原花青素 B2 通过 Hedgehog 通路抑制肝纤维化过程中肝星状细胞的激活和血管生成。
Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis.
机构信息
Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
J Cell Mol Med. 2019 Sep;23(9):6479-6493. doi: 10.1111/jcmm.14543. Epub 2019 Jul 21.
BACKGROUND
Liver fibrosis is a wound-healing process of liver featured by the over-deposition of extracellular matrix (ECM) and angiogenesis. However, the effective treatment is lacking. Procyanidin B2 (PB2) is a flavonoid extract abundant in grape seeds with anti-oxidant, anti-inflammatory and anti-cancer properties. The present study aimed to determine effects of PB2 on liver fibrosis.
METHOD
The CCl4-induced mouse liver fibrosis model and a human hepatic stellate cell (HSC) line (LX2 cells) were used to study the activation, ECM production and angiogenesis of HSCs through Western blotting analysis, immunohistochemistry, immunofluorescence staining, flow cytometry and tubulogenesis assay. A Hedgehog (Hh) pathway inhibitor (cyclopamine) and Smoothened agonist (SAG) were used to investigate the role of PB2 on Hh pathway.
RESULTS
The results showed that PB2 could inhibit the proliferation and induce apoptosis of HSCs. PB2 could also down-regulate the expressions of VEGF-A, HIF-1α, α-SMA, Col-1 and TGF-β1 of HSCs in vivo and in vitro. The application of SAG and cyclopamine proved that PB2 targets on Hh pathway.
CONCLUSIONS
PB2 inhibited the Hh pathway to suppress the activation, ECM production and angiogenesis of HSCs, therefore reverses the progression of liver fibrosis in vivo and in vitro.
背景
肝纤维化是肝脏的一种创伤愈合过程，其特征为细胞外基质（ECM）过度沉积和血管生成。然而，目前缺乏有效的治疗方法。原花青素 B2（PB2）是一种富含葡萄籽的类黄酮提取物，具有抗氧化、抗炎和抗癌特性。本研究旨在确定 PB2 对肝纤维化的影响。
方法
使用 CCl4 诱导的小鼠肝纤维化模型和人肝星状细胞（LX2 细胞）系，通过 Western blot 分析、免疫组织化学、免疫荧光染色、流式细胞术和小管形成试验研究 HSCs 的激活、ECM 产生和血管生成。使用 Hedgehog（Hh）通路抑制剂（环巴胺）和 Smoothened 激动剂（SAG）研究 PB2 对 Hh 通路的作用。
结果
结果表明，PB2 可抑制 HSCs 的增殖并诱导其凋亡。PB2 还可下调体内和体外 HSCs 中 VEGF-A、HIF-1α、α-SMA、Col-1 和 TGF-β1 的表达。SAG 和环巴胺的应用证明 PB2 作用于 Hh 通路。
结论
PB2 通过抑制 Hh 通路抑制 HSCs 的激活、ECM 产生和血管生成，从而逆转体内和体外肝纤维化的进展。
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