Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol

Abstract

3-hydroxytyrosol (HT) is the main phenolic compound found in olive oil with known antioxidant, anti-inflammatory, and antimicrobial properties in several dermatological conditions, both when taken in the form of olive oil or pure in cosmeceutical formulations. To date, its direct effect on the wound healing process and the molecular mechanisms involved have not yet been elucidated. Thus, in the present study, we aimed to explore its effects in vitro in epidermal keratinocyte cultures focusing on the molecular mechanism implied. HT was able to induce keratinocyte proliferation in the low micromolar range, increasing the expression of cyclin dependent kinases fundamental for cell cycle progression such as CDK2 and CDK6. Furthermore, it increased cell migration through the activation of tissue remodeling factors such as matrix metalloproteinase-9 (MMP-9) protein. Then, we evaluated whether HT also showed antioxidant activity at this concentration range, protecting from H2O2-induced cytotoxicity. The HT prevented the activation of ATM serine/threonine kinase (ATM), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2), and p53, reducing the number of apoptotic cells. Our study highlighted novel pharmacological properties of HT, providing the first evidence of its capability to induce keratinocyte migration and proliferation required for healing processes and re-epithelialization.

Biological effects of the olive tree and its derivatives on the skin

“…Similarly, the protective role of viability was observed in those cells pre-treated with Htyr to which H 2 O 2 was subsequently added, significantly reducing cell apoptosis and showing antioxidant activity. 121…”

“…Moreover, it could improve the cell migration through the activation of some tissue remodeling factors. 121 Uvaol (natural pentacyclic triterpene found in olives and virgin olive oil)…”

Potential Effects of Phenolic Compounds That Can Be Found in Olive Oil on Wound Healing

“…In in vitro studies, HTyr was found to inhibit the production of nitric oxide and PGE-2 and the expression of cyclooxygenase-2 (COX-2) and metalloproteinase-9 and to increase the production of TNF-α in monocytes [ 66 ]. HTyr treatment has promoted the proliferation and migration of human keratinocytes, porcine vascular endothelial cells, and HUVEC-C cells, thereby favoring angiogenesis and the re-epithelialization of skin wounds [ 67 , 68 , 69 ]. The antioxidant activity of HTyr was demonstrated in human keratinocytes subjected to UVB rays, observing that it protects against DNA damage and reduces intracellular ROS [ 70 ].…”

Mangostanin, a Xanthone Derived from Garcinia mangostana Fruit, Exerts Protective and Reparative Effects on Oxidative Damage in Human Keratinocytes

“…At the end of the treatment with H 2 O 2 , methanol extract of Garcinia mangostana arils (1 µg/mL) and mangostanin (10 µM), cells were washed with ice-cold PBS 2% FBS and loaded with 20 µM of H 2 DCFDA for 30 min. The cells were washed again with PBS 2% FBS, acquired by flow cytometry where at least 10,000 events were collected and next analyzed by Cell-Quest Pro software (BD Biosciences, San Jose, CA, USA) [58].…”