柚皮苷元通过依赖 Nrf2 和 PPARa 减轻氧化应激和炎症反应来改善对乙酰氨基酚诱导的急性肝损伤。
Pectolinarigenin ameliorates acetaminophen-induced acute liver injury via attenuating oxidative stress and inflammatory response in Nrf2 and PPARa dependent manners.
机构信息
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University; Henan Engineering Technology Research Center of Organ Transplantation; Henan Research Centre for Organ Transplantation, No. 1, East Jianshe Road, Zhengzhou 450001, China.
出版信息
Phytomedicine. 2023 May;113:154726. doi: 10.1016/j.phymed.2023.154726. Epub 2023 Feb 24.
BACKGROUND
Cirsii Japonici Herba Carbonisata (Dajitan in Chinese) has been used to treat liver disorders in Asian countries. Pectolinarigenin (PEC), an abundant constituent in Dajitan, has been found to possess a wide range of biological benefits, including hepatoprotective effects. However, the effects of PEC on acetaminophen (APAP)-induced liver injury (AILI) and the underlying mechanisms have not been studied.
PURPOSES
To explore the role and mechanisms of PEC in protecting against AILI.
STUDY DESIGN AND METHODS
The hepatoprotective benefits of PEC were studied using a mouse model and HepG2 cells. PEC was tested for its effects by injecting it intraperitoneally before APAP administration. To assess liver damage, histological and biochemical tests were performed. The levels of inflammatory factors in the liver were measured using RT-PCR and ELISA. Western blotting was used to measure the expression of a panel of key proteins involved in APAP metabolism, as well as Nrf2 and PPARα. PEC mechanisms on AILI were investigated using HepG2 cells, while the Nrf2 inhibitor (ML385) and PPARα inhibitor (GW6471) were used to validate the importance of either Nrf2 and PPARα in the hepatoprotective effects of PEC.
RESULTS
PEC treatment decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) levels in the liver. PEC pretreatment increased the activity of superoxide dismutase (SOD) and glutathione (GSH) while decreasing malondialdehyde production (MDA). PEC could also up-regulate two important APAP detoxification enzymes (UGT1A1 and SULT1A1). Further research revealed that PEC reduced hepatic oxidative damage and inflammation, and up-regulated APAP detoxification enzymes in hepatocytes by activating the Nrf2 and PPARα signaling pathways.
CONCLUSIONS
PEC ameliorates AILI by decreasing hepatic oxidative stress and inflammation while increasing phase Ⅱ detoxification enzymes related to APAP harmless metabolism through activation of Nrf2 and PPARα signaling. Hence, PEC may serve as a promising therapeutic drug against AILI.
背景
中药丹参炭被用于治疗亚洲国家的肝脏疾病。在丹参中含量丰富的丹酚酸 B （PEC）已被发现具有广泛的生物学益处，包括肝保护作用。然而，PEC 对乙酰氨基酚（APAP）诱导的肝损伤（AILI）的作用及其潜在机制尚未得到研究。
目的
探索 PEC 防治 AILI 的作用和机制。
研究设计和方法
采用小鼠模型和 HepG2 细胞研究 PEC 的肝保护作用。通过在 APAP 给药前腹腔注射 PEC 来检测其作用。通过组织学和生化试验评估肝损伤程度。采用 RT-PCR 和 ELISA 测定肝内炎症因子水平。采用 Western blot 测定参与 APAP 代谢的一组关键蛋白以及 Nrf2 和 PPARα 的表达。采用 HepG2 细胞研究 PEC 对 AILI 的作用机制，同时使用 Nrf2 抑制剂（ML385）和 PPARα 抑制剂（GW6471）验证 Nrf2 和 PPARα 在 PEC 肝保护作用中的重要性。
结果
PEC 治疗可降低血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）水平。PEC 预处理可增加超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的活性，同时降低丙二醛（MDA）的产生。PEC 还可上调两种重要的 APAP 解毒酶（UGT1A1 和 SULT1A1）。进一步研究表明，PEC 通过激活 Nrf2 和 PPARα 信号通路，减少肝氧化损伤和炎症，上调肝细胞中与 APAP 无害代谢相关的解毒酶，从而改善 AILI。
结论
PEC 通过激活 Nrf2 和 PPARα 信号通路，减少肝氧化应激和炎症，增加与 APAP 无害代谢相关的Ⅱ相解毒酶，从而改善 AILI。因此，PEC 可能成为治疗 AILI 的一种有前途的药物。
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