Ginsenoside Rb1 Enhances Keratinocyte Migration by a Sphingosine-1-Phosphate-Dependent Mechanism

Abstract

The cutaneous wound healing process is tightly regulated by a range of cellular responses, including migration. Sphingosine-1-phosphate (S1P) is a signaling lipid produced in keratinocytes (KC) and it is known to stimulate skin wound repair through increased KC migration. Of the multifunctional triterpene ginsenosides, Rb1 enhances cutaneous wound healing process by increasing KC migration, but cellular mechanisms responsible for the Rb1-mediated increase in KC migration are largely unknown. Therefore, we hypothesized that, and assessed whether, Rb1 could stimulate KC migration through S1P-dependent mechanisms. Rb1 significantly increases S1P production by regulating the activity of metabolic conversion enzymes associated with S1P generation and degradation, sphingosine kinase 1 (SPHK1) and S1P lyase, respectively, in parallel with enhanced KC migration. However, blockade of ceramide to S1P metabolic conversion using a specific inhibitor of SPHK1 attenuated the expected Rb1-mediated increase in KC migration. Furthermore, a pan-S1P receptor inhibitor pertussis toxin significantly attenuated Rb1-induced stimulation of KC migration. Moreover, the Rb1-induced increases in KC migration required S1P receptor(s)-mediated activation of ERK1/2 and NF-κB, leading to production of key cutaneous migrating proteins, matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, the results show that Rb1 stimulates KC migration through an S1P→S1P receptor(s)→ERK1/2→NF-κB→MMP-2/-9 pathway. This research revealed a previously unidentified cellular mechanism for Rb1 in enhancing KC migration and pointing to a new therapeutic approach to stimulate the cutaneous wound healing process.

Phenotypic overlap between atopic dermatitis and autism

“…Pertinently, VPA treatment of seizure disorders in humans can also provoke often severe, cutaneous hypersensitivity reactions [56,57]. We show here further that characteristic AD-like, lipid biochemical features [58], likely induced by elevated IFNg levels [59][60][61], appear not only in the epidermis [62,63], but also in the brain. Together, these results explain the phenotypic overlap of these two disorders, while also supporting a new paradigm for disease pathogenesis in the subset of ASD patients associated with AD.…”

N-Palmitoyl Serinol Stimulates Ceramide Production through a CB1-Dependent Mechanism in In Vitro Model of Skin Inflammation

“…Immortalized, non-transformed (HaCaT) human keratinocytes (KC), derived from the human epidermis (a gift from N. Fusenig, Heidelberg, Germany), were grown as described previously [ 22 ]. Culture medium was switched to serum-free KC growth medium containing 0.07 mM calcium chloride and growth supplements (Thermo Fisher Scientific, Carlsbad, CA, USA) 1 day prior to the N-palmitoyl serinol (PS, Dr. Raymond Laboratories, Englewood Cliffs, NJ, USA) treatment.…”

“…Alterations in the epidermal ceramide content have been characterized in certain inflammatory skin diseases, including atopic dermatitis (AD) [4]. In AD skin lesions, the content of ceramides containing long-chain fatty acids (FAs) (22)(23)(24)(25)(26) carbons in length) is significantly reduced, whereas ceramides with shortchain FAs (<20 carbons in length) are conversely elevated, leading to compromised barrier integrity [4].…”

Tetracyclic and Pentacyclic Triterpenes with High Therapeutic Efficiency in Wound Healing Approaches

“…In another in vitro study by Lee et al, on human dermal fibroblasts, results showed that ginsenosides obtained from a Panax ginseng root extract exert a healing effect by increasing type I collagen synthesis through the activation of the Smad pathway; the antioxidant effect of the extract also contributes to the healing process [107]. In a more in-depth study of the mechanism of action of ginsenosides by Shin et al [108] it has been reported that the healing effect of ginsenosides is related to their property of increasing the migration of human keratinocytes through a sphingosine-1-phosphate (S1P) dependent mechanism. The data obtained by Shin et al support the hypothesis that ginsenosides act through the S1P pathway, noting that they increase S1P production by regulating the activity of enzymes associated with the generation and degradation of S1P [sphingosine kinase 1 and S1P lyase).…”