Hepatoprotective effect and mechanistic insights of deoxyelephantopin, a phyto-sesquiterpene.lactone, against fulminant hepatitis
Hepatoprotective effect and mechanistic insights of deoxyelephantopin, a phyto-sesquiterpene.lactone, against fulminant hepatitis
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DOI：
10.1016/j.jnutbio.2012.01.013
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发表时间：
2013-03-01
影响因子：
5.6
通讯作者：
Shyur, Lie-Fen
中科院分区：
文献类型：
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作者：
Huang, Chi-Chang;Lin, Kun-Ju;Shyur, Lie-Fen
脱氧象托品(Deoxphantopin，DET)是一种从植物药材象皮中分离得到的丰富的倍半萜内酯。本研究旨在为DET对内毒素/D-氨基半乳糖(LPS/D-GalN)诱导的暴发型肝炎的体内疗效及其作用机制提供科学依据。观察给予内毒素/D-Gain前预先给予DET(10 mg/kg体重，Pre-DET10)的保护作用，以及给予内毒素/D-Gain后给予10 mg/kg DET(Post-DET10)或保肝药物水飞蓟素(Post-SM10)的治疗效果。我们的研究结果表明，Pre-DET10可抑制脂多糖/D-Gain诱导的F4/80单核/巨噬细胞的浸润以及肝组织中硝基酪氨酸和环氧合酶-2蛋白的增加。此外，Post-DET10和PSOT-SM10治疗对肝细胞凋亡具有保护作用。三种治疗方法均可抑制血清转氨酶活性、肿瘤坏死因子-α和白介素6水平，以及血清和肝基质金属蛋白酶-9活性。DET10前或DET10后和SM10后联合抑制血红素加氧酶-1的表达最终降低了对脂多糖/D-Gain诱导的小鼠死亡率的保护，使小鼠的存活率分别从75%和62.5%降至50%。99m-二异丙基亚氨基二乙酸(DISIDA)单光子发射计算机断层扫描肝脏显像结果显示，DISIDA的摄取和排泄时间明显延迟，DET和水飞蓟素可有效恢复DISIDA的摄取和排泄。这份报告证明了DET在调节多个分子靶点或信号通路中的作用，这些分子靶点或信号通路在重型肝炎的发展过程中对抗炎症，并可能作为未来抗炎或肝保护药物开发的新的先导化合物。(C)2013 Elsevier Inc.保留所有权利。
Deoxyelephantopin (DET) is an abundant sesquiterpene lactone isolated from an anecdotally hepatoprotective phytomedicine, Elephantopus scaber. Our objective in this study was to provide scientific evidence for the in vivo efficacy and the underlying mechanisms of action of DET in lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced fulminant hepatitis. We investigated both the protective effect of pretreatment with DET (10 mg/kg body weight, Pre-DET10) prior to administration of LPS/D-GaIN and the therapeutic effect of treatment with 10 mg/kg DET (Post-DET10) or the hepatoprotective drug silymarin (Post-SM10) following the administration of LPS/D-GaIN. Our data showed that Pre-DET10 prevented LPS/D-GaIN-induced infiltration of F4/80 monocytes/macrophages and an increase of nitrotyrosine and cyclooxygenase-2 protein in liver tissues. Further, Post-DET10 and Psot-SM10 treatments protected against liver cell apoptosis. All three treatments suppressed serum aminotransferase activities, tumor necrosis factor-alpha and interleukin-6 levels, and serum and hepatic matrix metalloproteinase-9 activity. The Pre-DET10 or Post-DET10 and Post-SM10 treatments in combination with inhibition of heme oxygenase-1 expression ultimately decreased protection of mice from LPS/D-GaIN-induced mortality, with decreased survival from 75% and 62.5% to 50%, respectively. Results obtained from serial liver scintigraphy with Tc-99m-diisopropyl iminodiacetic acid (DISIDA) on single-photon emission computed tomography analysis showed that both liver uptake and excretion times of DISIDA were significantly delayed in LPS/D-GalN-treated animals and were effectively recovered by DET and silymarin treatment. This report demonstrates that DET functions in the modulating multiple molecular targets or signaling pathways that counteract inflammation during the progression of fulminant hepatitis and may serve as a novel lead compound for future development of anti-inflammatory or hepatoprotective agents. (C) 2013 Elsevier Inc. All rights reserved.