all mammalian cells and contain hydrolases and lipases required for protein and membrane degradation. In many cells of the immune system, lysosomes also contain secretory proteins that can be released by regulated exocytosis in response to an external stimulus, providing different cell types with a wide range of effector functions. Melanosomes also use a lysosome-related organelle to secrete melanin for pigmentation. Links between albinism and immunity in patients have uncovered a number of key proteins required for lysosomal secretion and have revealed a versatile secretory mechanism that can be fine-tuned by distinct interactions in different cell types.  相似文献