A fully dissociated compound of plant origin for inflammatory gene repression Export

@article{citeulike:6065822, abstract = {10.1073/pnas.0505554102 The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-\^{I}ºB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNF-induced proinflammatory gene expression, such as IL-6 and E-selectin, but, interestingly, does not at all enhance glucocorticoid response element-driven genes or induce GR binding to glucocorticoid response element-dependent genes . We further show that the specific gene-repressive effect of CpdA depends on the presence of functional GR, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the DNA-binding activity of p65 as well as an interference with the transactivation potential of NF-\^{I}ºB. Finally, we present evidence that CpdA is as effective as dexamethasone in counteracting acute inflammation and does not cause a hyperglycemic side effect. Taken together, this compound may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might thus hold great potential for therapeutic use.}, author = {De Bosscher, Karolien and Berghe, Wim V. and Beck, Ilse M. E. and Van Molle, Wim and Hennuyer, Nathalie and Hapgood, Janet and Libert, Claude and Staels, Bart and Louw, Ann and Haegeman, Guy}, citeulike-article-id = {6065822}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0505554102}, citeulike-linkout-1 = {http://www.pnas.org/content/102/44/15827.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/102/44/15827.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/16243974}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=16243974}, day = {1}, doi = {10.1073/pnas.0505554102}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {anti-gc, anti-inflam, plant\_origin}, month = {November}, number = {44}, pages = {15827--15832}, posted-at = {2009-11-04 00:45:28}, priority = {2}, title = {A fully dissociated compound of plant origin for inflammatory gene repression}, url = {http://dx.doi.org/10.1073/pnas.0505554102}, volume = {102}, year = {2005} }

TY - JOUR ID - citeulike:6065822 L3 - citeulike-article-id:6065822 N2 - 10.1073/pnas.0505554102 The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-κB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNF-induced proinflammatory gene expression, such as IL-6 and E-selectin, but, interestingly, does not at all enhance glucocorticoid response element-driven genes or induce GR binding to glucocorticoid response element-dependent genes . We further show that the specific gene-repressive effect of CpdA depends on the presence of functional GR, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the DNA-binding activity of p65 as well as an interference with the transactivation potential of NF-κB. Finally, we present evidence that CpdA is as effective as dexamethasone in counteracting acute inflammation and does not cause a hyperglycemic side effect. Taken together, this compound may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might thus hold great potential for therapeutic use. IS - 44 JF - Proceedings of the National Academy of Sciences of the United States of America EP - 15832 TI - A fully dissociated compound of plant origin for inflammatory gene repression VL - 102 SP - 15827 KW - anti-gc KW - anti-inflam KW - plant_origin AU - De Bosscher, Karolien AU - Berghe, Wim AU - Beck, Ilse AU - Van Molle, Wim AU - Hennuyer, Nathalie AU - Hapgood, Janet AU - Libert, Claude AU - Staels, Bart AU - Louw, Ann AU - Haegeman, Guy PY - 2005/11/01/ UR - http://dx.doi.org/10.1073/pnas.0505554102 ER -