BACKGROUND Higher levels of glucocorticoids (GCs), and impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis may cause or exacerbate the occurrence of metabolic and psychiatric disorders. It has been reported that ginseng saponin extract (GSE) has an inhibitory effect on the hyperactivity of the HPA axis induced by stresses and increased corticosterone level induced by intraperitoneal injection of adrenocorticotrophic hormone (ACTH) in mice. However, the molecular mechanisms by which GSE and its active ginsenosides inhibit corticosterone secretion remain elusive. MAIN METHODS Y1 mouse adrenocortical cells were treated with ACTH for up to 60 min to establish a cell model of corticosterone secretion. After treatment with different concentrations of GSE or ginsenoside monomers for 24 h prior to the addition of ACTH, analyses of cAMP content, PKA activity, and the levels of steroidogenesis regulators, melanocortin-2 receptor (MC2R), and melanocortin-2 receptor accessory protein (MRAP) in ACTH-induced Y1 cells were performed. RESULTS We demonstrated that GSE inhibits ACTH-stimulated corticosterone production in Y1 cells by inhibiting factors critical for steroid synthesis. Ginsenoside Rd, an active ingredient of GSE, inhibits corticosterone secretion in the cells and impedes ACTH-induced corticosterone biosynthesis through down-regulation of proteins in the cAMP/PKA/CREB signaling pathway. In addition, Western blot and qPCR analyses showed that ginsenoside Rd attenuated the induction of MC2R and MRAP by ACTH. CONCLUSION Our findings indicate that ginsenoside Rd inhibits ACTH-induced corticosterone production through blockading the MC2R-cAMP/PKA/CREB pathway in adrenocortical cells. Overall, this mechanism may represent an important therapeutic option for the treatment of stress-related disorders, further supporting the pharmacological benefits of ginseng.

中文翻译：

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人参皂苷Rd通过阻断Y1小鼠肾上腺皮质细胞中的MC2R-cAMP / PKA / CREB途径来减弱ACTH诱导的皮质酮分泌。

背景技术较高水平的糖皮质激素（GC）和下丘脑-垂体-肾上腺（HPA）轴的调节受损可能导致或加剧代谢和精神疾病的发生。据报道，人参皂苷提取物（GSE）对应激诱导的HPA轴功能亢进有抑制作用，而腹膜内注射肾上腺皮质营养激素（ACTH）则诱导皮质酮水平升高。但是，GSE及其活性人参皂甙抑制皮质类固醇分泌的分子机制仍然难以捉摸。主要方法用ACTH处理Y1小鼠肾上腺皮质细胞长达60分钟，以建立皮质酮分泌的细胞模型。在添加ACTH之前，用不同浓度的GSE或人参皂苷单体处理24小时后，分析了ACTH诱导的Y1细胞中cAMP含量，PKA活性以及类固醇生成调节剂，黑皮质素2受体（MC2R）和黑皮质素2受体辅助蛋白（MRAP）的水平。结果我们证明，GSE通过抑制类固醇合成的关键因子抑制Y1细胞中促肾上腺皮质激素刺激的皮质酮生成。人参皂苷Rd是GSE的活性成分，可通过下调cAMP / PKA / CREB信号通路中的蛋白质来抑制细胞中皮质酮的分泌，并阻止ACTH诱导的皮质酮生物合成。此外，蛋白质印迹和qPCR分析表明人参皂苷Rd减弱了ACTH对MC2R和MRAP的诱导。结论我们的发现表明人参皂苷Rd通过阻断肾上腺皮质细胞的MC2R-cAMP / PKA / CREB途径来抑制ACTH诱导的皮质酮生成。总体而言，该机制可能代表了与压力有关的疾病的重要治疗选择，进一步支持了人参的药理作用。