Saikosaponin d ameliorates pancreatic fibrosis by inhibiting autophagy of pancreatic stellate cells via PI3K/Akt/mTOR pathway
Saikosaponin d ameliorates pancreatic fibrosis by inhibiting autophagy of pancreatic stellate cells via PI3K/Akt/mTOR pathway
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DOI：
10.1016/j.cbi.2019.01.005
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发表时间：
2019-02-25
影响因子：
5.1
通讯作者：
Zhang, Shu-Kun
中科院分区：
文献类型：
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作者：
Cui, Li-Hua;Li, Cai-Xia;Zhang, Shu-Kun
慢性胰腺炎的特征在于胰腺纤维化，与胰腺星状细胞（PSC）的过度活化和转化生长因子-β 1（TGF-β 1）的表达增加相关。近年来，我们的研究表明自噬抑制剂可以抑制PSC的活化，减少胶原的分泌。柴胡皂苷d（Saikosaponin d，SSd）是药用植物柴胡（Bupleurumfalcatum）的主要活性成分，具有抗肝纤维化作用。然而，尚不清楚SSd是否在胰腺纤维化中起作用。本研究旨在探讨SSd对体内、外PSC自噬和活化的影响。在体内，静脉注射二丁基二氯化锡诱导大鼠慢性胰腺炎模型。以2.0 mg/kg体重/天的剂量通过管饲法给予SSd。4周后，收集胰腺进行组织学和分子分析。在体外，分离和培养PSCs用于用不同剂量的SSd处理。结果表明，SSd抑制PSC自噬和活化，同时也减少细胞外基质（ECM）的形成和胰腺损伤。SSd通过激活PI 3 K/Akt/mTOR通路抑制自噬。SSd还促进ECM的降解，增加MMPs/TIMPs的比例，并抑制TGF-β 1/Smads通路。从这些结果中，我们得出结论，SSd通过PI 3 K/Akt/mTOR途径减少PSC的自噬来预防胰腺纤维化，该途径与TGF-β 1/Smads途径具有串扰。
Chronic pancreatitis is characterized by pancreatic fibrosis, associated with excessive activation of pancreatic stellate cells (PSCs) and increased expression of transforming growth factor-beta 1 (TGF-beta 1). Recently, our studies have shown that autophagy inhibitor could inhibit PSCs activation and reduce collagen secretion. Saikosaponin d (SSd), the major active component of bupleurum falcatum (a medicinal plant), has anti-fibrosis effects in liver. However, it is unclear whether SSd has a role in pancreatic fibrosis. This study aimed to investigate the effect of SSd on the autophagy and activation of PSCs in vivo and in vitro. In vivo, a rat chronic pancreatitis model was induced by intravenous injection of dibutyltin dichloride. SSd was administered at a dose of 2.0 mg/kg body weight per day by gavage. After 4 weeks, the pancreas was collected for histological and molecular analysis. In vitro, PSCs were isolated and cultured for treatment with different dosages of SSd. The results showed that SSd inhibited PSCs autophagy and activation while also reducing extracellular matrix (ECM) formation and pan-creatic damage. SSd inhibited autophagy through activating the PI3K/Akt/mTOR pathway. SSd also promoted degradation of ECM with an increasing ratio of MMPs/TIMPs and suppressed the TGF-beta 1/Smads pathway. From these results, we concluded that SSd prevents pancreatic fibrosis by reducing autophagy of PSCs through PI3K/Akt/mTOR pathway, which has crosstalk with the TGF-beta 1/Smads pathway.