Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.
Department of Radiation Oncology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China.
Eur J Pharmacol. 2018 Mar 5;822:128-137. doi: 10.1016/j.ejphar.2018.01.020.
A large population of drug candidates have failed "from bench to bed" due to unwanted toxicities. We intend to develop an alternative approach for drug discovery, that is, to seek candidates from "safe" compounds. Rebaudioside A (Reb-A) is an approved commercial sweetener from Stevia rebaudiana Bertoni. We found that Reb-A protects against carbon tetrachloride (CCl)-induced oxidative injury in human liver hepatocellular carcinoma (HepG2) cells. Reb-A showed antioxidant activity on reducing cellular reactive oxygen species and malondialdehyde levels while increasing glutathione levels and superoxide dismutase and catalase activities. Reb-A treatment induced nuclear factor erythroid-derived 2-like 2 (Nrf2) activation and antioxidant response element activity, as well as the expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Further mechanistic studies indicated that c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), mitogen-active protein kinase (MAPK) and protein kinase C epsilon (PKCε) signaling was upregulated. Thus, the present in vitro study conclusively demonstrated that Reb-A is an activator of Nrf2 and is a potential candidate hepatoprotective agent. More importantly, the present study illustrated that seeking drug candidates from "safe" compounds is a promising strategy.
由于不良毒性，大量候选药物未能实现“从实验室到病床”。我们拟开发一种药物发现的替代方法，即从“安全”的化合物中寻找候选药物。甜菊糖苷 A（Reb-A）是甜叶菊（Stevia rebaudiana Bertoni）中批准的商业甜味剂。我们发现 Reb-A 可保护人肝癌细胞（HepG2）免受四氯化碳（CCl）诱导的氧化损伤。Reb-A 通过降低细胞活性氧和丙二醛水平，同时增加谷胱甘肽水平和超氧化物歧化酶和过氧化氢酶活性来显示抗氧化活性。Reb-A 处理诱导核因子红细胞衍生 2 样 2（Nrf2）激活和抗氧化反应元件活性，以及血红素加氧酶-1（HO-1）和 NAD（P）H 醌氧化还原酶 1（NQO1）的表达。进一步的机制研究表明，c-Jun N 末端激酶（JNK）、细胞外信号调节蛋白激酶（ERK）、丝裂原激活蛋白激酶（MAPK）和蛋白激酶 C ɛ（PKCε）信号被上调。因此，本体外研究明确表明 Reb-A 是 Nrf2 的激活剂，是一种有潜力的肝保护剂候选药物。更重要的是，本研究表明，从“安全”的化合物中寻找药物候选物是一种很有前途的策略。
