Bisdemethoxycurcumin Induces apoptosis in activated hepatic stellate cells via cannabinoid receptor 2.
Bisdemethoxycurcumin Induces apoptosis in activated hepatic stellate cells via cannabinoid receptor 2.
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DOI：
10.3390/molecules20011277
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发表时间：
2015-01-14
期刊：
影响因子：
--
通讯作者：
Kim HP
中科院分区：
文献类型：
--
作者：
Lee PJ;Woo SJ;Jee JG;Sung SH;Kim HP
活化的肝星状细胞(HSCs)是肝脏中主要的纤维化细胞，当肝损伤停止时，HSCs会发生凋亡，这可能有助于肝纤维化的缓解。双去甲氧基姜黄素(BDMC)是姜黄素的天然衍生物，具有抗炎和抗癌活性。到目前为止，BDMC在肝纤维化中的治疗潜力还没有在活化的HSC凋亡的背景下进行研究。在本研究中，我们比较了BDMC和姜黄素在HSC-T6细胞系中的活性，证明BDMC相对诱导了强大的细胞凋亡。BDMC诱导的细胞凋亡是通过联合抑制Bcl2和HO-1等细胞保护蛋白和增加活性氧的产生而实现的。有趣的是，BDMC诱导的细胞凋亡在大麻素受体(CBR)2拮抗剂sr144528的共同处理下被逆转，这一点被使用siCBR2的受体基因下调所证实。此外，与BDMC孵育增加了HSC-T6细胞中死亡诱导信号复合体的形成。BDMC显著降低细胞内总ATP水平，上调ATP抑制因子-1的表达。总之，这些结果表明，BDMC通过损害细胞能量学和引起细胞保护蛋白下调而诱导活化的HSCs凋亡，但不是在肝细胞中，这可能是通过涉及CBR2的机制。
Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.
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