College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757, South Korea.
Neurochem Int. 2011 Feb;58(2):153-60. doi: 10.1016/j.neuint.2010.11.008. Epub 2010 Nov 18.
Xanthohumol (2',4',4-trihydroxy-6'-methoxy-3'-prenylchalcone) is a major chalcone derivative isolated from hop (Humulus lupulus L.) commonly used in brewing due to its bitter flavors. Xanthohumol has anti-carcinogenic, free radical-scavenging, and anti-inflammatory activities, but its precise mechanisms are not clarified yet. The basic leucine zipper (bZIP) protein NRF2 is a key transcription factor mediating the antioxidant and anti-inflammatory responses in animals. Therefore, we tested whether xanthohumol exerts anti-inflammatory activity in mouse microglial BV2 cells via NRF2 signaling. Xanthohumol significantly inhibited the excessive production of inflammatory mediators NO, IL-1β, and TNF-α, and the activation of NF-κB signaling in LPS-induced stimulated BV2 cells. Xanthohumol up-regulated the transcription of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), and increased the level of the endogenous antioxidant GSH. In addition, xanthohumol induced nuclear translocation of NRF2 and further activation of ARE promoter-related transcription. The anti-inflammatory response of xanthohumol was attenuated by transfection with NRF2 siRNA and in the presence of the HO-1 inhibitor, ZnPP, but not the NQO1 inhibitor, dicoumarol. Taken together, our study suggests that xanthohumol exerts anti-inflammatory activity through NRF2-ARE signaling and up-regulation of downstream HO-1, and could be an attractive candidate for the regulation of inflammatory responses in the brain.
黄腐酚（2'，4'，4-三羟基-6'-甲氧基-3'-异戊烯基查尔酮）是一种主要的查尔酮衍生物，从啤酒花（Humulus lupulus L.）中分离出来，由于其苦味而常用于酿造。黄腐酚具有抗癌、清除自由基和抗炎活性，但确切的机制尚未阐明。碱性亮氨酸拉链（bZIP）蛋白 NRF2 是一种关键的转录因子，介导动物的抗氧化和抗炎反应。因此，我们测试了黄腐酚是否通过 NRF2 信号通路在小鼠小胶质细胞 BV2 细胞中发挥抗炎活性。黄腐酚显著抑制 LPS 诱导的 BV2 细胞中炎症介质 NO、IL-1β和 TNF-α的过度产生以及 NF-κB 信号的激活。黄腐酚上调 NAD(P)H：醌氧化还原酶 1（NQO1）和血红素加氧酶-1（HO-1）的转录，并增加内源性抗氧化剂 GSH 的水平。此外，黄腐酚诱导 NRF2 的核转位和 ARE 启动子相关转录的进一步激活。用 NRF2 siRNA 转染和存在 HO-1 抑制剂 ZnPP 可减弱黄腐酚的抗炎反应，但不影响 NQO1 抑制剂二香豆素。总之，我们的研究表明，黄腐酚通过 NRF2-ARE 信号通路发挥抗炎作用，并上调下游 HO-1，可成为调节大脑炎症反应的有吸引力的候选物。
