Lupeol, a Pentacyclic Triterpene, Promotes Migration, Wound Closure, and Contractile Effect In Vitro: Possible Involvement of PI3K/Akt and p38/ERK/MAPK Pathways.

Fernando Pereira Beserra,Meilang Xue,Meilang Xue,Christopher Jackson,Ariane Leite Rozza,Cláudia Helena Pellizzon,Gabriela Maia

doi:10.3390/molecules23112819

Abstract

Skin wound healing is a dynamic and complex process involving several mediators at the cellular and molecular levels. Lupeol, a phytoconstituent belonging to the triterpenes class, is found in several fruit plants and medicinal plants that have been the object of study in the treatment of various diseases, including skin wounds. Various medicinal properties of lupeol have been reported in the literature, including anti-inflammatory, antioxidant, anti-diabetic, and anti-mutagenic effects. We investigated the effects of lupeol (0.1, 1, 10, and 20 μg/mL) on in vitro wound healing assays and signaling mechanisms in human neonatal foreskin keratinocytes and fibroblasts. Results showed that, at high concentrations, Lupeol reduced cell proliferation of both keratinocytes and fibroblasts, but increased in vitro wound healing in keratinocytes and promoted the contraction of dermal fibroblasts in the collagen gel matrix. This triterpene positively regulated matrix metalloproteinase (MMP)-2 and inhibited the NF-κB expression in keratinocytes, suggesting an anti-inflammatory effect. Lupeol also modulated the expression of keratin 16 according to the concentration tested. Additionally, in keratinocytes, lupeol treatment resulted in the activation of Akt, p38, and Tie-2, which are signaling proteins involved in cell proliferation and migration, angiogenesis, and tissue repair. These findings suggest that lupeol has therapeutic potential for accelerating wound healing.

Highlights

The skin is the largest organ of the human body limiting the organism’s exterior with the external environment whose main functions are protection against external agents, thermoregulation, and perception [1]
Human keratinocytes or fibroblasts were treated with lupeol at various concentrations ranging from 0.1 to 20 μg/mL before cell proliferation and viability were assessed by crystal violet and MTT ([3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide]) assay, respectively
Human keratinocytes or fibroblasts were treated with lupeol at various concentrations ranging 3 of 17

Summary

Introduction

The skin is the largest organ of the human body limiting the organism’s exterior with the external environment whose main functions are protection against external agents, thermoregulation, and perception [1]. Wound healing is a highly complex physiological process involving ordered events classified into three phases that overlap: hemostasis and inflammation (inflammatory phase), granulation tissue formation and re-epithelialization (proliferative phase), and wound contraction and tissue remodeling (extracellular matrix remodeling phase) [3]. This is a natural phenomenon that occurs through cellular and molecular responses and interactions with the main objective of reconstituting and restoring the integrity of the injured tissue [4]. During the cutaneous wound healing process, re-epithelialization via keratinocyte proliferation and migration and (myo)fibroblasts contraction result in wound closure [5]

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