• Journal of Life Science
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• v.25 no.9
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• pp.976-983
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• 2015

Achyranthoside C dimethyl ester (ACDE) is an oleanolic acid glycoside from Achyranthes japonica which has been used in traditional medicine for the treatment of edema and arthritis. In this study, we investigated the anti-inflammatory effects of ACDE in RAW264.7 macrophages. ACDE significantly induced heme oxygenase-1 (HO-1) gene expression in RAW264.7 cells, while ACDE improved LPS-induced toxicity of cells. And ACDE induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. Further study demonstrated that ACDE-induced expression of HO-1 was inhibited by inhibitors of phosphatidylinositol 3-kinase (PI-3K) (LY294002), c-Jun kinase (JNK) (SP600125), extracellular signal regulated kinase (ERK) (PD98059) and p38 kinase (SB203580). Moreover, ACDE phosphorylated Akt, JNK, ERK, and p38 MAPK. In addition, ACDE inhibited LPS-induced NO secretion as well as inducible NO synthase (iNOS) expression in a dose-dependent manner. The inhibitory effects of ACDE on iNOS expression were abrogated by small interfering RNA (siRNA)-mediated knock-down of HO-1. Therefore, these results suggest that ACDE suppresses the production of pro-inflammatory mediator such as NO by inducing HO-1 expression via PI-3K/Akt/MAPK-Nrf2 signaling pathway. These findings could help us to understand the active principle included in the roots of A. japonica and the molecular mechanisms underlying anti-inflammatory action of ACDE.

• Journal of Life Science
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• v.23 no.6
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• pp.736-742
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• 2013

Achyranthoside E dimethyl ester (AEDE) is an oleanolic acid glycoside from Achyranthes japonica. In this study, we investigated the effects of AEDE on nitric oxide (NO) production and underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated macrophages. AEDE inhibited LPS-induced NO secretion as well as inducible NO synthase (iNOS) expression, without affecting cell viability. Further study demonstrated that AEDE induced heme oxygenase-1 (HO-1) gene expression. In addition, the inhibitory effects of AEDE on iNOS expression were abrogated by small interfering RNA-mediated knock-down of HO-1. Moreover, AEDE induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. AEDE-induced expression of HO-1 was inhibited by inhibitors of phosphatidylinositol 3-kinase (PI-3K) and extracellular signal regulated kinase (ERK1/2). AEDE phosphorylated Akt and ERK1/2 as well. Therefore, these results suggest that AEDE suppresses the production of pro-inflammatory mediator such as NO by inducing HO-1 expression via PI-3K/Akt/ERK-Nrf2 signaling. These findings provide the scientific rationale for anti-inflammatory therapeutic use of AEDE.

• Journal of Ginseng Research
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• v.39 no.3
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• pp.238-242
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• 2015

Background: Panax ginseng has been used to prolong longevity and is believed to be useful for improving skin complexion. Ginsenosides are the most active components isolated from ginseng, and ginsenoside Rg3 (G-Rg3) in particular has been demonstrated to possess antioxidative, antitumorigenic, and anti-inflammatory properties. The aim of this study was to examine the ability of G-Rg3 to inhibit melanogenesis. Methods: The effects of G-Rg3 on melanin contents and the protein levels of tyrosinase, microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein 1 (TRP1) were evaluated. Melanogenesis-regulating signaling molecules such as Akt and extracellular signal-regulated kinase (ERK) were also examined to explore G-Rg3-induced antimelanogenic mechanisms. Results: G-Rg3 was found to significantly inhibit the synthesis of melanin in normal human epidermal melanocytes and B16F10 cells in a dose-dependent manner. The activity of cellular tyrosinase and the expression of MITF, tyrosinase, and TRP1 were all reduced, whereas ERK was strongly activated. PD98059 (a specific inhibitor of ERK) attenuated the G-Rg3-induced inhibition of melanin synthesis and tyrosinase activity. Conclusion: Taken together, these results showed that G-Rg3 induces the activation of ERK, which accounts for its antimelanogenic effects. G-Rg3 may be a promising safe skin-whitening agent, adding to the long list of uses of P. ginseng for the enhancement of skin beauty.

