As a well-known analgesic drug, acetaminophen (APAP) is commonly used to relieve pain for patients with chronic painful diseases. Our previous study has shown that long-term ingestion of APAP caused liver fibrosis in mice. This study further investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating APAP-induced liver fibrosis in mice and the anti-fibrotic effect of natural compound andrographolide (Andro). Our results showed that hepatic collagen deposition and hepatic stellate cells (HSCs) activation induced by APAP were more serious in Nrf2 knock-out mice than in normal wild-type mice. Andro reduced HSCs activation in vitro, and also decreased hepatic collagen deposition and HSCs activation induced by APAP in mice. Andro alleviated liver oxidative stress injury induced by APAP in mice and reduced cellular formation of reactive oxygen species (ROS) in HSCs. Andro enhanced Nrf2 nuclear translocation and increased the expression of Nrf2 downstream antioxidant genes both in vitro and in vivo. Furthermore, the Andro-provided protection against APAP-induced liver fibrosis was diminished in Nrf2 knock-out mice. In summary, Nrf2 is critically involved in preventing liver fibrosis induced by long-term administration of APAP in mice, and Andro alleviates APAP-induced liver fibrosis by attenuating liver oxidative stress injury via inducing Nrf2 activation. This study points out the potential application of Andro in the treatment of liver fibrosis in clinic.

译文

作为一种众所周知的镇痛药物,对乙酰氨基酚 (APAP) 通常用于缓解慢性疼痛性疾病患者的疼痛。我们先前的研究表明,长期摄入APAP会导致小鼠肝纤维化。本研究进一步探讨了核因子红细胞2相关因子2 (Nrf2) 在调节APAP诱导的小鼠肝纤维化中的关键作用以及天然化合物穿心莲内酯 (Andro) 的抗纤维化作用。我们的结果表明,在Nrf2敲除小鼠中,APAP诱导的肝胶原沉积和肝星状细胞 (HSCs) 激活比正常野生型小鼠更严重。Andro在体外减少了HSCs的激活,也减少了APAP诱导的小鼠肝胶原沉积和HSCs的激活。Andro减轻了APAP引起的小鼠肝脏氧化应激损伤,并减少了hsc中活性氧 (ROS) 的细胞形成。在体外和体内,Andro增强了Nrf2核易位,并增加了Nrf2下游抗氧化基因的表达。此外,在Nrf2敲除小鼠中,对APAP诱导的肝纤维化的保护作用减弱。总之,Nrf2在小鼠中通过长期施用APAP诱导的肝纤维化的预防中至关重要,并且Andro通过诱导Nrf2激活减轻肝脏氧化应激损伤来减轻APAP诱导的肝纤维化。本研究指出了Andro在临床治疗肝纤维化中的潜在应用。

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