Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways
Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways
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DOI：
10.1016/j.jphs.2014.12.010
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发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
Yao, Jihong
中科院分区：
文献类型：
--
作者：
Lin, Musen;Zhai, Xiaohan;Yao, Jihong
对乙酰氨基酚（APAP）是世界范围内用于治疗疼痛和发热的药物。然而，APAP过量是西方国家急性肝功能衰竭的主要原因。丹参酚酸B（SalB）是从丹参中提取的主要水溶性化合物，具有抗氧化和抗炎作用。我们的目的是评估SalB的能力，防止APAP诱导的急性肝毒性诱导核因子红细胞2相关因子2（Nrf 2）的表达。SalB预处理可改善APAP引起的急性肝损伤，如血液天冬氨酸转氨酶水平和组织学结果所示。此外，SalB预处理增加Nrf 2，血红素加氧酶-1（HO-1）和谷氨酸-l-半胱氨酸连接酶催化亚基（GCLC）的表达。此外，HO-1抑制剂锌原卟啉和GCLC抑制剂丁硫酰亚胺逆转SalB的保护作用。此外，siRNA介导的Nrf 2缺失减少了SalB对HO-1和GCLC的诱导，SalB预处理激活了磷脂酰肌醇-3-激酶（PI 3 K）和蛋白激酶C（PKC）信号通路。两种抑制剂（PI 3 K和PKC）阻断SalB对APAP诱导的细胞死亡的保护作用，消除SalB诱导的Nrf 2活化并降低HO-1和GCLC表达。这些结果表明，SalB通过激活PI 3 K和PKC途径诱导Nrf 2、HO-1和GCLC表达，从而保护免受APAP诱导的肝损伤。(C)2015年日本药理学会。Elsevier B. V.制作和主持。保留所有权利。
Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.