Juglone ameliorates skin wound healing by promoting skin cell migration through Rac1/Cdc42/PAK pathway

Abstract

Skin cell regeneration and wound healing are key processes in the recovery from skin injuries. Rapid cell migration and regeneration of skin cells lead to faster and better healing of wounded skin. In the present study, we aimed to investigate the wound healing potential of juglone, a naturally occurring Pin1 inhibitor found in walnuts. Cultured skin cells (NHDF and HaCaT) and hairless mice were treated with juglone after wound creation to examine its effects on cell migration and wound healing rate. The expressions of cell migration related proteins (Rac1, Cdc42, and α-PAK), collagen deposition, and angiogenesis were analyzed. Juglone treatment resulted in faster rate of growth and migration and recovered cell morphology, particularly at a concentration of 5 µM, in skin cells compared to the untreated group. In vivo experiments showed that mice treated with juglone showed faster wound healing rate with better skin morphology and collagen deposition than the vehicle group. Furthermore, juglone increased the activation and/or expression of Cdc42, Rac1, and α-pak in HaCaT cells, and resulted in enhanced angiogenesis in endothelial cells (HUVECs). Juglone also activated MAPKs signaling by activation of ERK, JNK, and p38 proteins. Taken together, these data suggest that juglone may be a potential candidate for wound healing and skin regeneration which ameliorates wound healing mainly by promoting skin cell migration through Rac1/Cdc42/PAK pathway.

NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway

“…Migration assays using NHdFs and HacaT cells revealed increased migration rates in the presence of NEd416, proving it an effective Sirt1 activator for its effects on skin cell migration and pointing toward the involvement of Sirt1 in cell migration during wound healing. These findings are consistent with the results of previous studies of the involvement of Sirt1 and its activators in tissue healing and cell migration (24,25,27).…”

“…Thus, in addition to later stages such as migration and tissue remodeling, NEd416 positively regulated the early stages of wound closure and inflammation. Resveratrol and juglone are Sirt1 activators from plant sources that showed wound healing potential in previous studies (27,37,38). Sirt1 activators, including NEd416, regulate wound healing mainly in the later phases.…”

“…Two identical wounds were created on the posterior dorsal region of each mouse using a 6-mm biopsy punch. NEd416 solutions to H&E and Masson's Trichrome staining as described by Wahedi et al (27). Images were captured using an inverted microscope (magnification, x10).…”

“…Our previous studies focused on identifying novel Sirt1 activators and evaluating their potential for skin wound healing and regeneration (26,27). In the present study, a novel synthetic activator of Sirt1, (E)-3-(2,4-dichlorophenyl)-N-phenylacrylamide (NEd416; Fig.…”

Juglone down-regulates the Akt-HIF-1α and VEGF signaling pathways and inhibits angiogenesis in MIA Paca-2 pancreatic cancer in vitro

“…It is a component of ancient medicine for ringworm, fungal, bacterial and viral infections (Thakur, 2011), and limited studies have been conducted to understand the antitumor properties of juglone (Aithal et al, 2009;Avci et al, 2016;Filaet al, 2008;Sugie et al, 1998;Wu et al, 2017). Juglone at concentration of 5-10 μM is not toxic to normal cells (Costantino et al, 2016;Wahedi et al, 2016). The present study was designed to determine juglone inhibitory activities against the migration and invasion of human pancreatic cancer MIA Paca-2 cells in vitro.…”