Identifi cation of the Underlying Genetic Factors of Skin Aging in a Korean Population Study.

Genetic polymorphisms may affect the molecular mechanisms underlying determination of skin type. So far, several genetic studies have been reported; however, very few studies have been conducted to examine the relationship between genotype and skin phenotypes. In this study, the genome sequences of individuals tested for five cosmetic characteristics (wrinkles, moisture content, pigmentation, oil content, and ensitivity) were determined, and we also conducted five genome-wide association studies (GWASs) to identify predictive markers. Some single-nucleotide polymorphisms (SNPs) within those genes were more frequent in individuals exhibiting stronger traits. GWASs revealed that two genome-wide significant SNPs within FCRL5 and OCA2 genes were associated with wrinkles and pigmentation, respectively (p < 5 × 10-8), and that genomewide SNPs in 21 genes (wrinkles: FCRL5, REEP3, ADSS, and SPTLC1; moisture: TBX4, TRPM3, CEMIP2, CTSH, and TTC39C; pigmentation: OCA2, NCLN, TNS1, CDC42BPA, HS3ST4, and UNCX; oil: SYN2, CNDP1, GAS6, INSR, and TNFRSF19; and sensitivity: CREB5) might be associated with five skin phenotypes. Among these, a genome-wide significant SNP (rs117381658) and the SNP located downstream of FCRL5, which encodes a member of the immunoglobulin receptor family, were associated with an increased risk of wrinkles (p = 1.52 × 10-8). The other genome-wide significant SNP (rs74653330) was associated with a decreased risk of pigmentation (p = 1.04 × 10-8), which is located in the coding region of OCA2 that encodes for a transporter of melanin. Our study reports genetic factors associated with skin cosmetology parameters in the Korean population. We hope our findings will provide a foundation for further genetic and molecular studies related to custom cosmetics. Based on these findings, the industry will be able to provide consumers with ingredients capable of palliating the lack of function associated in genes with SNPs.

A systems-biological study on the identification of safe and effective molecular targets for the reduction of ultraviolet B-induced skin pigmentation.

Melanogenesis is the process of melanin synthesis through keratinocytes-melanocytes interaction, which is triggered by the damaging effect of ultraviolet-B (UVB) rays. It is known that melanogenesis influences diverse cellular responses, including cell survival and apoptosis, via complex mechanisms of feedback and crosstalk. Therefore, an attempt to suppress melanin production by modulating the melanogenesis pathway may induce perturbations in the apoptotic balance of the cells in response to UVB irradiation, which results in various skin diseases such as melasma, vitiligo, and skin cancer. To identify such appropriate target strategies for the reduction of UVB-induced melanin synthesis, we reconstructed the melanogenesis signaling network and developed a Boolean network model. Mathematical simulations of the melanogenesis network model revealed that the inhibition of beta-catenin in the melanocytes effectively reduce melanin production while having minimal influence on the apoptotic balance of the cells. Exposing cells to a beta-catenin inhibitor decreased pigmentation but did not significantly change the B-cell Chronic lymphocytic leukemia/lymphoma 2 expression, a potent regulator of apoptotic balance. Thus, our systems analysis suggests that the inhibition of beta-catenin may be the most appropriate target strategy for the reduction of UVB-induced skin pigmentation.

Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS-ERK activation.

Mitochondrial dynamics control mitochondrial functions as well as their morphology. However, the role of mitochondrial dynamics in melanogenesis is largely unknown. Here, we show that mitochondrial dynamics regulate melanogenesis by modulating the ROS-ERK signaling pathway. Genetic and chemical inhibition of Drp1, a mitochondrial fission protein, increased melanin production and mitochondrial elongation in melanocytes and melanoma cells. In contrast, down-regulation of OPA1, a mitochondria fusion regulator, suppressed melanogensis but induced massive mitochondrial fragmentation in hyperpigmented cells. Consistently, treatment with CCCP, a mitochondrial fission chemical inducer, also efficiently repressed melanogenesis. Furthermore, we found that ROS production and ERK phosphorylation were increased in cells with fragmented mitochondria. And inhibition of ROS or ERK suppressed the antimelanogenic effect of mitochondrial fission in α-MSH-treated cells. In addition, the activation of ROS-ERK pathway by mitochondrial fission induced phosphorylation of serine73 on MITF accelerating its proteasomal degradation. In conclusion, mitochondrial dynamics may regulate melanogenesis by modulating ROS-ERK signaling pathway.

