Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents
Abstract
:1. Introduction
2. Paracrine Cytokine Mechanisms Underlying the Hyperpigmentation of UVB-Melanosis, Solar Lentigo and Melasma
3. Intracellular Signaling Mechanisms Associated with Endothelin-1 (EDN1) and Stem Cell Factor (SCF)
4. Effects of Specific Signaling Inhibitors on EDN1 or SCF Signaling
5. Effects of EDN1 or SCF on the Pigmentation of Human Epidermal Equivalents (HEEs)
6. Effects of Signaling Inhibitors on EDN1 or SCF-Stimulated Pigmentation
7. Screening of Herb Extracts or Natural Chemicals Capable of Interrupting the EDN1 or SCF-Triggered Intracellular Signaling Cascades
8. Withania somnifera
9. Effect of the Withania somnifera Extract (WSE) on EDN1 Signaling in Acral Lentigo Malignant (ALM) Melanoma Cells
10. Effect of the WSE on the EDN1-Stimulated Pigmentation of HEEs
11. Effect of the WSE on the Expression of Melanocyte-Specific Genes and Proteins
12. Summary of Substances Identified that Are Capable of Interrupting the SCF- or EDN1-Activated Intracellular Signaling Cascades and Their Abrogating Effects on the SCF- or EDN1-Stimulated Pigmentation in HEEs
13. Conclusions
Conflicts of Interest
Abbreviations
EDN1 | endothelin-1 |
EDNRB | endothelin B receptor |
IL | interleukin |
MAPK | mitogen activated protein kinase |
MITF | microphthalmia associated transcription factor |
NHM | normal human melanocytes |
PKA | protein kinase A |
PKC | protein kinase C |
SCF | stem cell factor |
TYRP-1 | tyrosinase-related protein-1 |
DCT | dopachrome tautomerase |
TYK | tyrosine kinase |
WSE | Withania somnifera extract |
MTE | Melia toosendan extract |
TNF | tumor necrosis factor |
αMSH | alpha melanocyte stimulating hormone |
bFGF | basic fibroblast growth factor |
ACTH | adrenocorticotropic hormone |
MC1R | melanocortin 1 receptor |
HEEs | human epidermal equivalents |
PAR2 | proteinase-activated receptor 2 |
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Five criteria to determine if a cytokine is an intrinsic factor involved in UVB hyperpigmentation | EDN1 | mSCF | αMSH | bFGF |
---|---|---|---|---|
EDNRB | c-KIT | MC1R | c-Met | |
1. The cytokine(s) should have the potential to activate melanocytes at physiological concentration in vitro. | ○ (1–10 nM) | ○ (1–10 nM) | Δ (>100 nM) | Δ (>100 nM) |
2. The cytokine(s) should exist in supernatants of UVB-exposed keratinocytes at concentrations sufficient to stimulate melanocytes. | ○ | – | ○ | × |
3. The stimulatory effect of culture supernatants on melanocytes should be neutralized by an antibody to the cytokine if it is secretable. | ○ | – | ○ | × |
4. The cytokine(s) should be highly expressed in UVB-exposed epidermis. | ○ | ○ | ○ | ○ |
5. The hyperpigmentation induced should be suppressed by antibodies that inhibit the corresponding receptor or by receptor antagonists in vivo. | ○ | ○ | × | × |
Withaferin A (WFA) | Astaxanthin (AX) | |||||||
---|---|---|---|---|---|---|---|---|
Herb extract of natural chemical | Tyrosinase activity | Cytotoxicity (MTT assay in NHM) | Inhibitory effects on signaling and targeted signal molecules | 3D human epidermal equivalent | Reference | |||
Direct inhibition | Abrogating effect | SCF signaling | EDN1 signaling | SCF | EDN1 | |||
Withania somnfera (WSE) | ○ | × | ○ | Ras/Raf-1 | PKC/Raf-1 | × | × | [40,50] |
Melia toosendan (MTE) | ○ | × | ○ | ○ | PKC/Raf-1 | ○ | × | [39] |
Astaxanthin (AX) | ○ | × | ○ | Raf-1/MEK | ○ | × | ○ | [51] |
Withaferin A (WFA) | ○ | × | ○ | c-KIT | PKC/Raf-1 | × | × | [22,39,52] |
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Imokawa, G.; Ishida, K. Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents. Int. J. Mol. Sci. 2014, 15, 8293-8315. https://doi.org/10.3390/ijms15058293
Imokawa G, Ishida K. Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents. International Journal of Molecular Sciences. 2014; 15(5):8293-8315. https://doi.org/10.3390/ijms15058293
Chicago/Turabian StyleImokawa, Genji, and Koichi Ishida. 2014. "Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents" International Journal of Molecular Sciences 15, no. 5: 8293-8315. https://doi.org/10.3390/ijms15058293