Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China.
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People's Republic of China.
Arch Med Res. 2021 Feb;52(2):163-173. doi: 10.1016/j.arcmed.2020.10.009. Epub 2020 Oct 21.
Hepatic ischemia-reperfusion injury (IRI) is the main leading cause of morbidity and mortality of patients after liver surgery and transplantation. Fisetin, a kind of flavonoid, has been reported to protect against myocardial and cerebral IRI. However, the effects of fisetin on liver IRI were poorly investigated.
C57BL/6 mice were used to establish the liver IRI model in vivo. Intraperitoneal injection of fisetin was performed one hour before IR treatment (1 h ischemia and 6h reperfusion). In vitro experimental study was conducted using AML-12 hepatocytes with 1 h hypoxia and 12 h reoxygenation (HR) treatment. Tissue damage was evaluated through serum AST and ALT levels and hematoxylin-eosin (HE) staining. Cell apoptosis was assessed by TUNEL staining and protein levels of Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP. Oxidative stress was evaluated by ROS and MDA levels and the activity of SOD and GSH-Px. Immunohistochemistry and immunofluorescence assay were performed to observe the translocation of Nrf2 from the cytoplasm into the nucleus.
The histopathological assessment showed that fisetin attenuated IR-induced liver damage obviously. Besides, fisetin served a protective role in IR liver to alleviate cell apoptosis and oxidative stress in vivo and in vitro. Introduction of high concentration of fisetin promoted the translocation of Nrf2 from the cytoplasm into the nucleus, increasing protein expression of its downstream elements, at least HO-1 in IR liver tissues and hepatocytes after HR. Inhibition of Nrf2 could reverse the effects of fisetin on cell viability, cell apoptosis, and also oxidative stress of HR hepatocytes, suggesting that Nrf2 signaling was necessary in fisetin-mediated regulations of liver IRI.
Fisetin alleviates liver damage, cell apoptosis, and oxidative stress induced by liver IRI, at least through Nrf2/HO-1 signaling pathway, suggesting that fisetin could be considered as a targeted drug for liver IRI treatment.
肝缺血再灌注损伤（IRI）是肝外科和肝移植术后患者发病率和死亡率的主要原因。根皮素是一种类黄酮，已被报道可预防心肌和脑 IRI。然而，根皮素对肝 IRI 的影响研究甚少。
体内实验采用 C57BL/6 小鼠建立肝 IRI 模型。IRI 处理前 1 小时（1 小时缺血和 6 小时再灌注）进行腹腔注射根皮素。体外实验采用 AML-12 肝细胞进行 1 小时缺氧和 12 小时复氧（HR）处理。通过血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平和苏木精-伊红（HE）染色评估组织损伤。通过 TUNEL 染色和 Bax、Bcl-2、cleaved-caspase-3 和 cleaved-PARP 蛋白水平评估细胞凋亡。通过 ROS 和 MDA 水平以及 SOD 和 GSH-Px 活性评估氧化应激。通过免疫组化和免疫荧光检测观察 Nrf2 从细胞质向核内易位。
组织病理学评估表明，根皮素明显减轻了 IR 引起的肝损伤。此外，根皮素在体内和体外均对 IR 肝起保护作用，可减轻细胞凋亡和氧化应激。高浓度根皮素的引入促进了 Nrf2 从细胞质向核内易位，增加了 HR 后肝组织和肝细胞中其下游元件（至少 HO-1）的蛋白表达。Nrf2 抑制可逆转根皮素对 HR 肝细胞活力、细胞凋亡和氧化应激的作用，表明 Nrf2 信号通路是根皮素介导的肝 IRI 调节所必需的。
根皮素减轻肝 IRI 引起的肝损伤、细胞凋亡和氧化应激，至少通过 Nrf2/HO-1 信号通路，提示根皮素可作为肝 IRI 治疗的靶向药物。
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