Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2020 Nov;41(11):1433-1445. doi: 10.1038/s41401-020-0406-6. Epub 2020 May 13.
In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg· d, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.
一般来说，尽管病因不同，但多种肝脏疾病都被认为需要进行抗炎治疗。但是，目前用于缓解肝脏炎症的药物存在缺陷，因此需要开发更有效和更安全的肝脏损伤药物。在这项研究中，我们从 Pholidota chinensis 中筛选了一系列（二氢）二苯乙烯或（二氢）菲衍生物，以研究它们的潜在生物学活性。在 31 种化合物中，二氢二苯乙烯 gigantol 对人肝细胞对抗石胆酸毒性的保护作用最强，并在体外表现出良好的抗氧化和抗炎作用。在 CCl 诱导的急性肝损伤小鼠中，gigantol（10、20、40 mg·kg·d，po，连续 7 天）预处理可剂量依赖性降低血清转氨酶水平并改善肝组织的病理变化。脂质过氧化和炎症反应的升高也被 gigantol 显著缓解。药代动力学研究表明，gigantol 在小鼠肝脏中高度富集，这与其预防肝损伤的疗效一致。使用无标记定量蛋白质组学分析，我们发现 gigantol 主要调节 CCl 处理小鼠肝脏中的免疫系统过程，补体和凝血级联是主要途径；gigantol 显著抑制补体成分 C9 的表达，C9 是末端补体复合物（TCC）C5b-9 形成的关键成分。免疫组化（IHC）或实时 PCR 验证了这些结果。共聚焦显微镜分析表明，gigantol 可显著抑制 TCC 在肝脏中的血管沉积。总之，我们首次证明口服 gigantol 可有效缓解肝脏氧化应激和炎症，可能通过抑制肝脏中 C5b-9 的形成发挥新的作用机制。
