| First Author | Di Gregorio J | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 2 | Pages | e0171093 |
| PubMed ID | 28207769 | Mgi Jnum | J:245624 |
| Mgi Id | MGI:5916118 | Doi | 10.1371/journal.pone.0171093 |
| Citation | Di Gregorio J, et al. (2017) Role of glycogen synthase kinase-3beta and PPAR-gamma on epithelial-to-mesenchymal transition in DSS-induced colorectal fibrosis. PLoS One 12(2):e0171093 |
| abstractText | BACKGROUND: Intestinal fibrosis is characterized by abnormal production and deposition of extracellular matrix (ECM) proteins by activated myofibroblasts. The main progenitor cells of activated myofibroblasts are the fibroblasts and the epithelial cells, the latter through the epithelial-mesenchymal transition (EMT). AIM: To evaluate the action of the new PPAR-gamma modulator, GED-0507-34 Levo (GED) on the expression of EMT associated and regulatory proteins such as TGF-beta, Smad3, E-cadherin, Snail, ZEB1, beta-catenin, and GSK-3beta, in a mouse model of DSS-induced intestinal fibrosis. METHODS: Chronic colitis and fibrosis were induced by oral administration of 2.5% DSS (w/v) for 6 weeks. GW9662 (GW), a selective PPAR-gamma inhibitor, was also administered by intraperitoneal injection at the dose of 1 mg/kg/day combined with GED treatment. All drugs were administered at the beginning of the second cycle of DSS (day 12). 65 mice were randomly divided into five groups (H2O as controls n = 10, H2O+GED n = 10, DSS n = 15, DSS+GED n = 15, DSS+GED+GW n = 15). The colon was excised for macroscopic examination and histological and morphometric analyses. The level of expression of molecules involved in EMT and fibrosis, like TGF-beta, Smad3, E-cadherin, Snail, ZEB1, beta-catenin, GSK-3beta and PPAR-gamma, was assessed by immunohistochemistry, immunofluorescence, western blot and Real Time PCR. RESULTS: GED improved the DSS-induced chronic colitis and fibrosis. GED was able to reduce the expression of the main fibrosis markers (alpha-SMA, collagen I-III and fibronectin) as well as the pivotal pro-fibrotic molecules IL-13, TGF-beta and Smad3, while it increased the anti-fibrotic PPAR-gamma. All these GED effects were nullified by co-administration of GW with GED. Furthermore, GED was able to normalize the expression levels of E-cadherin and beta-catenin and upregulated GSK-3beta, that are all known to be involved both in EMT and fibrosis. CONCLUSIONS: The DSS-induced intestinal fibrosis was improved by the new PPAR-gamma modulator GED-0507-34 Levo through the modulation of EMT mediators and pro-fibrotic molecules and through GSK-3beta induction. |