• BMB Reports
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• v.45 no.12
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• pp.724-729
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• 2012

In this study, we evaluated the anti-melanogenesis effects of Caffeoylserotonin (CaS) in B16 melanoma cells. Treatment with CaS reduced the melanin content and tyrosinase (TYR) activity in B16 melanoma cells in a dose-dependent manner. CaS inhibited the expression of melanogenesis-related proteins, including microphthalmia-associated transcription factor (MITF), TYR, and tyrosinase-related protein-1 (TRP-1), but not TRP-2. ${\alpha}$-MSH is known to interact with melanocortin 1 receptor (MC1R) thus activating adenylyl cyclase and increasing intracellular cyclic AMP (cAMP) levels. Furthermore, cAMP activates extracellular signal-regulated kinase 2 (ERK2) via phosphorylation, which phosphorylates MITF, thereby targeting the transcription factor to proteasomes for degradation. The CaS reduced intracellular cAMP levels to unstimulated levels and activated ERK phosphorylation within 30 min. The ERK inhibitor PD98059 abrogated the suppressive effect of CaS on ${\alpha}$-MSH-induced melanogenesis. Based on this study, the inhibitory effects of CaS on melanogenesis are derived from the downregulation of MITF signaling via the inhibition of intracellular cAMP levels, as well as acceleration of ERK activation.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8539-8548
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• 2014

Mitogen-activated protein kinase (MAPK) is an important signaling pathway in living beings in response to extracellular stimuli. There are 5 main subgroups manipulating by a set of sequential actions: ERK(ERK1/ERK2), c-Jun N(JNK/SAPK), p38 MAPK($p38{\alpha}$, $p38{\beta}$, $p38{\gamma}$ and $p38{\delta}$), and ERK3/ERK4/ERK5. When stimulated, factors of upstream or downstream change, and by interacting with each other, these groups have long been recognized to be related to multiple biologic processes such as cell proliferation, differentiation, death, migration, invasion and inflammation. However, once abnormally activated, cancer may occur. Several components of the MAPK network have already been proposed as targets in cancer therapy, such as p38, JNK, ERK, MEK, RAF, RAS, and DUSP1. Among them, alteration of the RAS-RAF-MEK-ERK-MAPK(RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations in genes. The reported roles of MAPK signaling in apoptotic cell death are controversial, so that further in-depth investigations are needed to address these controversies. Based on an extensive analysis of published data, the goal of this review is to provide an overview on recent studies about the mechanism of MAP kinases, and how it generates certain tumors, as well as related treatments.

• Korean Journal of Veterinary Research
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• v.58 no.1
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• pp.1-7
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• 2018

Genus Artemisia occurs as a hardy plant and has a wide range of culinary and medicinal features. In this study, we aimed to describe the melanin inhibitory activity of one Artemisia species, i.e., Artemisia capillaris Thunb. Ethanol extracts of fermented Artemisia capillaris (Art.EtOH.FT) and non-fermented Artemisia capillaris (Art.EtOH.CT) were tested for their ability to inhibit tyrosinase activity and melanin pigmentation. Both extracts showed dose-dependent inhibition against ${\alpha}$-melanocyte stimulating hormone-stimulated melanin formation and tyrosinase activity, without cytotoxicity. At $100{\mu}g/mL$, both extracts showed greater inhibition than kojic acid, the positive control. Protein expressions of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2) at the transcriptional level were determined by using real-time and semi-quantitative polymerase chain reaction. To complete the mechanistic study, presences of upstream elements of MITF, the phosphorylated-extracellular signal-regulated kinase (p-ERK), and phosphorylated-mitogen-activated protein kinase kinase (p-MEK) were confirmed by using western blot analysis. Expressions of p-TYR, p-TRP-1 and p-TRP-2, downstream factors for p-ERK and p-MITF, were translationally inhibited by both extracts. Art.EtOH.FT induced more potent effects than Art.EtOH.CT, especially signal transduction effects. In summary, Artemisia capillaris extracts appear to act as potent hypopigmentation agents.

• Korean Journal of Plant Resources
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• v.35 no.6
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• pp.704-712
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• 2022

Research on whitening materials using natural alternatives is actively being conducted. The aim of this study was to investigate the in vitro inhibitory effects of Ranunculus chinensis Bunge (RCB) on melanogenesis and associated enzymes, such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 in B16F10 murine melanoma cells. We found that RCB extract significantly attenuated melanin synthesis and reduced the activity of intracellular tyrosinase, a rate-limiting melanogenic enzyme. Western blot analysis showed that RCB extract decreased the protein expression of tyrosinase and TRP-1. In addition, it significantly decreased the expression of microphthalmia-associated transcription factor (MITF), a key regulator of melanogenesis. Extracellular signal-regulated kinase (ERK) activation has been reported to be involved in the inhibition of melanogenesis. Thus, we investigated whether the hypopigmentary effects of RCB extract were related to the activation of ERK. RCB extract induced ERK phosphorylation in a dose-dependent manner. Furthermore, it markedly inhibited body pigmentation in a zebrafish model. Our results suggest that RCB extract inhibits melanogenesis by activating ERK pathway-mediated suppression of MITF and its downstream target genes, including tyrosinase. Therefore, RCB extract can be used as a whitening agent in the development of functional cosmetics.

