Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-κB signaling pathways

Li, Xi; Jin, Qianwen; Yao, Qunyan; Xu, Beili; Li, Zheng; Tu, Caixia

doi:10.1016/j.toxlet.2016.09.002

Cited by 66 publications

(72 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…). Notably, hypoxia has been shown to be a pro‐fibrotic stimulus that contributes to the development of fibrosis through an HIF‐mediated transcriptional response . Here, we observed that hypoxia could induce PlGF expression accompanying HIF‐1α activation in HSCs; however, HIF‐1α knockdown in HSCs abrogated hypoxia‐induced PlGF expression, indicating that these effects were HIF‐1α‐dependent (Fig.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease

Yao

Liu

et al. 2017

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family and is involved in pathological angiogenesis associated with chronic liver diseases. However, the precise mechanisms underlying PlGF signalling contributing to liver fibrosis and angiogenesis remain largely unexplored. This study aimed to assess the effect of reducing PlGF expression using small interfering RNA (siRNA) on experimental liver fibrosis and angiogenesis, and to elucidate the underlying molecular mechanisms. Fibrosis was induced in mice by carbon tetrachloride (CCl 4 ) for 8 weeks, and mice were treated with PlGF siRNA or non-targeting control siRNA starting two weeks after initiating CCl 4 injections. The results showed that PlGF was highly expressed in cirrhotic human and mice livers; which mainly distributed in activated hepatic stellate cells (HSCs). PlGF silencing robustly reduced liver inflammation, fibrosis, intrahepatic macrophage recruitment, and inhibited the activation of HSCs in vivo. Moreover, PlGF siRNA-treated fibrotic mice showed diminished hepatic microvessel density and angiogenic factors, such as hypoxia-inducible factor-1a (HIF-1a), VEGF and VEGF receptor-1. Moreover, down-regulation of PlGF with siRNA in HSCs inhibited the activation and proliferation of HSCs. Mechanistically, overexpression of PlGF in activated HSCs was induced by hypoxia dependent on HIF-1a, and PlGF induces HSC activation and proliferation via activation the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathways. These findings indicate that PlGF plays an important role in liver fibrosis-associated angiogenesis and that blockage of PlGF could be an effective strategy for chronic liver disease.

show abstract

Section: Discussionsupporting

confidence: 92%

“…Western blot and quantitative real-time RT-PCR were performed as described previously [7,25,30] and provided in the Appendix S1.…”

Section: Western Blot and Quantitative Real-time Rt-pcrmentioning

confidence: 99%

Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease

Yao

Liu

et al. 2017

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several independent studies highlighted the importance of the chemokines receptor CCR2 and its main ligand, MCP-1, for monocyte/macrophage recruitment during experimental hepatic fibrosis, suggesting that inhibition of CCR2 or MCP-1 might bear therapeutic potential in chronic liver diseases (8, 9, 33, 41). In addition, macrophages also express multiple toll-like receptors (TLRs)—such as TLR4 and TLR9, and it has been reported that TLRs interact with oxDNA and microbial components, such as LPS, Hsp60, and other ligands, and result in macrophage activation and the productions of pro-inflammatory mediators (such as TNF-α and MCP-1) (32, 35, 42–44). In this study, we also found that PlGF silencing inhibited the levels of TLR4 and TLR9 gene and protein expression in fibrotic liver after 4-week BDL (Figures 6C,E), contributing to amelioration of liver inflammation and fibrosis (42–44).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, macrophages also express multiple toll-like receptors (TLRs)—such as TLR4 and TLR9, and it has been reported that TLRs interact with oxDNA and microbial components, such as LPS, Hsp60, and other ligands, and result in macrophage activation and the productions of pro-inflammatory mediators (such as TNF-α and MCP-1) (32, 35, 42–44). In this study, we also found that PlGF silencing inhibited the levels of TLR4 and TLR9 gene and protein expression in fibrotic liver after 4-week BDL (Figures 6C,E), contributing to amelioration of liver inflammation and fibrosis (42–44). Thus, these results indicated that the interaction of HSCs with pro-inflammatory cells such as Kupffer cells was a crucial event in HSCs activation and fibrosis (6–9, 29), while chemokines and their receptors were likely to serve as important contributors to this interaction (6–9, 25, 32, 44).…”

Section: Discussionmentioning

confidence: 99%

Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

Jin

Yao

et al. 2017

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA) or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs) activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1) mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate that PlGF plays an important role in liver inflammation, angiogenesis, and fibrosis by promoting hepatic macrophage recruitment and activation, and suggest that blockage of PlGF could be a promising novel therapy for chronic fibrotic liver diseases.

show abstract

“…Another agent, rutin, which is similar in chemical structure to baicalein, has also shown hepatoprotective activity against biliary obstruction or CCl 4 -induced liver injury [36,37]. Similarly, quercetin has been demonstrated to be liver-protective in a variety of animal models [38][39][40]. The hepatoprotective effect of baicalein can match that of rutin and quercetin.…”

Section: Resultsmentioning

confidence: 99%

Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

Niu

Wan

Bian

et al. 2016

Biotechnology & Biotechnological Equipment

View full text Add to dashboard Cite

Cisplatin is widely used for the treatment of a variety of cancers but with a high incidence of hepatotoxicity. Baicalein is originally isolated from the root of Scutellaria baicalensis Georgi with broad bioactivities. The present study aims to investigate the protective effect of baicalein against cisplatin-induced acute liver injury and the underlying mechanism of this protective effect. Administration of cisplatin (40 mg/kg) for 24 h increased the serum alanine and aspartate aminotransferases and alkaline phosphatase levels, while baicalein could reverse all those changes induced by cisplatin. Liver histological analysis further evidenced the protection of baicalein against cisplatin-induced liver injury. Baicalein counteracted the increased liver malondialdehyde (amount induced by cisplatin, while baicalein could further increase the cisplatin-induced elevation of the amount of reduced glutathione in the liver. Further results showed that baicalein reversed the cisplatin-induced decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S transferase and glutathione reductase. On the other hand, baicalein alleviated the increase in the serum levels of tumour necrosis factor alpha and interleukin 6 induced by cisplatin. Taken together, our results demonstrate that baicalein can inhibit cisplatininduced hepatic oxidative stress and inflammation, which contributes greatly to the amelioration of cisplatin-induced liver injury.

show abstract

Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-κB signaling pathways

Cited by 66 publications

References 33 publications

Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease

Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease

Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

Contact Info

Product

Resources

About