Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.
Phytomedicine. 2013 Feb 15;20(3-4):295-302. doi: 10.1016/j.phymed.2012.10.013. Epub 2012 Dec 4.
Glucocorticoids are widely used in the clinical setting as remedies for inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. However, the constant increase in the number of patients suffering from glucocorticoid resistance could present a serious problem for clinicians. In these cases, it may be reasonable to use additional treatments to restore the therapeutic effect of glucocorticoids. Glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid (18βGA) are bioactive compounds in licorice that have been used for thousands of years in traditional Chinese medicine to treat coughs. We showed that GA and 18βGA exhibit potential anti-inflammatory and antioxidant properties. GA and 18βGA induced dual specificity protein phosphatase 1 (DUSP1) expression, and this effect was unchanged by the addition of RU486, a glucocorticoid receptor antagonist. The stimulation of DUSP1 expression by GA and 18βGA occurred via both glucocorticoid receptor (GR) and PI3K signaling, and the simultaneous activation of transcription elements, such as AP1 (activator protein 1), CRE (cAMP response element), GRE (glucocorticoid receptor element) and NFAT (nuclear factor of activated T-cells), was confirmed. Furthermore, we designed an in vitro glucocorticoid resistance model to verify the effects of GA and 18βGA on glucocorticoid resistance that was induced by ROS. The data showed that these two phytochemicals restored glucocorticoid sensitivity by depleting ROS through HO-1 expression. p38 and NO, which are factors that are induced by reactive oxygen species and caused depletion of GR signaling, were inhibited by GA and 18βGA treatment. This phenomenon was considered to be related to the coordinated modulation of GR and PI3K signaling by GA and 18βGA, in conjugation with AP1, CRE, GRE and NFAT activation. This study provides a possible strategy for enhancing the efficacy of glucocorticoids and may improve the prognosis of patients with serious inflammatory diseases.
糖皮质激素被广泛应用于临床，作为治疗哮喘和慢性阻塞性肺疾病等炎症性疾病的药物。然而，糖皮质激素抵抗患者数量的不断增加，可能会给临床医生带来严重的问题。在这种情况下，使用额外的治疗方法来恢复糖皮质激素的治疗效果可能是合理的。甘草酸（GA）和 18β-甘草次酸（18βGA）是甘草中的生物活性化合物，在中国传统医学中已使用了数千年，用于治疗咳嗽。我们表明，GA 和 18βGA 具有潜在的抗炎和抗氧化特性。GA 和 18βGA 诱导双特异性蛋白磷酸酶 1（DUSP1）的表达，而这种作用不受糖皮质激素受体拮抗剂 RU486 的影响。GA 和 18βGA 通过糖皮质激素受体（GR）和 PI3K 信号通路刺激 DUSP1 的表达，同时还证实了转录因子如 AP1（激活蛋白 1）、CRE（cAMP 反应元件）、GRE（糖皮质激素受体元件）和 NFAT（活化 T 细胞核因子）的激活。此外，我们设计了一种体外糖皮质激素抵抗模型，以验证 GA 和 18βGA 对 ROS 诱导的糖皮质激素抵抗的作用。数据表明，这两种植物化学物质通过 HO-1 表达来消耗 ROS，从而恢复糖皮质激素的敏感性。GA 和 18βGA 处理还抑制了由活性氧诱导的 p38 和 NO 等因素，这些因素导致 GR 信号通路耗竭。这种现象被认为与 GA 和 18βGA 通过协调调节 GR 和 PI3K 信号通路，以及激活 AP1、CRE、GRE 和 NFAT 有关。这项研究为增强糖皮质激素的疗效提供了一种可能的策略，并可能改善严重炎症性疾病患者的预后。
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