Depigmentation effect of kadsuralignan F on melan-a murine melanocytes and human skin equivalents.

The development of melanogenic inhibitors is important for the prevention of hyperpigmentation, and, recently, consideration has been given to natural materials or traditionally used ingredients such as Chinese medicine. The aim of this study is the evaluation of a new anti-melanogenic candidate, kadsuralignan F, from the natural plant Kadsura coccinea, as well as the determination of mechanisms of melanogenesis inhibition at a molecular level. Kadsuralignan F significantly reduced melanin synthesis in a dose-dependent manner in a murine melanocyte cell line and human skin equivalents. There was no direct inhibition on mushroom tyrosinase or cell-extract tyrosinase activity, and mRNA expression of tyrosinase and other melanogenic genes such as tyrosinase-related protein-1 (trp-1) or trp-2 were not affected by kadsuralignan F. Interestingly, the protein level of tyrosinase was dramatically downregulated with kadsuralignan F treatment. We found that a decrease of tyrosinase protein by kadsuralignan F was fully recovered by MG132, a proteasome inhibitor, but not by chloroquine, a lysosome inhibitor. In this study, we found that kadsuralignan F, a lignan from an extract of Kadsura coccinea, has an inhibitory activity on melanin synthesis through tyrosinase degradation. These findings suggest that kadsuralignan F can be used as an active ingredient for hyperpigmentation treatment.

Identification of sake extract as a new anti-melanogenic ingredient by in vitro and clinical trials.

Overproduction of melanin is the cause of skin hyperpigmentation, which is related to several skin diseases and cosmetic concerns. Sake is a Japanese alcoholic beverage produced from rice and water by fermentation, but is little known for its effect on melanogenesis. To identify the effect of sake extract on melanin synthesis, a melanin assay was performed in melan-A murine melanocytes. Sake extract treatment significantly inhibited melanin production in a dose-dependent manner, and tyrosinase, the rate-limiting enzyme of melanogenesis, decreased significantly at the protein level. Further investigations were performed with multiple assay systems; a sake extract reduced melanin production in melan-A/SP-1 murine cell co-culture, and also in MelanoDerm, a skin equivalent model of human keratinocytes-melanocytes. Finally, subjects were treated with a formula containing the sake extract. Topical application of the sake extract product improved skin lightness (L*) significantly within 7 days. We identified sake extract as a new anti-melanogenic ingredient through in vitro and in vivo experiments. These results suggest that a sake extract can be used to improve skin hyperpigmentation.

Effects of ortho-dihydroxyisoflavone derivatives from Korean fermented soybean paste on melanogenesis in B16 melanoma cells and human skin equivalents.

In this study we investigated the inhibitory effects and possible mechanisms of action of 8'-hydroxydaidzein and 3'-hydroxydaidzein, two ortho-dihydroxyisoflavone derivatives from Korean fermented soybean paste, on melanogenesis in B16 murine melanoma cells. The two hydroxydaidzeins reduced melanin synthesis comparably to treatment with kojic acid, a proven whitening agent, in B16 melanoma cells. Furthermore, when in vitro human skin equivalents were treated with the hydroxydaidzeins, the levels of melanogenesis were significantly reduced relative to a kojic acid control. The RT-PCR results demonstrated that depigmentation was due to transcriptional repression of several melanogenesis genes, including microphthalmia-associated transcription factor (MITF), by the hydroxydaidzeins. The immunoblotting results confirmed that diminution of MITF expression subsequently decreased expression of tyrosinase, and tyrosinase-related proteins 1 and 2. Cumulatively, these results suggest that hydroxydaidzeins would be potent attenuators of melanin synthesis as well as effective inhibitors of hyperpigmentation in human skin.