Tian Wencong, Song Peng, Zang Junhao, Zhao Jia, Liu Yanhong, Wang Chuntao, Fang Hong, Wang Hongzhi, Zhao Yongjie, Liu Xingqiang, Gao Yang, Cao Lei
Department of General Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, 300122, PR China.
School of Medicine, Nankai University Tianjin, 300071, PR China.
J Ethnopharmacol. 2025 Jan 31;340:119169. doi: 10.1016/j.jep.2024.119169. Epub 2024 Nov 29.
As a traditional Chinese medicine, Salvia miltiorrhiza Bunge has been widely used to treat ischemic and inflammation-related diseases for more than 2000 years. S. miltiorrhiza Bunge has hepatoprotective effects, but the underlying mechanism is not fully understood.
To verify the effect of tanshinone IIA (Tan IIA), the main fat-soluble component of S. miltiorrhiza Bunge, on liver damage induced by sepsis/LPS-induced inflammation and further explore the underlying mechanisms.
Mice were administered Tan IIA 2 h before cecal ligation and puncture (CLP). Liver damage was evaluated by hematoxylin-eosin staining and changes in related serum factor levels. The expression of silent information regulator sirtuin 1 (SIRT1), Sestrin2, HO-1 and inflammatory cytokines was examined by immunohistochemistry or western blotting. LPS was used to induce the inflammatory response in vitro, and the activity of the related signaling pathway in response to Tan IIA was detected by western blotting. The SIRT1 inhibitor EX-527 and small interfering RNAs (siRNAs) were employed to determine the key roles of SIRT1 and Sestrin2 in Tan IIA's function.
We found that Tan IIA significantly improved the pathological changes and function of the liver, and alleviated liver damage in CLP mice. Additionally, SIRT1, Sestrin2, and HO-1 expression was significantly elevated after Tan IIA treatment compared with that in the CLP group both in vivo and in vitro, and Tan IIA treatment additionally suppressed pro-inflammatory cytokine release. However, inhibition of either SIRT1 or Sestrin2 remarkably abrogated the protective effects of Tan IIA. Most importantly, Sestrin2 appeared to function downstream of SIRT1 based on their expression changes after EX-527 or siRNA treatment.
Tan IIA inhibited sepsis/LPS-induced inflammation through the SIRT1/Sestrin2/HO-1 pathway, thereby protecting against sepsis-induced liver injury (SLI). This study suggests that Tan IIA has therapeutic potential against SLI and that the SIRT1/Sestrin2/HO-1 signaling pathway might be a viable target for SLI treatment.
丹参作为一种传统中药，两千多年来一直被广泛用于治疗缺血性疾病和炎症相关疾病。丹参具有肝脏保护作用，但其潜在机制尚未完全明确。
验证丹参主要脂溶性成分丹参酮IIA（Tan IIA）对脓毒症/脂多糖（LPS）诱导的炎症所致肝损伤的作用，并进一步探究其潜在机制。
在小鼠盲肠结扎穿孔（CLP）术前2小时给予Tan IIA。通过苏木精-伊红染色及相关血清因子水平变化评估肝损伤情况。采用免疫组织化学或蛋白质印迹法检测沉默信息调节因子sirtuin 1（SIRT1）、Sestrin2、血红素加氧酶-1（HO-1）及炎性细胞因子的表达。体外使用LPS诱导炎症反应，通过蛋白质印迹法检测Tan IIA作用后相关信号通路的活性。使用SIRT1抑制剂EX-527和小干扰RNA（siRNA）确定SIRT1和Sestrin2在Tan IIA功能中的关键作用。
我们发现Tan IIA显著改善了肝脏的病理变化和功能，减轻了CLP小鼠的肝损伤。此外，与CLP组相比，Tan IIA处理后体内和体外的SIRT1、Sestrin2和HO-1表达均显著升高，且Tan IIA处理还抑制了促炎细胞因子的释放。然而，抑制SIRT1或Sestrin2均显著消除了Tan IIA的保护作用。最重要的是，基于EX-527或siRNA处理后它们的表达变化来看，Sestrin2似乎在SIRT1的下游发挥作用。
Tan IIA通过SIRT1/Sestrin2/HO-1途径抑制脓毒症/LPS诱导炎症，从而预防脓毒症诱导的肝损伤（SLI）。本研究表明Tan IIA对SLI具有治疗潜力，且SIRT1/Sestrin2/HO-1信号通路可能是SLI治疗的一个可行靶点。
