Tetramethylpyrazine reduces glucose and insulin-induced activation of hepatic stellate cells by inhibiting insulin receptor-mediated PI3K/AKT and ERK pathways.

Hepatic stellate cell (HSC) activation is the central event during liver fibrogenesis. Metabolic syndrome characterized by hyperglycemia and hyperinsulinemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of tetramethylpyrazine (TMP) on HSC activation induced by glucose and insulin (Glu/Ins) and the underlying mechanisms. Results showed that Glu/Ins significantly stimulated proliferation, invasion, adhesion, and extracellular matrix (ECM) production in HSCs. TMP inhibited HSC proliferation, invasion and adhesion, and reduced the expression of marker genes related to HSC activation in Glu/Ins-activated HSCs. Mechanistic evidence revealed that TMP reduced insulin receptor (InsR) expression and blocked the downstream phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) cascades, which was required for TMP attenuation of HSC activation. Moreover, TMP modulated the genes relevant to ECM homeostasis favoring ECM degradation. It could be concluded that TMP inhibited Glu/Ins-stimulated HSC activation and ECM production by inhibiting InsR-mediated PI3K/AKT and ERK pathways.

Zhang F ，Zhang Z ，Kong D ，Zhang X ，Chen L ，Zhu X ，Lu Y ，Zheng S ... -  《-》

Tetramethylpyrazine inhibits angiotensin II-induced activation of hepatic stellate cells associated with interference of platelet-derived growth factor β receptor pathways.

Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs) is a pivotal event during liver fibrogenesis. Compelling evidence indicates that the renin-angiotensin system (RAS) takes part in the pathogenesis of liver fibrosis. Angiotensin II (Ang II), the primary effector peptide of the RAS, has been demonstrated to be a potent pro-fibrogenic molecule for HSC activation. In this study we investigated the effects of tetramethylpyrazine (TMP) on HSC activation induced by Ang II in order to elucidate the underlying mechanisms. Our results demonstrated that Ang II significantly promoted cell growth, upregulated the expression of the fibrotic markers α-smooth muscle actin (α-SMA) and α1(I) procollagen, and enhanced the invasion capacity in HSCs. TMP inhibited proliferation and arrested the cell cycle at the G2/M checkpoint associated with altering several cell cycle regulatory proteins in Ang II-treated HSCs. TMP also modulated Bcl-2 family proteins and activated the caspase cascade leading to apoptosis in Ang II-treated HSCs. Moreover, TMP reduced the expression of α-SMA and α1(I) procollagen at mRNA and protein levels, and these effects were associated with interference of the platelet-derived growth factor β receptor (PDGF-βR) mediated PI3K/AKT/mTOR pathway in HSCs exposed to Ang II. Furthermore, Ang II-enhanced HSC invasion capacity was diminished by TMP, which was associated with interference of PDGF-βR/FAK signaling. These data collectively indicated that interference of PDGF-βR-mediated fibrotic pathways was involved in TMP inhibition of HSC activation caused by Ang II, providing novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis.

Zhang X ，Zhang F ，Kong D ，Wu X ，Lian N ，Chen L ，Lu Y ，Zheng S ... -  《-》

Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis.

Cai CX ，Buddha H ，Castelino-Prabhu S ，Zhang Z ，Britton RS ，Bacon BR ，Neuschwander-Tetri BA ... -  《-》

Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction by transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells.

Zhang F ，Kong D ，Chen L ，Zhang X ，Lian N ，Zhu X ，Lu Y ，Zheng S ... -  《-》

Oligomeric proanthocyanidin derived from grape seeds inhibited NF-κB signaling in activated HSC: Involvement of JNK/ERK MAPK and PI3K/Akt pathways.

In current study, we aimed to reveal the potential antifibrotic effects of oligomeric proanthocyanidin (OPC) from grape seeds on lipopolysaccharide (LPS)-activated, HSC-T6, a rat hepatic stellate cell line. HSC-T6 cells were treated with OPC 1h prior to LPS, and then incubated for indicated time. OPC inhibited cells viability of HSC-T6 cells and decrease protein expression of collagen I, α-smooth muscle actin (α-SMA), tissue inhibitors of metalloproteinases I (TIMP-1) on LPS-induced HSC-T6 cells. OPC also significantly inhibited phosphorylation of LPS-stimulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Furthermore, OPC pretreatment blocked LPS-triggered nuclear factor-kappa B (NF-κB) translocation from cytosol to nuclear. OPC, as well as specific inhibitors of NF-κB, PI3K and JNK could effectively inhibited α-SMA and collagen I expression. In conclusion, we demonstrated that the anti-fibrotic mechanism of OPC might be involved the inhibition of HSC activation and transdifferentiation by suppressing NF-κB activation through JNK/ERK MAPK and PI3K/Akt phosphorylation. Thus, OPC possesses the potential inhibitory property of HSC activation through NF-κB modulation involving MAPK-PI3K/AKT pathways.

Jiang M ，Wu YL ，Li X ，Zhang Y ，Xia KL ，Cui BW ，Lian LH ，Nan JX ... -  《-》