Department of General Practice, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China.
Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130021, China.
Int Immunopharmacol. 2022 Jul;108:108710. doi: 10.1016/j.intimp.2022.108710. Epub 2022 Apr 8.
Sepsis is a life-threatening medical condition caused by infection-triggered aberrant immune responses, leading to host tissue and organ injury. Despite advances in medical interventions, the mortality rate for septic shock remains high. Recent studies highlight the role of oxidative stress in the occurrence and development of sepsis, providing a potential therapeutic target for preventing sepsis-associated organ injury. In this study, we showed that Maackiain, a natural compound isolated from Sophora flavescens, exerted a protective role in a cecal ligation and puncture (CLP)-induced murine model of sepsis. Maackiain treatment reduced organ injury, and mitigated systematic inflammation and oxidative stress in septic mice. Maackiain also reduced the levels of inflammatory cytokines and reactive oxygen species (ROS) in RAW264.7 macrophage cells stimulated with lipopolysaccharide (LPS). We further demonstrated that Maackiain initiated activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in RAW264.7 cells in an AMP-activated protein kinase (AMPK)-dependent way. Moreover, inhibition of AMPK/Nrf2 axis abrogated the anti-inflammatory and anti-oxidant effects of Maackiain both in vitro and in vivo. Collectively, our study indicates that Maackiain treatment inhibits inflammatory response and oxidative stress via activation of AMPK/Nrf2/HO-1 pathway, thus exerting a protective effect against sepsis, providing an alternative option for sepsis prevention.
脓毒症是一种危及生命的医学病症，由感染引发的异常免疫反应引起，导致宿主组织和器官损伤。尽管医疗干预取得了进展，但脓毒性休克的死亡率仍然很高。最近的研究强调了氧化应激在脓毒症发生和发展中的作用，为预防与脓毒症相关的器官损伤提供了一个潜在的治疗靶点。在这项研究中，我们表明，从苦参中分离出来的天然化合物苦参碱在盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠模型中发挥了保护作用。苦参碱治疗减轻了脓毒症小鼠的器官损伤，并减轻了系统性炎症和氧化应激。苦参碱还降低了脂多糖（LPS）刺激的 RAW264.7 巨噬细胞中炎症细胞因子和活性氧（ROS）的水平。我们进一步证明，苦参碱通过依赖 AMP 激活蛋白激酶（AMPK）的方式，在 RAW264.7 细胞中启动核因子红细胞 2 相关因子 2（Nrf2）/血红素加氧酶-1（HO-1）通路的激活。此外，抑制 AMPK/Nrf2 轴在体外和体内均消除了苦参碱的抗炎和抗氧化作用。总之，我们的研究表明，苦参碱通过激活 AMPK/Nrf2/HO-1 通路抑制炎症反应和氧化应激，从而对脓毒症发挥保护作用，为脓毒症的预防提供了一种替代选择。
