Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
Drug Clinical Trial Institution, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, China.
Phytomedicine. 2021 Jul;87:153586. doi: 10.1016/j.phymed.2021.153586. Epub 2021 May 5.
Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases.
The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis.
Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin.
Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury.
The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1β (IL-1β) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro.
These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.
化学性肝损伤是急性肝衰竭和死亡的主要原因之一。然而，迄今为止，急性肝损伤的治疗策略仍然有限。因此，迫切需要寻找新的治疗靶点和有效的药物。NOD 样受体含 pyrin 结构域蛋白 3（NLRP3）炎性小体是一种由多种蛋白质组成的复合物，已被证明在炎症和应激病理条件下诱导细胞死亡，被认为是治疗多种疾病的新靶点。
本研究旨在探讨木犀草素对肝脏是否具有保护作用，并进一步阐明其是否通过硫氧还蛋白相互作用蛋白（TXNIP）-NLRP3 轴来实现。
用或不用木犀草素处理腹腔注射脂多糖（LPS）引起的小鼠急性肝损伤。
选择雄性 C57BL/6 小鼠和小鼠原代肝细胞。通过 siRNA 实现 TXNIP 蛋白敲低，通过 qPCR 和 Western blot 进行研究，以探讨木犀草素缓解急性肝损伤的作用机制。
结果表明，木犀草素通过抑制 TXNIP-NLRP3 轴对 LPS 诱导的小鼠急性肝损伤具有明显的保护作用。木犀草素通过抑制 TXNIP、凋亡相关斑点样蛋白（ASC）、半胱天冬酶-1（caspase-1）、白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）来抑制 NLRP3 炎性小体的激活，从而减轻肝损伤。此外，木犀草素通过抑制炎症相关基因肿瘤坏死因子-α（TNF-α）、IL-10 和 IL-6 的产生来抑制 LPS 诱导的肝脏炎症。更重要的是，木犀草素通过抑制氧化应激和调节 MDA、SOD 和 GSH 水平来减轻 LPS 诱导的肝细胞损伤。然而，在体外，木犀草素对 LPS 诱导的急性肝损伤的保护作用被 si-TXNIP 阻断。
这些综合数据表明，木犀草素可能通过 TXNIP-NLPR3 轴减轻 LPS 诱导的肝损伤，为后续研究提供新的治疗靶点和治疗药物。
