Kawahara Ko-Ichi, Hashiguchi Teruto, Masuda Kazuo, Saniabadi Abbi R, Kikuchi Kiyoshi, Tancharoen Salunya, Ito Takashi, Miura Naoki, Morimoto Yoko, Biswas Kamal K, Nawa Yuko, Meng Xiaojie, Oyama Yoko, Takenouchi Kazunori, Shrestha Binita, Sameshima Hisayo, Shimizu Toshiaki, Adachi Taro, Adachi Masakazu, Maruyama Ikuro
Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
Int J Mol Med. 2009 May;23(5):615-20. doi: 10.3892/ijmm_00000172.
High mobility group box-1 protein (HMGB1), primarily from the nucleus, is released into the extracellular milieu either passively from necrotic cells or actively through secretion by monocytes/macrophages. Extracellular HMGB1 acts as a potent inflammatory agent by promoting the release of cytokines such as tumor necrosis factor (TNF)-alpha, has procoagulant activity, and is involved in death due to sepsis. Accordingly, HMGB1 is an appropriate therapeutic target. In this study, we found that an extract of Prunus mume Sieb. et Zucc. (Ume) fruit (Ume extract), an abundant source of triterpenoids, strongly inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. The inhibitory effect on HMGB1 release was enhanced by authentic oleanolic acid (OA), a naturally occurring triterpenoid. Similarly, the HMGB1 release inhibitor in Ume extract was found to be OA. Regarding the mechanisms of the inhibition of HMGB1 release, the OA or Ume extract was found to activate the transcription factor Nrf2, which binds to the antioxidative responsive element, and subsequently the heme oxygenase (HO)-1 protein was induced, indicating that the inhibition of HMGB1 release from LPS-stimulated RAW264.7 cells was mediated via the Nrf2/HO-1 system; an essentially antioxidant effect. These results suggested that natural sources of triterpenoids warrant further evaluation as 'rescue' therapeutics for sepsis and other potentially fatal systemic inflammatory disorders.
高迁移率族蛋白B1（HMGB1）主要来自细胞核，可从坏死细胞被动释放到细胞外环境中，也可由单核细胞/巨噬细胞主动分泌。细胞外HMGB1通过促进肿瘤坏死因子（TNF）-α等细胞因子的释放，作为一种强效炎症因子发挥作用，具有促凝活性，并参与败血症导致的死亡。因此，HMGB1是一个合适的治疗靶点。在本研究中，我们发现梅（Prunus mume Sieb. et Zucc.）果实提取物（乌梅提取物），一种丰富的三萜类化合物来源，能强烈抑制脂多糖（LPS）刺激的巨噬细胞样RAW264.7细胞释放HMGB1。天然存在的三萜类化合物齐墩果酸（OA）增强了对HMGB1释放的抑制作用。同样，发现乌梅提取物中的HMGB1释放抑制剂为OA。关于抑制HMGB1释放的机制，发现OA或乌梅提取物可激活转录因子Nrf2，Nrf2与抗氧化反应元件结合，随后诱导血红素加氧酶（HO）-1蛋白，这表明LPS刺激的RAW264.7细胞中HMGB1释放的抑制是通过Nrf2/HO-1系统介导的；这本质上是一种抗氧化作用。这些结果表明，三萜类化合物的天然来源作为败血症和其他潜在致命性全身炎症性疾病的“挽救”疗法值得进一步评估。
