scholarly journals Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin

2018 ◽  
Vol 51 (6) ◽  
pp. 2794-2813 ◽  
Author(s):  
Manshu Yu ◽  
Jun Shi ◽  
Meixiao Sheng ◽  
Kun Gao ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Mesothelial Cells ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Gsk 3Β ◽  
Canonical Wnt

Background/Aims: The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a crucial event in the induction of peritoneal fibrosis (PF), in which canonical Wnt/β-catenin signaling participates. Smads signaling is reported to interact with β-catenin and synergistically regulates EMT. This study was aimed to reveal the effect of Astragalus on β-catenin in EMT of PMCs. Methods: To obtain the role of β-catenin in EMT, gene transfer into HMrSV5 cell line and rats has been achieved. After Astragalus treatment, EMT markers and signaling pathway-related indicators were detected by western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation and real time-PCR. Results: β-catenin knockdown suppressed EMT of HMrSV5 cells. Astragalus alleviated EMT of PMCs characterized by increased E-cadherin and decreased α-SMA and Vimentin. In rat model of peritoneal dialysis (PD), Astragalus attenuated peritoneal thickening and fibrosis. Astragalus down-regulated β-catenin by stabilizing the Glycogen synthase kinase-3β (GSK-3β)/β-catenin complex and further inhibited the nuclear translocation of β-catenin. Meanwhile, Astragalus down-regulated β-catenin by enhancing Smad7 expression. Silencing Smad7 antagonized the EMT-inhibitory effect of Astragalus. Conclusion: Astragalus inhibits EMT of PMCs by down-regulating β-catenin. The modulation of β-catenin in peritoneum can be a novel tool to prevent PF.

scholarly journals Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3β/β-catenin axis activation

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Pengpeng Yan ◽  
Huanna Tang ◽  
Xiaoying Chen ◽  
Shuiyu Ji ◽  
Wei Jin ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Glycogen Synthase ◽  
Protective Effects ◽  
Peritoneal Fibrosis ◽  
Snail Expression ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Gsk 3Β ◽  
Metalloproteinase 9

Peritoneal fibrosis is a severe complication arising from long-term peritoneal dialysis (PD). Tamoxifen (Tamo) has been clinically proven effective in a series of fibrotic diseases, such as PD-associated encapsulating peritoneal sclerosis (EPS), but the mechanisms underlying Tamoxifen’s protective effects are yet to be defined. In the present study, C57BL/6 mice received intraperitoneal injections of either saline, 4.25% high glucose (HG) PD fluid (PDF) or PDF plus Tamoxifen each day for 30 days. Tamoxifen attenuated thickening of the peritoneum, and reversed PDF-induced peritoneal expression of E-cadherin, Vimentin, matrix metalloproteinase 9 (MMP9), Snail, and β-catenin. Mouse peritoneal mesothelial cells (mPMCs) were cultured in 4.25% glucose or 4.25% glucose plus Tamoxifen for 48 h. Tamoxifen inhibited epithelial-to-mesenchymal transition (EMT) as well as phosphorylation of glycogen synthase kinase-3β (GSK-3β), nuclear β-catenin, and Snail induced by exposure to HG. TWS119 reversed the effects of Tamoxifen on β-catenin and Snail expression. In conclusion, Tamoxifen significantly attenuated EMT during peritoneal epithelial fibrosis, in part by inhibiting GSK-3β/β-catenin activation.

scholarly journals TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 839
Author(s):  
Jung-Yoon Heo ◽  
Jun-Young Do ◽  
Yunmee Lho ◽  
A-Young Kim ◽  
Sang-Woon Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Peritoneal Fibrosis ◽  
Membrane Function ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Emt Markers ◽  
Tgf Β1

We investigated the effect of SB525334 (TGF-β receptor type 1 (TβRI) inhibitor) on the epithelial to mesenchymal transition (EMT) signaling pathway in human peritoneal mesothelial cells (HPMCs) and a peritoneal fibrosis mouse model. In vitro experiments were performed using HPMCs. HPMCs were treated with TGF-β1 and/or SB525334. In vivo experiments were conducted with male C57/BL6 mice. The 0.1% chlorhexidine gluconate (CG) was intraperitoneally injected with or without SB52534 administration by oral gavage. Mice were euthanized after 28 days. EMT using TGF-β1-treated HPMCs included morphological changes, cell migration and invasion, EMT markers and collagen synthesis. These pathological changes were reversed by co-treatment with SB525334. CG injection was associated with an increase in peritoneal fibrosis and thickness, which functionally resulted in an increase in the glucose absorption via peritoneum. Co-treatment with SB525334 attenuated these changes. The levels of EMT protein markers and immunohistochemical staining for fibrosis showed similar trends. Immunofluorescence staining for EMT markers showed induction of transformed cells with both epithelial and mesenchymal cell markers, which decreased upon co-treatment with SB525334. SB525334 effectively attenuated the TGF-β1-induced EMT in HPMCs. Cotreatment with SB525334 improved peritoneal thickness and fibrosis and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

scholarly journals Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4739
Author(s):  
Yunmee Lho ◽  
Jun-Young Do ◽  
Jung-Yoon Heo ◽  
A-Young Kim ◽  
Sang-Woon Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Β Receptor ◽  
Receptor Inhibitor

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

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