ENMD-1068 inhibits liver fibrosis through attenuation of TGF-β1/Smad2/3 signaling in mice.
ENMD-1068 inhibits liver fibrosis through attenuation of TGF-β1/Smad2/3 signaling in mice.
复制标题
DOI：
10.1038/s41598-017-05190-7
复制
发表时间：
2017-07-14
影响因子：
4.6
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Sun Q;Wang Y;Zhang J;Lu J
蛋白水解酶激活受体2(PAR-2)在肝纤维化的发病机制中起重要作用。本实验研究了PAR-2拮抗剂N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine(ENMD1068)对四氯化碳诱导的小鼠肝纤维化及小鼠肝星状细胞(HSC)活化的影响。在注射CCl_4前，分别给小鼠腹腔注射25 mg/kg或50 mg/kg ENMD-1068或空白对照组的200 μL溶液，每周2次，连续4周。用转化生长因子-β1加或不加ENMD-1068刺激分离的肝星状细胞，观察PAR-2在转化生长因子-β1诱导的肝星状细胞活化和胶原生成中的作用。我们发现，在四氯化碳诱导的肝纤维化小鼠中，α-1068能显著降低ALT/AST、胶原含量和α-SMA的水平。有趣的是，我们发现转化生长因子-β1信号相关的α-SMA、I型和III型胶原的表达水平以及Smad2/3的C末端磷酸化水平在经ENMD1068处理的HSC中显著降低。此外，我们还发现ENMD-1068处理抑制了胰酶或SLIGRL-NH_2刺激的钙释放和转化生长因子-β-1诱导的Smad转录活性。我们证明ENMD-1068通过抑制转化生长因子-β-1/Smad信号转导而降低HSC的活化和胶原的表达。
Protease-activated receptor 2 (PAR-2) plays an important role in the pathogenesis of liver fibrosis. We studied the effect of N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine (ENMD-1068), a PAR-2 antagonist, on the development of CCl4-induced liver fibrosis in mice and activation of hepatic stellate cells (HSCs) isolated from the mice. Before CCl4 injection, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control twice per week for 4 weeks. The isolated HSCs were stimulated by TGF-β1 with or without ENMD-1068 to evaluate the role of PAR-2 in TGF-β1 induced HSCs activation and collagen production. We showed that the levels of ALT/AST, collagen content, and α-smooth muscle actin (α-SMA) were significantly reduced by treatment with ENMD-1068 in CCl4-induced fibrotic mice. Interestingly, we found TGF-β1 signaling-related expression levels of α-SMA, type I and III collagen, and C-terminal phosphorylation of Smad2/3 were significantly decreased in the ENMD-1068 treated HSCs. Moreover, we showed ENMD-1068 treatment inhibited trypsin or SLIGRL-NH2 stimulated calcium release and TGF-β1 induced Smad transcriptional activity in HSCs. We demonstrated that ENMD-1068 reduces HSCs activation and collagen expression through the inhibiton of TGF-β1/Smad signal transduction.
登录
查看更多内容
影响因子：
82.9
作者：
Mehal, Wajahat Z.;Iredale, John;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
阿魏酸在体外通过 ERK1/2 和 Smad 信号通路抑制肝星状细胞的活化
影响因子：
5.8
作者：
Xu, Tianjiao;Pan, Zhi;Niu, Yingcai
通讯作者：
Niu, Yingcai
影响因子：
4.8
作者：
Chung, Hyunjae;Ramachandran, Rithwik;Muruve, Daniel A.
通讯作者：
Muruve, Daniel A.
影响因子：
9.8
作者：
Wang, Yifeng;Lin, Min;Liu, Fenghua
通讯作者：
Liu, Fenghua
影响因子：
7.3
作者：
Navarro-Nunez, L.;Rivera, J.;Lozano, M. L.
通讯作者：
Lozano, M. L.