Glycyrrhizic acid and 18β-glycyrrhetinic acid recover glucocorticoid resistance via PI3K-induced AP1, CRE and NFAT activation

Tzu Chien Kao, Chi Hao Wu, Gow Chin Yen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)295-302
Number of pages8
JournalPhytomedicine
Volume20
Issue number3-4
DOIs
Publication statusPublished - Feb 15 2013

Fingerprint

Glycyrrhetinic Acid
Glycyrrhizic Acid
NFATC Transcription Factors
Transcription Factor AP-1
Response Elements
Phosphatidylinositol 3-Kinases
Glucocorticoid Receptors
Glucocorticoids
Dual Specificity Phosphatase 1
Protein Phosphatase 1
Glycyrrhiza
Chinese Traditional Medicine
Phytochemicals
Therapeutic Uses
Glucocorticoid Receptor Deficiency
Cough
Chronic Obstructive Pulmonary Disease
Transcriptional Activation
Reactive Oxygen Species
Anti-Inflammatory Agents

Keywords

  • 18β-Glycyrrhetinic acid
  • Glucocorticoid receptor
  • Glucocorticoid resistance
  • Glycyrrhizic acid
  • Phosphoinositide 3-kinase

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Pharmaceutical Science
  • Complementary and alternative medicine
  • Molecular Medicine

Cite this

Glycyrrhizic acid and 18β-glycyrrhetinic acid recover glucocorticoid resistance via PI3K-induced AP1, CRE and NFAT activation. / Kao, Tzu Chien; Wu, Chi Hao; Yen, Gow Chin.

In: Phytomedicine, Vol. 20, No. 3-4, 15.02.2013, p. 295-302.

Research output: Contribution to journalArticle

Kao, Tzu Chien ; Wu, Chi Hao ; Yen, Gow Chin. / Glycyrrhizic acid and 18β-glycyrrhetinic acid recover glucocorticoid resistance via PI3K-induced AP1, CRE and NFAT activation. In: Phytomedicine. 2013 ; Vol. 20, No. 3-4. pp. 295-302.
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