Isoliquiritigenin from licorice flavonoids attenuates NLRP3-mediated pyroptosis by SIRT6 in vascular endothelial cells
Isoliquiritigenin from licorice flavonoids attenuates NLRP3-mediated pyroptosis by SIRT6 in vascular endothelial cells
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DOI：
10.1016/j.jep.2022.115952
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发表时间：
2022-11-29
影响因子：
5.4
通讯作者：
Lin, Rong
中科院分区：
文献类型：
--
作者：
He, Jianyu;Deng, Ying;Lin, Rong
民族药理学相关性：甘草是一种用于心血管疾病的传统中药。最近的研究发现，补充甘草提取物可以减轻高胆固醇血症患者动脉粥样硬化（AS）的发展。甘草黄酮是甘草的主要活性成分，具有抗炎、调节脂质代谢、抗氧化等多种药理作用。本研究的目的：探讨甘草黄酮类化合物抗动脉粥样硬化的活性成分及其作用机制。材料与方法：采用网络药理学方法筛选甘草黄酮类化合物抗动脉粥样硬化的活性成分。结果：构建了甘草黄酮类化合物-靶点网络，筛选出甘草黄酮类化合物中的3个活性成分，即异甘草素（isoliquiritigenin，ISL）、光甘草定（glabridin）和柚皮素（naringenin）。这3种成分的半数最大有效浓度值表明ISL是对抗TNF-α诱导的内皮细胞损伤的关键活性成分。京都基因和基因组百科全书（KEGG）通路分析表明ISL可能通过核苷酸结合和寡聚化结构域（NOD）样受体信号通路治疗AS。一项体外研究证实，ISL抑制TNF-α诱导的NLRP 3活化和HUVEC中的细胞凋亡。分子对接和细胞热位移分析表明ISL与III类组蛋白去乙酰化酶sirtuin 6（SIRT 6）之间具有良好的相容性。此外，我们发现ISL上调TNF-α处理的HUVECs中SIRT 6的表达。进一步的研究发现，SIRT 6敲低降低了ISL对pyroptosis的抑制作用，而NLRP 3 in-hibitor逆转了TNF-α处理的HUVECs.Conclusions这一过程：我们的研究结果表明，ISL是甘草黄酮的关键活性成分。ISL通过SIRT 6抑制NLRP 3介导的血管内皮细胞凋亡，SIRT 6可能是ISL治疗AS的潜在靶点。
Ethnopharmacologic relevance: Licorice is a traditional Chinese medicine that has been used for cardiovascular diseases. Recent studies found that supplementation with licorice extracts attenuated the development of atherosclerosis (AS) in hypercholesterolemic patients. Many studies have shown that licorice flavonoids, the main active components of licorice, have a variety of pharmacological effects, including anti-inflammation, regulation of lipid metabolism, and antioxidation. However, the key active components against AS in licorice flavonoids are still unclear.Aim of the study: The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms.Materials and methods: Network pharmacology was used to screen the active components of licorice flavonoids that have anti-atherosclerotic effects. Combining bioinformatics analysis and in vitro studies, the effects and underlying mechanisms of the active component isoliquiritigenin (ISL) on cell pyroptosis were further investi-gated in tumor necrosis factor (TNF)-alpha-treated human umbilical vein endothelial cells (HUVECs).Results: We constructed a compound-target network and screened 3 active components, namely, ISL, glabridin, and naringenin in licorice flavonoids. The half maximal effective concentration values of these 3 components suggested that ISL was the key active component against TNF-alpha-induced endothelial cell injury. Kyoto Ency-clopedia of Genes and Genomes (KEGG) pathway analysis showed that ISL could potentially treat AS via the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway. An in vitro study verified that ISL suppressed TNF-alpha-induced NLRP3 activation and pyroptosis in HUVECs. The molecular docking and cellular thermal shift assay showed good compatibility between ISL and class III histone deacetylase sirtuin 6 (SIRT6). Moreover, we found that ISL upregulated the expression of SIRT6 in TNF-alpha-treated HUVECs. Further study found that SIRT6 knockdown reduced the inhibitory effect of ISL on pyroptosis, whereas the NLRP3 in-hibitor reversed this process in TNF-alpha-treated HUVECs.Conclusions: Our results demonstrate that ISL is a key active component of licorice flavonoids. ISL attenuates NLRP3-mediated vascular endothelial cell pyroptosis via SIRT6, and SIRT6 may be a potential target of ISL for the treatment of AS.