Inflammation ( IF 4.5 ) Pub Date : 2021-08-18 , DOI: 10.1007/s10753-021-01529-5 Pan Shen 1 , Liang Han 1 , Guang Chen 1 , Zhe Cheng 1 , Qiong Liu 1, 1
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Emodin is a natural bioactive compound from traditional Chinese herbs that exerts anti-inflammatory, antioxidant, anticancer, hepatoprotective, and neuroprotective effects. However, the protective effects of emodin in acetaminophen (APAP)-induced hepatotoxicity are not clear. The present study examined the effects of emodin on APAP-induced hepatotoxicity and investigated the potential molecular mechanisms. C57BL/6 mice were pretreated with emodin (15 and 30 mg/kg) for 5 consecutive days and then given APAP (300 mg/kg) to establish an APAP-induced liver injury model. Mice were sacrificed to detect the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) and the liver tissue levels of glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Histological assessment, Western blotting, and ELISA were performed. Emodin pretreatment significantly reduced the levels of ALT, AST, and ALP; increased the levels of ALB; alleviated hepatocellular damage and apoptosis; attenuated the exhaustion of GSH and SOD and the accumulation of MDA; and increased the expression of antioxidative enzymes, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1). Emodin also inhibited the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Emodin inhibited interferon (IFN)-α, cyclic GMP-AMP synthase (cGAS), and its downstream signaling effector stimulator of interferon genes (STING) expression to protect the liver against APAP-induced inflammatory responses and apoptosis. These results suggest that emodin protected hepatocytes from APAP-induced liver injury via the upregulation of the Nrf2-mediated antioxidative stress pathway, the inhibition of the NLRP3 inflammasome, and the downregulation of the cGAS-STING signaling pathway.
Graphical abstract
中文翻译：
大黄素通过 cGAS-STING 通路减轻对乙酰氨基酚诱导的肝毒性
大黄素是一种来自传统中草药的天然生物活性化合物，具有抗炎、抗氧化、抗癌、保肝和保护神经的作用。然而，大黄素在对乙酰氨基酚（APAP）引起的肝毒性中的保护作用尚不清楚。本研究检测了大黄素对 APAP 诱导的肝毒性的影响，并研究了潜在的分子机制。C57BL/6小鼠用大黄素（15和30 mg/kg）连续5天预处理，然后给予APAP（300 mg/kg）建立APAP诱导的肝损伤模型。处死小鼠，检测血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）和白蛋白（ALB）的水平以及肝组织中谷胱甘肽（GSH）、丙二醛（MDA）和超氧化物的水平歧化酶（SOD）。进行组织学评估、蛋白质印迹和ELISA。大黄素预处理显着降低了ALT、AST和ALP水平；增加 ALB 的水平；减轻肝细胞损伤和细胞凋亡；减弱GSH和SOD的消耗和MDA的积累；并增加抗氧化酶的表达，包括核因子红细胞 2 相关因子 2 (Nrf2)、血红素加氧酶 1 (HO-1) 和 NAD(P)H 醌脱氢酶 1 (NQO1)。大黄素还抑制 NLRP3 的表达并降低促炎因子的水平，包括白细胞介素 1 β (IL-1β)、IL-6 和肿瘤坏死因子-α (TNF-α)。大黄素抑制干扰素 (IFN)-α、环状 GMP-AMP 合酶 (cGAS)、及其下游的干扰素基因 (STING) 表达信号效应刺激物，以保护肝脏免受 APAP 诱导的炎症反应和细胞凋亡。这些结果表明，大黄素通过上调 Nrf2 介导的抗氧化应激通路、抑制 NLRP3 炎性体和下调 cGAS-STING 信号通路来保护肝细胞免受 APAP 诱导的肝损伤。
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