Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd., Ningbo 315100, China.
The Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo 315000, China.
Int J Mol Sci. 2023 Jul 11;24(14):11320. doi: 10.3390/ijms241411320.
A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We found that subcutaneous injection of acacetin prodrug (5, 10, 20 mg/kg) decreased serum ALT, AST, and ALP, corrected the abnormal MDA and GSH in liver, and improved intrahepatic hemorrhage and destruction of liver structures in APAP (300 mg/kg)-treated mice. Molecular mechanism analysis revealed that the expressions of endoplasmic reticulum (ER) stress markers ATF6, CHOP, and p-PERK, apoptosis-related protein BAX, and cleaved caspase 3 were decreased by acacetin in a dose-dependent manner in vivo and in vitro. Moreover, via the acacetin-upregulated peroxisome-proliferator-activated receptor gamma (PPARγ) of HepG2 cells and liver, the suppressive effect of acacetin on ER stress and apoptosis was abolished by PPARγ inhibitor (GW9662) or PPARγ-siRNA. Molecular docking revealed that acacetin can bind to three active pockets of PPARγ, mainly by hydrogen bond. Our results provide novel evidence that acacetin prodrug exhibits significant protective effect against APAP-induced liver injury by targeting PPARγ, thereby suppressing ER stress and hepatocyte apoptosis. Acacetin prodrug is likely a promising new drug candidate for treating patients with acute liver injury induced by APAP.
我们小组之前已经合成并报道了一种水溶性的芹菜素前药。对乙酰氨基酚（APAP）过量是导致急性肝损伤的主要原因。我们发现，皮下注射芹菜素前药（5、10、20mg/kg）可降低血清 ALT、AST 和 ALP，纠正肝内异常 MDA 和 GSH，并改善 APAP（300mg/kg）处理小鼠的肝内出血和肝结构破坏。分子机制分析表明，芹菜素在体内和体外均以剂量依赖性方式降低内质网（ER）应激标志物 ATF6、CHOP 和 p-PERK、凋亡相关蛋白 BAX 和 cleaved caspase 3 的表达。此外，通过上调 HepG2 细胞和肝脏中的过氧化物酶体增殖物激活受体γ（PPARγ），PPARγ 抑制剂（GW9662）或 PPARγ-siRNA 可消除芹菜素对 ER 应激和细胞凋亡的抑制作用。分子对接表明，芹菜素可以结合 PPARγ 的三个活性口袋，主要通过氢键结合。我们的研究结果为芹菜素前药通过靶向 PPARγ 对 APAP 诱导的肝损伤具有显著的保护作用提供了新的证据，从而抑制 ER 应激和肝细胞凋亡。芹菜素前药可能是治疗 APAP 诱导的急性肝损伤患者的一种有前途的新药候选物。
