Department of Pathogen Biology, Logistics University of the Chinese People's Armed Police Force, Tianjin, China; Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Tianjin, China.
Department of Urology, The Affiliated Hospital of Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Int Immunopharmacol. 2018 Jun;59:76-85. doi: 10.1016/j.intimp.2018.03.041. Epub 2018 Apr 7.
AIMS/OBJECTIVE: Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models.
Male ApoE mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well-accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB.
PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL)-loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-κB) and activate peroxisome proliferator-activated receptor gamma (PPARγ) was confirmed using luciferase reporter assays. Conversely, the selective PPARγ antagonist GW9662 reversed the influence of PB in macrophages.
Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-κB activation PPARγ-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases.
动脉粥样硬化是一种大动脉硬化的进行性疾病，其特征为慢性炎症和异常免疫反应。已发现白头翁素 B（PB）通过抑制炎症反应发挥多种作用。然而，目前尚无使用相关体内和体外模型全面评估 PB 对动脉粥样硬化的影响。
雄性 ApoE 小鼠用 PB 经口给予高脂肪饮食（HFD）以阐明其抗动脉粥样硬化活性。RAW264.7 巨噬细胞系，一种公认的动脉粥样硬化细胞模型，用于研究 PB 的抗炎作用和分子机制。
PB 通过调节血浆脂质谱以及抑制动脉粥样硬化小鼠巨噬细胞中的炎症反应，显著减轻动脉粥样硬化病变。同时，PB 明显抑制促炎细胞因子的表达，并调节氧化型低密度脂蛋白（ox-LDL）负载巨噬细胞中的胆固醇流出相关基因。PB 还显著抑制 Dil 标记的 ox-LDL 的细胞摄取。此外，通过荧光素酶报告基因检测证实了 PB 抑制核因子 kappa B（NF-κB）和激活过氧化物酶体增殖物激活受体γ（PPARγ）的能力。相反，选择性 PPARγ拮抗剂 GW9662 逆转了 PB 在巨噬细胞中的影响。
综上所述，这些发现表明 PB 通过抑制巨噬细胞介导的炎症反应和细胞 ox-LDL 摄取，以及通过抑制 NF-κB 激活 PPARγ依赖性促进胆固醇流出，发挥对动脉粥样硬化的保护作用。因此，PB 可能是一种有前途的炎症和动脉粥样硬化疾病的治疗药物。
