绞股蓝中绞股蓝皂苷通过 PCSK9/LOX-1 通路改善内皮功能障碍的化学表征和缓解动脉粥样硬化的作用,Journal of Agricultural and Food Chemistry

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绞股蓝中绞股蓝皂苷通过 PCSK9/LOX-1 通路改善内皮功能障碍的化学表征和缓解动脉粥样硬化的作用
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2022-09-19 , DOI: 10.1021/acs.jafc.2c02681
Ya-Ping Huang ₁ , Yun-Shan Wang _{1,

2,

3} , Yuan-Yuan Liu _{2,

3} , Cui-Hua Jiang ₃ , Jie Wang ₄ , Xin-Yu Jiang ₅ , Bi-Wen Liu ₂ , Lei Wang ₆ , Wen-Cai Ye ₆ , Jian Zhang _{2,

3} , Zhi-Qi Yin ₁ , Ke Pan ₁

Affiliation

膳食皂苷具有改善动脉粥样硬化（AS）的潜力。Gynostemma pentaphyllum (GPs)的 Gypenosides已被用作具有抗动脉粥样硬化活性的功能性食品。本研究旨在探讨GPs在体内和体外对AS的保护作用、潜在机制和活性物质。结果表明，给予 GPs 可降低血清 TC 和 LDL-C 浓度，上调血浆 HDL-C 含量，抑制 ICAM-1、VCAM-1 和 MCP-1 的分泌，并减轻 VitD _{3中的血管病变}加上高胆固醇饮食诱导的 AS 大鼠以及 ox-LDL 刺激的 HUVECs 中粘附因子水平的降低，这可能与抑制 PCSK9/LOX-1 通路有关。对 GPs 的进一步活性指导植物化学研究导致鉴定出五种新的达玛烷型糖苷 ( 1-5 )和十种已知的类似物 ( 6-15 )。生物测定评估显示化合物1、6、7、12、13和14 _ _ _ _可观察到 PCSK9 和 LOX-1 的表达，以及受损 HUVECs 中粘附因子的分泌。分子对接实验表明，GPs 的活性皂苷可能与位于催化和 C 端结构域的 PCSK9 的变构口袋结合，并且 2α-OH-原人参二醇型绞股蓝皂苷可能通过以下方式对 PCSK9 上的变构结合位点发挥更高的亲和力。与 ARG-458 的氢键相互作用。这些发现为 GP 及其生物活性化合物在预防和发现新的 AS 治疗策略中的潜在营养应用提供了新的见解。

"点击查看英文标题和摘要"

Chemical Characterization and Atherosclerosis Alleviation Effects of Gypenosides from Gynostemma pentaphyllum through Ameliorating Endothelial Dysfunction via the PCSK9/LOX-1 Pathway

Dietary saponins have the potential to ameliorate atherosclerosis (AS). Gypenosides of Gynostemma pentaphyllum (GPs) have been used as functional foods to exhibit antiatherosclerotic activity. The present study aimed to explore the protective effect, underlying mechanism and active substances of GPs on AS in vivo and in vitro. Results demonstrated GPs administration reduced the serum concentrations of TC and LDL-C, upregulated the plasma HDL-C content, inhibited the secretion of ICAM-1, VCAM-1, and MCP-1, and alleviated vascular lesions in VitD₃ plus high cholesterol diet-induced AS rats as well as reduced adhesion factors levels in ox-LDL-stimulated HUVECs, which was potentially associated with suppressing PCSK9/LOX-1 pathway. Further activity-guided phytochemical investigation of GPs led to the identification of five new dammarane-type glycosides (1–5) and ten known analogs (6–15). Bioassay evaluation showed compounds 1, 6, 7, 12, 13, and 14 observably reduced the expressions of PCSK9 and LOX-1, as well as the secretion of adhesion factors in injured HUVECs. Molecular docking experiments suggested that the active saponins of GPs might bind to the allosteric pocket of PCSK9 located at the catalytic and C-terminal domains, and 2α–OH-protopanaxadiol-type gypenosides might exert a higher affinity for an allosteric binding site on PCSK9 by hydrogen-bond interaction with ARG-458. These findings provide new insights into the potential nutraceutical application of GPs and their bioactive compounds in the prevention and discovery of novel therapeutic strategies for AS.

更新日期：2022-09-19

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