Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats

Abstract

AIMTo explore the exact interaction between Notch and transforming growth factor (TGF)-β signaling in liver fibrosis.METHODSWe established a rat model of liver fibrosis induced by concanavalin A. Peripheral blood mononuclear cells (PBMCs) were isolated from the modeled rats, and cultured with γ-secretase inhibitor DAPT and TGF-β inhibitor for 24 h. The mRNA levels of Notch and TGF-β signaling were detected by quantitative real-time polymerase chain reaction. Expression of Notch and TGF-β proteins was analyzed by western blotting.RESULTSCompared to control rats, Notch and TGF-β signaling was activated in PBMCs of model rats. Administration of DAPT and TGF-β inhibitor suppressed Notch and TGF-β signal transducer in PBMCs of model rats. DAPT reduced mRNA and protein expression of TGF-β signaling, such as TGF-β1 and Smad3. TGF-β inhibitor also downregulated Notch1, Hes1 and Hes5, and mRNA and protein expression of the Notch signaling pathway.CONCLUSIONNotch and TGF-β signaling play a role in liver fibrosis. TGF-β signaling upregulates Notch signaling, which promotes TGF-β signaling.

Epidermal Stem Cells in Wound Healing and Regeneration

“…The Notch receptor must be hydrolyzed and cleaved by the protease γ-secretase to release the intracellular domain, thereby activating the signaling pathway. 4,6-diamidino-2-phenylindoleindole (DAPT), as a blocker of the Notch signaling pathway, can specifically block the action of γ-secretase, thereby preventing the activation of Notch [73].…”

Widespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf

“…Half of the cranial nerve genes identified were also functionally annotated as participating in or being responsive to TGF beta/BMP signaling (Fig. 3C), including Gdf6; Hes1, a key Notch signaling gene down-regulated by TGF beta inhibitors; and Phox2b, which encodes a TGF beta-regulated transcription factor that acts as a "switch" between sensory and visceral neuron identities and influences their physical position within cranial sensory pathways (D'Autreaux et al 2011;Dias et al 2014;Wang et al 2017).…”

Class�C1 decoy oligodeoxynucleotide inhibits profibrotic genes expression in rat hepatic stellate cells

“…It is broadly accepted that TGF-β1 canonical signaling, also known as the TGF-β1/SMADs signaling pathway, is crucial for the occurrence and progression of hepatic fibrosis, whereas non-canonical signaling, which is associated with multiple different pathways, such as MaPK, Pi3K-aKT and Wnt, also contributes to the activation of HScs and liver fibrosis (7,8). Several previous studies have revealed the existence of crosstalk between Notch and TGF-β signaling in the activation of HScs, and the notch downstream TF HES1 plays an important role in this crosstalk (9)(10)(11)(12)(13). Thus, blocking the signal transduction of TGF-β1 or regulating the effect of SMads on the expression of target genes in order to decrease ecM synthesis and increase ecM degradation may be a promising approach to reversing hepatic fibrosis.…”

“…Recent studies have reported the role of Notch signaling in hepatic fibrosis and the crosstalk between notch and TGF-β signaling. There is evidence that the expression of major components of the notch signaling pathway, including notch3, Jagged1 and the downstream transcription factor (TF) Hairy and enhancer of Split 1 (HeS1), is induced by TGF-β canonical signaling via SMADs (9,10). another study reported that notch signaling also contributes Class C1 decoy oligodeoxynucleotide inhibits profibrotic genes expression in rat hepatic stellate cells to TGF-β-induced expression of a-SMa and coli and, when inhibited, a-SMA and COLI expression decreased (11).…”