Valerian inhibits rat hepatocarcinogenesis by activating GABA(A) receptor-mediated signaling.
Valerian inhibits rat hepatocarcinogenesis by activating GABA(A) receptor-mediated signaling.
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DOI：
10.1371/journal.pone.0113610
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wanibuchi H
中科院分区：
文献类型：
--
作者：
Kakehashi A;Kato A;Ishii N;Wei M;Morimura K;Fukushima S;Wanibuchi H
由于多种活性成分与 γ-氨基丁酸 (GABA) A 受体 (GABA(A)R) 系统相互作用，缬草被广泛用作改善睡眠质量的传统药物。最近，据报道，干细胞中 GABA 信号传导的激活可以抑制体内细胞周期的进展。此外，GABA(A)R 激动剂可能对肝癌发生具有抑制作用。本研究旨在利用中期大鼠肝脏生物测定来研究缬草对肝癌发生的调节作用。雄性 F344 大鼠在二乙基亚硝胺 (DEN) 引发肝癌后，在饮用水中添加一种最强效的缬草 (Valeriana satchensis)，剂量为 0、50、500 和 5000 ppm。与 DEN 起始对照大鼠相比，所有施用剂量的缬草均显着抑制谷胱甘肽 S-转移酶胎盘形式阳性 (GST-P+) 灶的形成。所有剂量的缬草均显着抑制大鼠肝脏中 8-羟基-2'-脱氧鸟苷的生成，这可能是由于抑制 Nrf2、CYP7A1 和诱导过氧化氢酶表达。缬草组的 GST-P+ 病灶区域的细胞增殖受到显着抑制，而细胞凋亡则被诱导，这与 c-myc、Mafb、cyclin D1 的抑制以及 p21Waf1/Cip1、p53 和 Bax mRNA 表达的诱导有关。有趣的是，在 DEN 对照大鼠的 GST-P+ 病灶中观察到 GABA(A)R α 1 亚基的表达，且与缬草治疗相关的显着升高。这些结果表明，缬草通过抑制氧化DNA损伤、抑制细胞增殖并通过激活GABA(A)R介导的信号传导诱导GST-P+病灶细胞凋亡，从而对大鼠肝癌发生具有抑制作用。
Valerian is widely used as a traditional medicine to improve the quality of sleep due to interaction of several active components with the γ-aminobutyric acid (GABA) A receptor (GABA(A)R) system. Recently, activation of GABA signaling in stem cells has been reported to suppress cell cycle progression in vivo. Furthermore, possible inhibitory effects of GABA(A)R agonists on hepatocarcinogenesis have been reported. The present study was performed to investigate modulating effects of Valerian on hepatocarcinogenesis using a medium-term rat liver bioassay. Male F344 rats were treated with one of the most powerful Valerian species (Valeriana sitchensis) at doses of 0, 50, 500 and 5000 ppm in their drinking water after initiation of hepatocarcinogenesis with diethylnitrosamine (DEN). Formation of glutathione S-transferase placental form positive (GST-P+) foci was significantly inhibited by Valerian at all applied doses compared with DEN initiation control rats. Generation of 8-hydroxy-2′-deoxyguanosine in the rat liver was significantly suppressed by all doses of Valerian, likely due to suppression of Nrf2, CYP7A1 and induction of catalase expression. Cell proliferation was significantly inhibited, while apoptosis was induced in areas of GST-P+ foci of Valerian groups associated with suppression of c-myc, Mafb, cyclin D1 and induction of p21Waf1/Cip1, p53 and Bax mRNA expression. Interestingly, expression of the GABA(A)R alpha 1 subunit was observed in GST-P+ foci of DEN control rats, with significant elevation associated with Valerian treatment. These results indicate that Valerian exhibits inhibitory effects on rat hepatocarcinogenesis by inhibiting oxidative DNA damage, suppressing cell proliferation and inducing apoptosis in GST-P+ foci by activating GABA(A)R-mediated signaling.
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