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2017 ; 12
(2
): e0171093
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Role of glycogen synthase kinase-3? and PPAR-? on epithelial-to-mesenchymal
transition in DSS-induced colorectal fibrosis
#MMPMID28207769
Di Gregorio J
; Sferra R
; Speca S
; Vetuschi A
; Dubuquoy C
; Desreumaux P
; Pompili S
; Cristiano L
; Gaudio E
; Flati V
; Latella G
PLoS One
2017[]; 12
(2
): e0171093
PMID28207769
show ga
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-? modulator, GED-0507-34 Levo (GED)
on the expression of EMT associated and regulatory proteins such as TGF-?, Smad3,
E-cadherin, Snail, ZEB1, ?-catenin, and GSK-3?, 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-?
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-?, Smad3, E-cadherin, Snail, ZEB1,
?-catenin, GSK-3? and PPAR-?, 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 (?-SMA, collagen I-III and fibronectin) as well as
the pivotal pro-fibrotic molecules IL-13, TGF-? and Smad3, while it increased the
anti-fibrotic PPAR-?. 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 ?-catenin and upregulated GSK-3?, that are all known to be
involved both in EMT and fibrosis. CONCLUSIONS: The DSS-induced intestinal
fibrosis was improved by the new PPAR-? modulator GED-0507-34 Levo through the
modulation of EMT mediators and pro-fibrotic molecules and through GSK-3?
induction.
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