期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 394, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2020.114956
关键词
DPP-IV; PI3K/Akt (PKB) axis; E-cadherin; beta-catenin; Vimentin; EMT
Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3 beta, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-kappa B, TNF-alpha, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zebl and pY654-beta-catenin but increased E-cadherin, NPSH and colon/spleen indices - effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.
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