Shi Xiujin, Zhang Yi, Lin Baidi, Zhou Yang, Suo Wei, Wei Juanjuan, Zhang Lin, Lin Jie, Xiao Fucheng, Zhao Limin, Lin Yang
Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Department of Endocrinology and Metabolism, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Exp Physiol. 2021 Mar;106(3):653-662. doi: 10.1113/EP089021. Epub 2021 Feb 2.
What is the central question of this study? Does danthron alleviate experimental atherosclerosis by inhibiting the formation of foam cells? What are the main findings and their importance? Danthron improved serum lipid profiles and significantly reduced the atherosclerotic plaque areas and lipid accumulation in the aortic root of ApoE mice. Danthron inhibited foam cell formation in oxidized low-density lipoprotein-induced RAW264.7 macrophages. Furthermore, danthron exerted its function in atherosclerosis at least partly through activating the AMP-activated protein kinase-sirtuin 1 signalling pathway. These findings suggest that danthron has the potential to alleviate atherosclerosis.
Danthron, an ingredient isolated from Rheum palmatum L., has been revealed to reduce lipid accumulation in vitro. This study aimed to discover the effects of danthron on the development of atherosclerosis and to delineate the underlying mechanisms. For in vivo studies, male ApoE mice were fed a high-fat diet and orally treated with danthron (30 or 60 mg/kg/day) for 12 weeks. For in vitro studies, RAW264.7 cells were induced by oxidized low-density lipoprotein (ox-LDL, 50 μg/ml) for 48 h and subsequently administered danthron at appropriate concentrations for 24 h. AMP-activated protein kinase (AMPK) inhibitor compound C was added to ox-LDL-stimulated RAW264.7 cells 2 h before danthron administration to confirm the role of the AMPK signalling pathway in the regulation by danthron of foam cell formation. We found that danthron improved serum lipid profiles, and significantly reduced atherosclerotic plaque areas and lipid accumulation in the aortic root of atherosclerotic mice. Moreover, danthron upregulated the mRNA and protein expression of ATP-binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor α (LXRα), which play a crucial role in lipid metabolism, and activated the AMPK-sirtuin 1 (SIRT1) pathway. In an in vitro study, danthron inhibited foam cell formation in ox-LDL-induced RAW264.7 macrophages with an increase in the expression of ABCA1, ABCG1 and LXRα as well as activation of the AMPK-SIRT1 pathway. Furthermore, compound C abolished the effects of danthron on lipid accumulation and the protein expression of ABCA1/G1 and LXRα in vitro. Our results highlight that danthron possesses potential benefits in alleviating experimental atherosclerosis by targeting foam cell formation by activating the AMPK-SIRT1 signalling pathway.
本研究的核心问题是什么？番泻苷是否通过抑制泡沫细胞形成来减轻实验性动脉粥样硬化？主要发现及其重要性是什么？番泻苷改善了血清脂质谱，并显著减少了载脂蛋白E基因敲除（ApoE）小鼠主动脉根部的动脉粥样硬化斑块面积和脂质蓄积。番泻苷抑制了氧化型低密度脂蛋白诱导的RAW264.7巨噬细胞中泡沫细胞的形成。此外，番泻苷至少部分地通过激活AMP活化蛋白激酶-沉默信息调节因子1（AMP-activated protein kinase-sirtuin 1，AMPK-SIRT1）信号通路在动脉粥样硬化中发挥作用。这些发现表明番泻苷具有减轻动脉粥样硬化的潜力。
从掌叶大黄中分离出的成分番泻苷已被证实可在体外减少脂质蓄积。本研究旨在探究番泻苷对动脉粥样硬化发展的影响并阐明其潜在机制。在体内研究中，雄性ApoE小鼠喂食高脂饮食，并口服给予番泻苷（30或60毫克/千克/天），持续12周。在体外研究中，RAW264.7细胞用氧化型低密度脂蛋白（ox-LDL，50微克/毫升）诱导48小时，随后给予适当浓度的番泻苷处理24小时。在给予番泻苷前2小时，将AMP活化蛋白激酶（AMPK）抑制剂化合物C添加到ox-LDL刺激的RAW264.7细胞中，以确认AMPK信号通路在番泻苷调节泡沫细胞形成中的作用。我们发现，番泻苷改善了血清脂质谱，并显著减少了动脉粥样硬化小鼠主动脉根部的动脉粥样硬化斑块面积和脂质蓄积。此外，番泻苷上调了在脂质代谢中起关键作用的三磷酸腺苷结合盒转运体A1（ATP-binding cassette transporter A1，ABCA1）、ABCG1和肝X受体α（liver X receptor α，LXRα）的mRNA和蛋白表达，并激活了AMPK-沉默信息调节因子1（SIRT1）通路。在体外研究中，番泻苷抑制了ox-LDL诱导的RAW264.7巨噬细胞中泡沫细胞的形成，同时ABCA1、ABCG1和LXRα的表达增加以及AMPK-SIRT1通路被激活。此外，化合物C消除了番泻苷在体外对脂质蓄积以及ABCA1/G1和LXRα蛋白表达的影响。我们的结果突出表明，番泻苷通过激活AMPK-SIRT1信号通路靶向泡沫细胞形成，在减轻实验性动脉粥样硬化方面具有潜在益处。