• Journal of Life Science
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• v.20 no.11
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• pp.1617-1624
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• 2010

Recently, it has been found that Asiasari radix showed a hypopigmenting effect on melanogenesis through activation of mitogen-activated protein kinase (MEK)/extracellular signal-activated kinase (ERK) in B16F10 melanoma cells. However, the hypopigmenting effect of A. radix on the $\alpha$-melanocyte stimulating hormone ($\alpha$-MSH)-stimulated melanogenesis has remained unknown. The purpose of this study was to investigate the inhibitory mechanism of the partially purified A. radix (PPAR)-induced hypopigmentating effects on $\alpha$-MSH-stimulated melanogenesis in B16F10 mouse melanoma cells. PPAR strongly inhibited tyrosinase activity and leads to decreased melanin synthesis in $\alpha$-MSH-stimulated B16F10 melanoma cells. PPAR also decreased the $\alpha$-MSH-induced over-expression of the melanogenic enzymes, tyrosinase, tyrosinase-related protein (TRP)-1, dopachrome tautomerase (Dct) and microphthalmia-associated transcription factor (MITF). We further showed that PPAR inhibits $\alpha$-MSH-induced melanogenesis via phosphorylation of MEK/ERK and PI3K/Akt, and that their activation was blocked by MEK inhibitors, PD98059 and PI3K inhibitors, LY294002 in $\alpha$-MSH-stimulated B16F10 melanoma cells. These results suggest that PPAR inhibits $\alpha$-MSH-induced melanogenesis by activation of MEK/ERK and PI3K/Akt through MITF degradation, which may lead to down-regulation of tyrosinase.

• Journal of Applied Biological Chemistry
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• v.64 no.4
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• pp.447-451
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• 2021

In this study, we discovered for the first time that linarin, a flavonoid compound, enhances melanin biosynthesis in B16F10 cells, and subsequently elucidated the underlying mechanism of linarin-induced melanogenesis. Linarin showed no cytotoxicity at a concentration of 42 μM and significantly increased intracellular tyrosinase activity and melanin content in B16F10 cells. Mechanistic analysis showed that linarin increased the expression of tyrosinase, tyrosinase-related protein 1 (TRP-1), and microphthalmia-associated transcription factor (MITF) that are related to melanogenesis. Moreover, linarin decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT). Finally, we evaluated the effect of the structure-activity relationship of linarin and its aglycone on melanogenesis. The results indicated that linarin enhances the expression of melanogenic proteins by activating MITF expression via the modulation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and protein kinase B signaling pathways in B16F10 cells, thereby enhancing melanogenesis.

• Horticultural Science & Technology
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• v.31 no.6
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• pp.813-820
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• 2013

Monoterpenoids were recently found as main biologically active compounds which is responsible for various physiological effect in goat's beard (Aruncus dioicus). Ethyl acetate extract of A. dioicus (ADE) was treated to B16F10 melanoma cells for the examination of whitening activity. MTT assay was performed to evaluate cell toxicity and the result showed that slight cell toxicity (> 10%) by over $500{\mu}g{\cdot}mL^{-1}$. Thus, 0, 5, 10, or $50{\mu}g{\cdot}mL^{-1}$ ADE was used for further experiments. We found that tyrosinase activity was decreased according to ADE concentration, and the total melanin content was also dramatically reduced. Especially with $50{\mu}g{\cdot}mL^{-1}$ ADE treatment tyrosinase activity was reduced to 35.6%, and 58.8% of melanin content was lowered. In addition, whitening related proteins including tyrosinase, tyrosinase related protein 1 (TRP1), TRP2, microphthalmia associated transcription factor (MITF) and cAMP and protein kinase A (PKA) were reduced by ADE treatment. It caused decreased phosphorylation of cAMP response binding protein (CREB) but increased phosphorylation of extracellular signal related kinase (ERK). Therefore, in this paper we would like to suggest the potent usage of A. dioicus natively grown in Ulleungdo, Korea as materials of functional cosmetics by confirming whitening activity related with melanin content.