Schisandrol B and schisandrin B inhibit TGFβ1-mediated NF-κB activation via a Smad-independent mechanism

Abstract

Aberrant transforming growth factor β1 (TGFβ1) signaling plays a pathogenic role in the development of vascular fibrosis. We have reported that Schisandra chinensis fruit extract (SCE), which has been used as a traditional oriental medicine, suppresses TGFβ1-mediated phenotypes in vascular smooth muscle cells (VSMCs). However, it is still largely unknown about the pharmacologic effects of SCE on various TGFβ1 signaling components. In this study, we found that SCE attenuated TGFβ1-induced NF-κB activation and nuclear translocation in VSMCs. Among the five active ingredients of SCE that were examined, schisandrol B (SolB) and schisandrin B (SchB) most potently suppressed TGFβ1-mediated NF-κB activation. In addition, SolB and SchB effectively inhibited IKKα/β activation and IκBα phosphorylation in TGFβ1-treated VSMCs. The pharmacologic effects of SolB and SchB on NF-κB activation were independent of the Smad-mediated canonical pathway. Therefore, our study demonstrates that SCE and its active constituents SolB and SchB suppress TGFβ1-mediated NF-κB signaling pathway in a Smad-independent mechanism. Our results may help further investigations to develop novel multi-targeted therapeutic strategies that treat or prevent vascular fibrotic diseases.

Polydatin prevents bleomycin‑induced pulmonary fibrosis by inhibiting the TGF‑β/Smad/ERK signaling pathway

“…These findings indicate the existence of other downstream receptors of TGF-β1 to regulate the process of fibrosis. This downstream signaling pathway is called the Smad-independent signaling pathway ( 72 ). The ERK/MAPK pathway is a Smad-independent signaling pathway.…”

Immunomodulatory effects of fermentedPlatycodon grandiflorumextract through NF-κB signaling in RAW 264.7 cells

“…Cells were co-transfected with 3×κB-Luc reporter gene plasmids [ 19 ] and pNL1.1.TK vector using FuGENE® HD Transfection Reagent (Promega). Twenty-four h after transfection, the cells were incubated with LPS (1 μg/mL) or FPGE (0, 20, 100, or 500 μg/mL).…”

Transcriptome Analysis of the Anti-TGFβ Effect of Schisandra chinensis Fruit Extract and Schisandrin B in A7r5 Vascular Smooth Muscle Cells

“…DNA microarray experiments were performed using total RNA from A7r5 cells, following treatment with 100 mg/mL SCE or 10 μM SchB for 24 h in the presence or absence of 1 ng/mL TGFβ1 (R&D Systems) as described in our previous papers [ 22 , 23 ]. SCE were prepared by ethanol extraction using ultrasonic bath and SchB was purified from SCE using the HPLC system as described previously [ 20 , 24 ].…”

“…Recently, accumulating evidence suggests that Schisandra chinensis fruit and its active ingredients have a potential role in the treatment of vascular fibrosis [ 19 ]. We have reported that Schisandra chinensis fruit extract (SCE) and its ingredient schisandrin B (SchB, Figure 1 b) have a potent anti-fibrotic activity by suppressing the TGFβ signaling pathways in VSMCs [ 20 , 21 , 22 ]. SCE and SchB block TGFβ-induced phosphorylation and nuclear translocation of the Smad complex, which decreases the expression of ECM proteins [ 20 ].…”

“…In addition, SCE and SchB inhibit the phosphorylation of myosin light chain in a Smad-independent manner, which leads to suppressing in actin stress fiber formation and cell migration [ 21 ]. Moreover, SCE and SchB attenuate TGFβ-mediated activation of IKKα/β, thereby inhibiting NF-κB activity [ 22 ]. However, little is known about how SCE and SchB affect the transcriptional output of the TGFβ signaling pathways.…”