Abstract

Licorice (Glycyrrhiza) species have been widely used as a traditional medicine and a natural sweetener in foods. The 18β-glycyrrhetinic acid (18β-GA) is a bioactive compound in licorice that exhibits potential anti-cancer, anti-inflammatory, and anti-microbial activities. Many synthesized derivatives of 18β-GA have been reported to be cytotoxic and suggested for the treatment of malignant diseases. In this study, we explored the possible pharmacological roles of an 18β-GA derivative in skin biology using primary human dermal fibroblasts and HaCaT keratinocytes as cell models. We found that this 18β-GA derivative did not cause cell death, but significantly enhanced the proliferation of dermal fibroblasts and HaCaT keratinocytes. A scratch wound healing assay revealed that the 18β-GA derivative promoted the migration of fibroblasts. Due to the important role of aquaporin-3 in cell migration and proliferation, we also investigated the expression of aquaporin-3 and found this compound up-regulated the expression of aquaporin-3 in dermal fibroblasts and HaCaT keratinocytes. In dermal fibroblasts, the 18β-GA derivative induced the phosphorylation of Akt, ERK, and p38. The inhibitor of Akt predominantly suppressed the 18β-GA derivative-induced expression of aquaporin-3. Collectively, this compound had a positive effect on the proliferation, migration, and aquaporin-3 expression of skin cells, implying its potential role in the treatment of skin diseases characterized by impaired wound healing or dermal defects.

Highlights

  • The roots and rhizomes of licorice (Glycyrrhiza) species have been widely used in herbal medicine for a long time

  • Glycyrrhizic acid, a triterpenoid saponin glycoside, is the major water-soluble constituent of licorice [3, 6]. Glycyrrhetinic acid is another natural triterpenoid in licorice, which is obtained by hydrolyzing glycyrrhizic acid by glucuronidase; it exists in two forms: 18α-glycyrrhetinic acid (18α-GA) and a stereoisomeric form, 18β-glycyrrhetinic acid (18β-GA) [6]

  • The phosphorylation of c-Jun NH2-terminal kinase (JNK), induced by THF or the 18β-GA-d, was barely detected. These results indicated that the Akt, ERK1/2, and p38 pathways could possibly regulate the pharmacological effects of the 18β-GA-d on human dermal fibroblasts

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Summary

Introduction

The roots and rhizomes of licorice (Glycyrrhiza) species have been widely used in herbal medicine for a long time. Delayed wound healing process with reduced keratinocyte proliferation and migration was observed in AQP-3-knockout mice [22]. AQP-3 has been reported to regulate human skin fibroblast migration, indicating its role in the wound healing process [23]. These findings indicated that AQP-3 played a critical role in regulating the proliferation and migration of skin cells. We explored other possible effects of this 18β-GAd on the biological functions of the skin using primary human dermal fibroblasts derived from. 18ß-GA derivative promotes proliferation, migration and aquaporin-3 expression in human dermal fibroblasts adult foreskin and HaCaT keratinocytes as cell models. Because AQP-3 is the predominant skin AQP crucial for the physiological functions of the skin such as cell proliferation, migration, and intact barrier function, we evaluated the influence of the 18β-GA-d on the expression of AQP-3 in skin cells

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