Lv Hongming, Qi Zhimin, Wang Sisi, Feng Haihua, Deng Xuming, Ci Xinxin
Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
Front Immunol. 2017 Jul 7;8:785. doi: 10.3389/fimmu.2017.00785. eCollection 2017.
Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i.e., HO, NO, and [Formula: see text]), and increasing the glutathione and superoxide dismutase contents. Moreover, AA treatment significantly inhibited mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway activation the partial induction of programmed cell death 4 (PDCD4) protein expressions, which are involved in inflammatory responses. Furthermore, AA treatment dramatically induced the expression of the glutamate-cysteine ligase modifier subunit, the glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, and NAD (P) H: quinoneoxidoreductase 1 (NQO1), which are largely dependent on activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) through the induction of AMP-activated protein kinase (AMPK) and glycogen synthase kinase-3β (GSK3β) phosphorylation. Accordingly, AA exhibited protective roles against LPS/d-GalN-induced FHF by inhibiting oxidative stress and inflammation. The underlying mechanism may be associated with the inhibition of MAPK and NF-κB activation the partial induction of PDCD4 and upregulation of Nrf2 in an AMPK/GSK3β pathway activation-dependent manner.
炎症和氧化应激在暴发性肝衰竭（FHF）的发病机制中至关重要。齐墩果酸（AA）是一种广泛存在于各种蔬菜和水果中的五环三萜，据报道具有抗氧化和抗炎特性。在本研究中，我们研究了AA对脂多糖（LPS）和D-半乳糖胺（GalN）诱导的FHF的保护作用及其潜在的分子机制。我们的研究结果表明，AA治疗通过降低致死率、降低丙氨酸转氨酶和天冬氨酸转氨酶水平、白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α的产生、丙二醛形成、髓过氧化物酶水平和活性氧生成（即HO、NO和[公式：见原文]），并增加谷胱甘肽和超氧化物歧化酶含量，有效保护免受LPS/D-GalN诱导的FHF。此外，AA治疗显著抑制丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）信号通路激活以及程序性细胞死亡4（PDCD4）蛋白表达的部分诱导，这些都参与炎症反应。此外，AA治疗显著诱导谷氨酸-半胱氨酸连接酶调节亚基、谷氨酸-半胱氨酸连接酶催化亚基、血红素加氧酶-1和NAD（P）H：醌氧化还原酶1（NQO1）的表达，这些主要依赖于通过诱导AMP活化蛋白激酶（AMPK）和糖原合酶激酶-3β（GSK3β）磷酸化激活核因子-红系2相关因子2（Nrf2）。因此，AA通过抑制氧化应激和炎症对LPS/D-GalN诱导的FHF发挥保护作用。潜在机制可能与以AMPK/GSK3β途径激活依赖性方式抑制MAPK和NF-κB激活、部分诱导PDCD4以及上调Nrf2有关。
