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10.1097/01.MIB.0000437615.98881.31 http://scihub22266oqcxt.onion/10.1097/01.MIB.0000437615.98881.31 C4893808!4893808 !24280883     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24280883 &cmd=llinks): Failed to open stream: HTTP request failed! 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Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-?-induced fibrogenesis in human colonic myofibroblasts |pdf=|usr=}}{{24280883 }} gab.com Text Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF- -induced fibrogenesis in human colonic myofibroblasts JO: Inflamm Bowel Dis http://www.kidney.de/pget.php?&tw=1&pmid=24280883 #FOAvip BACKGROUND: Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil forming protein kinase signaling is a key pathway in multiple types of solid organ fibrosis, including intestinal fibrosis. However, the pleiotropic effects of RhoA/Rho-associated coiled-coil forming protein kinase signaling have frustrated targeted drug discovery efforts. Recent recognition of the role of Rho-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) suggest a novel locus for pharmacological intervention. METHODS: Because RhoA signaling is mediated by both physical and biochemical stimuli, we examined whether pharmacological inhibition of RhoA or the downstream transcription pathway of MRTF-A/SRF could block intestinal fibrogenesis in 2 in vitro models. RESULTS: In this study, we demonstrate that inhibition of RhoA signaling blocks both matrix-stiffness and transforming growth factor beta-induced fibrogenesis in human colonic myofibroblasts. Repression of alpha-smooth muscle actin and collagen expression was associated with the inhibition of MRTF-A nuclear localization. CCG-1423, a first-generation Rho/MRTF/SRF pathway inhibitor, repressed fibrogenesis in both models, yet has unacceptable cytotoxicity. Novel second-generation inhibitors (CCG-100602 and CCG-203971) repressed both matrix-stiffness and transforming growth factor beta-mediated fibrogenesis as determined by protein and gene expression in a dose-dependent manner. CONCLUSIONS: Targeting the Rho/MRTF/SRF mechanism with second-generation Rho/MRTF/SRF inhibitors may represent a novel approach to antifibrotic therapeutics. Twit Text FOAVip Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF- -induced fibrogenesis in human colonic myofibroblasts ????Inflamm Bowel Dis http://www.kidney.de/pget.php?&tw=1&pmid=24280883 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24280883 #FOAvip English Wikipedia <ref>{{Cite pmid|24280883 }}</ref> Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-?-induced fibrogenesis in human colonic myofibroblasts #MMPMID24280883 Johnson LA ; Rodansky ES ; Haak AJ ; Larsen SD ; Neubig RR ; Higgins PD Inflamm Bowel Dis 2014[Jan]; 20 (1 ): 154-65 PMID24280883 show ga BACKGROUND: Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil forming protein kinase signaling is a key pathway in multiple types of solid organ fibrosis, including intestinal fibrosis. However, the pleiotropic effects of RhoA/Rho-associated coiled-coil forming protein kinase signaling have frustrated targeted drug discovery efforts. Recent recognition of the role of Rho-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) suggest a novel locus for pharmacological intervention. METHODS: Because RhoA signaling is mediated by both physical and biochemical stimuli, we examined whether pharmacological inhibition of RhoA or the downstream transcription pathway of MRTF-A/SRF could block intestinal fibrogenesis in 2 in vitro models. RESULTS: In this study, we demonstrate that inhibition of RhoA signaling blocks both matrix-stiffness and transforming growth factor beta-induced fibrogenesis in human colonic myofibroblasts. Repression of alpha-smooth muscle actin and collagen expression was associated with the inhibition of MRTF-A nuclear localization. CCG-1423, a first-generation Rho/MRTF/SRF pathway inhibitor, repressed fibrogenesis in both models, yet has unacceptable cytotoxicity. Novel second-generation inhibitors (CCG-100602 and CCG-203971) repressed both matrix-stiffness and transforming growth factor beta-mediated fibrogenesis as determined by protein and gene expression in a dose-dependent manner. CONCLUSIONS: Targeting the Rho/MRTF/SRF mechanism with second-generation Rho/MRTF/SRF inhibitors may represent a novel approach to antifibrotic therapeutics. |Anilides/*pharmacology [MESH] |Benzamides/*pharmacology [MESH] |Blotting, Western [MESH] |Cell Adhesion/drug effects [MESH] |Cell Nucleus/drug effects/metabolism [MESH] |Cells, Cultured [MESH] |Colon/*drug effects/metabolism/pathology [MESH] |DNA-Binding Proteins/*antagonists & inhibitors/metabolism [MESH] |Extracellular Matrix/drug effects/metabolism [MESH] |Fibrosis/metabolism/pathology/*prevention & control [MESH] |Humans [MESH] |Myofibroblasts/*drug effects/metabolism/pathology [MESH] |Oncogene Proteins, Fusion/*antagonists & inhibitors/metabolism [MESH] |RNA, Messenger/genetics [MESH] |Real-Time Polymerase Chain Reaction [MESH] |Reverse Transcriptase Polymerase Chain Reaction [MESH] |Serum Response Factor/*antagonists & inhibitors/metabolism [MESH] |Signal Transduction/drug effects [MESH] |Trans-Activators [MESH] |Transforming Growth Factor beta/genetics/*metabolism [MESH]Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-?-induced(epmc).pdf DeepDyve Pubget Overpricing