Senkyunolide I attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways
Senkyunolide I attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways
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Senkyunolide I 通过抗氧化、抗炎和抗凋亡途径减轻小鼠肝脏缺血/再灌注损伤
DOI：
10.1016/j.intimp.2021.107717
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发表时间：
2021-04-29
影响因子：
5.6
通讯作者：
Deng, Xiao-ming
中科院分区：
文献类型：
--
作者：
Yang, Qing;Zhao, Zhen-zhen;Deng, Xiao-ming
背景：Senkyunolide I （SEI）在多种疾病模型中均具有相当的保护作用，但其对肝缺血再灌注（I/R）损伤的作用尚不清楚。本研究旨在探讨SEI在小鼠肝I/R损伤模型中的作用。方法：采用改良肝I/R模型，术后腹腔注射低、中、高剂量SEI。再灌注6 h后，采集血液和肝脏。自动分析仪检测血清ALT、AST， HE染色评价肝损伤程度。选择高剂量SEI进一步探讨其对肝脏I/R诱导的氧化应激、炎症反应和细胞凋亡的影响。SEI的药理作用也与阳性对照谷胱甘肽（GSH）进行了比较。采用ELISA法检测血清tnf - α、IL-1 13、IL-6，采用专用试剂盒检测SOD、GSH-Px活性及MDA含量，western blotting检测肝组织中HO-1、Bax、Bcl-2水平，观察NF- Kappa B p65、p38/ERK/JNK的表达及磷酸化情况。TUNEL法观察肝组织凋亡情况。利用H2O2刺激的HuCCT1细胞进一步研究SEI的抗氧化作用，并确定SEI对Nrf-2/HO-1的调控作用。结果：200 mg/kg的SEI是治疗肝I/R损伤的最佳剂量。与GSH类似，SEI可减轻I/R肝中ALT、AST升高和组织病理学损伤。经SEI处理的肝I/R小鼠血清tnf - α、IL-113和IL-6降低，肝组织中p65 nf - κ B和MAPK激酶（p38、ERK、JNK）的磷酸化被抑制。SEI降低了MDA含量，提高了HO-1水平，提高了SOD和GSH-Px活性。肝组织凋亡减少，SEI抑制Bax表达，升高Bcl-2表达。在体外实验中，H2O2降低了HuCCT1细胞的存活率，并受到SEI的保护。SEI降低了ROS和MDA的含量。Nrf-2向细胞核的转运增强，HO-1表达上调。结论：SEI可通过抗氧化、抗炎和抗凋亡途径减轻小鼠肝脏I/R损伤。
Background: Senkyunolide I (SEI)exerts considerable protective effects in various disease models, but its effect on hepatic ischemia-reperfusion (I/R) injury remains unknown. This research aimed to investigate the effect of SEI in a murine model of hepatic I/R injury. Methods: With modified liver I/R murine model, low, medium and high doses of SEI were injected intraperitoneally after operation. After 6 h of reperfusion, the blood and liver were collected. Serum ALT and AST were detected by automatic analyzer, while liver injury was evaluated by HE staining. High-dose SEI was selected to further explore its impacts on oxidative stress, inflammatory responses and apoptosis induced by hepatic I/R. The pharmacological effect of SEI was also compared with a positive control, glutathione (GSH). We used ELISA to detect serum TNF-alpha, IL-1 13 and IL-6, special kit to explore activities of SOD and GSH-Px, and the content of MDA, and western blotting to detect HO-1, Bax and Bcl-2 levels, and to perceive expressions and phosphorylations of NF- Kappa B p65 and p38/ERK/JNK in liver tissues. Apoptosis in liver tissue was evaluated by TUNEL. The antioxidative effect of SEI was further investigated using the HuCCT1 cells stimulated with H2O2 and the role of SEI on regulation of Nrf-2/HO-1 was determined. Results: 200 mg/kg of SEI was optimal dose for treating liver I/R injury. Elevated ALT, AST and histopathological injury in I/R liver was attenuated by SEI administration, similarly to GSH. Serum TNF-alpha, IL-113, and IL-6 were reduced in liver I/R mice treated with SEI, and in liver tissues, phosphorylation of p65 NF-Kappa B and MAPK kinases (p38, ERK, JNK), were inhibited. SEI reduced the MDA content, but increased HO-1 level and enhanced SOD and GSH-Px activities. Apoptosis of liver tissues was decreased, while SEI inhibited Bax and elevated Bcl-2 expression. In in vitro experiments, H2O2 reduced the survival rate of HuCCT1 cells, which was protected by SEI administration. SEI reduced the ROS and MDA content. The transportation of Nrf-2 into the nucleus was enhanced and HO-1 expression was upregulated. Conclusions: SEI attenuates hepatic I/R injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways.