International Journal of Molecular Sciences

Editorial

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3 pages, 172 KiB

Open AccessEditorial

Skin Pigmentation: Is the Control of Melanogenesis a Target within Reach?

by Alessandra Napolitano and Shosuke Ito

Int. J. Mol. Sci. 2018, 19(12), 4040; https://doi.org/10.3390/ijms19124040 - 14 Dec 2018

Cited by 5 | Viewed by 3315

Abstract

Skin pigmentation represents one of the most peculiar traits of human beings and its alteration as a consequence of pathological conditions has a dramatic impact on the wellness of individuals and their social relationships. [...] Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

Research

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13 pages, 3278 KiB

Open AccessArticle

Quercetin 3-O-(6″-O-E-caffeoyl)-β-D-glucopyranoside, a Flavonoid Compound, Promotes Melanogenesis through the Upregulation of MAPKs and Akt/GSK3β/β-Catenin Signaling Pathways

by Changhai Liu, Mayire Nueraihemaiti, Deng Zang, Salamet Edirs, Guoan Zou and Haji Akber Aisa

Int. J. Mol. Sci. 2023, 24(5), 4780; https://doi.org/10.3390/ijms24054780 - 1 Mar 2023

Cited by 4 | Viewed by 2124

Abstract

Quercetin 3-O-(6″-O-E-caffeoyl)-β-D-glucopyranoside is a flavonoid compound produced by various plants with reported antiprotozoal potential against E. histolytica and G. lamblia; however, its effects on skin pigment regulation have not been studied in detail. In this investigation, we discovered that quercetin 3-O-(6″-O-E-caffeoyl)—D-glucopyranoside (coded [...] Read more.

Quercetin 3-O-(6″-O-E-caffeoyl)-β-D-glucopyranoside is a flavonoid compound produced by various plants with reported antiprotozoal potential against E. histolytica and G. lamblia; however, its effects on skin pigment regulation have not been studied in detail. In this investigation, we discovered that quercetin 3-O-(6″-O-E-caffeoyl)—D-glucopyranoside (coded as CC7) demonstrated a more increased melanogenesis effect in B16 cells. CC7 exhibited no cytotoxicity or effective stimulating melanin content or intracellular tyrosinase activity. This melanogenic-promoting effect was accompanied by activated expression levels of microphthalmia-associated transcription factor (MITF), a key melanogenic regulatory factor, melanogenic enzymes, and tyrosinase (TYR) and tyrosinase-related protein-1 (TRP-1) and 2 (TRP-2) in the CC7-treated cells. Mechanistically, we found that CC7 exerted melanogenic effects by upregulating the phosphorylation of stress-regulated protein kinase (p38) and c-Jun N-terminal kinase (JNK). Moreover, the CC7 upregulation of phosphor-protein kinase B (Akt) and Glycogen synthase kinase-3 beta (GSK-3β) increased the content of β-catenin in the cell cytoplasm, and subsequently, it translocated into the nucleus, resulting in melanogenesis. Specific inhibitors of P38, JNK, and Akt validated that CC7 promotes melanin synthesis and tyrosinase activity by regulating the GSK3β/β-catenin signaling pathways. Our results support that the CC7 regulation of melanogenesis involves MAPKs and Akt/GSK3β/β-catenin signaling pathways. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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34 pages, 12689 KiB

Open AccessArticle

Multiphoton FLIM Analyses of Native and UVA-Modified Synthetic Melanins

by Ana-Maria Pena, Shosuke Ito, Thomas Bornschlögl, Sébastien Brizion, Kazumasa Wakamatsu and Sandra Del Bino

Int. J. Mol. Sci. 2023, 24(5), 4517; https://doi.org/10.3390/ijms24054517 - 24 Feb 2023

Cited by 5 | Viewed by 2535

Abstract

To better understand the impact of solar light exposure on human skin, the chemical characterization of native melanins and their structural photo-modifications is of central interest. As the methods used today are invasive, we investigated the possibility of using multiphoton fluorescence lifetime (FLIM) [...] Read more.

To better understand the impact of solar light exposure on human skin, the chemical characterization of native melanins and their structural photo-modifications is of central interest. As the methods used today are invasive, we investigated the possibility of using multiphoton fluorescence lifetime (FLIM) imaging, along with phasor and bi-exponential fitting analyses, as a non-invasive alternative method for the chemical analysis of native and UVA-exposed melanins. We demonstrated that multiphoton FLIM allows the discrimination between native DHI, DHICA, Dopa eumelanins, pheomelanin, and mixed eu-/pheo-melanin polymers. We exposed melanin samples to high UVA doses to maximize their structural modifications. The UVA-induced oxidative, photo-degradation, and crosslinking changes were evidenced via an increase in fluorescence lifetimes along with a decrease in their relative contributions. Moreover, we introduced a new phasor parameter of a relative fraction of a UVA-modified species and provided evidence for its sensitivity in assessing the UVA effects. Globally, the fluorescence lifetime properties were modulated in a melanin-dependent and UVA dose-dependent manner, with the strongest modifications being observed for DHICA eumelanin and the weakest for pheomelanin. Multiphoton FLIM phasor and bi-exponential analyses hold promising perspectives for in vivo human skin mixed melanins characterization under UVA or other sunlight exposure conditions. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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10 pages, 846 KiB

Open AccessCommunication

A Model Eumelanin from 5,6-Dihydroxyindole-2-Carboxybutanamide Combining Remarkable Antioxidant and Photoprotective Properties with a Favourable Solubility Profile for Dermo-Cosmetic Applications

by Rita Argenziano, Maria Laura Alfieri, Noemi Gallucci, Gerardino D’Errico, Lucia Panzella and Alessandra Napolitano

Int. J. Mol. Sci. 2023, 24(4), 4241; https://doi.org/10.3390/ijms24044241 - 20 Feb 2023

Viewed by 1867

Abstract

The search for new synthetic melanin-related pigments that maintain the antioxidant and photoprotective properties of naturally occurring dark eumelanins, while overcoming their unfavorable solubility, and molecular heterogeneity is presently a very active issue for dermo-cosmetic purposes. In this work, we explored the potential [...] Read more.

The search for new synthetic melanin-related pigments that maintain the antioxidant and photoprotective properties of naturally occurring dark eumelanins, while overcoming their unfavorable solubility, and molecular heterogeneity is presently a very active issue for dermo-cosmetic purposes. In this work, we explored the potential of a melanin obtained from the carboxybutanamide of a major eumelanin biosynthetic precursor, 5,6-dihydroxyindole-2-carboxylic acid (DHICA), by aerobic oxidation under slightly alkaline conditions. Analysis of the pigment by EPR, ATR-FTIR and MALDI MS indicated a substantial structural similarity to DHICA melanin, while investigation of the early intermediates confirmed unchanged regiochemistry of the oxidative coupling. The pigment exhibited a UVA–visible absorption even more intense than that of DHICA melanin, and a noticeable solubility in polar solvents of dermo-cosmetic relevance. The hydrogen- and/or electron-donor ability, and the iron (III) reducing power as determined by conventional assays provided evidence for marked antioxidant properties not merely ascribable to the more favorable solubility profile, while the inhibitory action of the radical- or photosensitized solar light-induced lipid peroxidation was more marked compared to that of DHICA melanin. Overall, these results hint at this melanin, which remarkable properties are, in part, due to the electronic effects of the carboxyamide functionality as a promising functional ingredient for dermo-cosmetic formulations. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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16 pages, 2682 KiB

Open AccessArticle

New Butyroside D from Argan Press Cake Possess Anti-Melanogenesis Effect via MITF Downregulation in B16F10 and HEM Cells

by Meryem Bouhoute, Yhiya Amen, Meriem Bejaoui, Aprill Kee Oliva Mizushima, Kuniyoshi Shimizu and Hiroko Isoda

Int. J. Mol. Sci. 2022, 23(24), 16021; https://doi.org/10.3390/ijms232416021 - 16 Dec 2022

Cited by 2 | Viewed by 2146

Abstract

Hyperpigmentation is a skin condition where patches of skin become darker in color due to excess melanin production upon UV exposure leading to melasma, which are lentigines or post inflammatory hyperpigmentation that psychologically affecting a great number of people. The present study investigates [...] Read more.

Hyperpigmentation is a skin condition where patches of skin become darker in color due to excess melanin production upon UV exposure leading to melasma, which are lentigines or post inflammatory hyperpigmentation that psychologically affecting a great number of people. The present study investigates the anti-melanogenic effect of Butyroside D and the underling mechanism. After the confirmation of the non-cytotoxic effect of Butyroside D on B16F10 cells, we proceeded with analyzing the impact of the treatment at low and high concentration (i.e., 0.2 μM and 2 μM) using gene profiling analysis and examined the differentiation in gene expression. Our results identify cyclic adenosine monophosphate (cAMP), Wnt/β-catenin and Mitogen-Activated Protein Kinase (MAPK) signaling pathways to be downregulated upon treatment with Butyroside D. These pathways were targeted to further validate the effect of Butyroside D on membrane receptors melanocortin 1 receptor (MC1R) and receptor tyrosine kinase (c-Kit), related microphthalmia-associated transcription factor (MITF) and consequently tyrosinase (TYR), and tyrosine-related protein-1 (TYRP-1) that were all shown to be downregulated and, therefore, leading to the repression of melanin biosynthesis. Finally, the anti-melanogenic effect of Butyroside D was confirmed on human epidermal melanocytes (HEM) cells by inhibiting the activation of cAMP pathway generally mediated through α-melanocyte-stimulating hormone (α-MSH) and MC1R. Overall, this study suggests the potential applicability of this purified compound for the prevention of hyperpigmentation conditions. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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17 pages, 4698 KiB

Open AccessArticle

SNA077, an Extract of Marine Streptomyces sp., Inhibits Melanogenesis by Downregulating Melanogenic Proteins via Inactivation of cAMP/PKA/CREB Signaling

by Su-Jin Lim, Da-Won Jung, Prima F. Hillman, Sang-Jip Nam and Chang-Seok Lee

Int. J. Mol. Sci. 2022, 23(23), 14922; https://doi.org/10.3390/ijms232314922 - 29 Nov 2022

Cited by 4 | Viewed by 1867

Abstract

Excess melanin in skin is known to be the main cause of hyper-pigmentary skin diseases such as freckles and lentigo. This study aimed to evaluate the depigmenting efficacy of an extract from the marine microorganism strain, Streptomyces sp. SNA077. To determine the anti-melanogenic [...] Read more.

Excess melanin in skin is known to be the main cause of hyper-pigmentary skin diseases such as freckles and lentigo. This study aimed to evaluate the depigmenting efficacy of an extract from the marine microorganism strain, Streptomyces sp. SNA077. To determine the anti-melanogenic efficacy of SNA077, we assessed the melanin contents of SNA077-treated B16, Melan-a, and MNT-1 cells. We observed the expression of key enzymes in melanogenesis via qRT-PCR and Western blot analyses. We further estimated the skin-whitening effect of SNA077 using a skin-equivalent model. SNA077 dramatically decreased the melanin production of B16 cells, Melan-a, and MNT-1 cells. In B16 cells treated with SNA077, the activity of cellular tyrosinase was clearly inhibited. In addition, the mRNA and protein expression levels of melanogenic genes were suppressed by SNA077 treatment in B16 and MNT-1 cells. Upstream of tyrosinase, the expression levels of phospho-CREB, phospho-p38, PKA activity, cyclic AMP production, and MC1R gene expression were inhibited by SNA077. Finally, SNA077 clearly showed a skin-brightening effect with a reduced melanin content in the skin tissue model. Collectively, our results suggest for the first time that an extract of marine Streptomyces sp. SNA077 could be a novel anti-melanogenic material for skin whitening. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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16 pages, 3259 KiB

Open AccessArticle

Effects of Aging on Hair Color, Melanosomes, and Melanin Composition in Japanese Males and Their Sex Differences

by Takashi Itou, Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2022, 23(22), 14459; https://doi.org/10.3390/ijms232214459 - 21 Nov 2022

Cited by 5 | Viewed by 2646

Abstract

In a previous study, we observed that the hair color of Japanese females darkens with age and that the causes of this are the increase in melanosome size, the amount of melanin, and the mol% of 5,6-dihydroxyindole (DHI) which has a high absorbance. [...] Read more.

In a previous study, we observed that the hair color of Japanese females darkens with age and that the causes of this are the increase in melanosome size, the amount of melanin, and the mol% of 5,6-dihydroxyindole (DHI) which has a high absorbance. In this study, we extended the same analyses to male hair to examine the sex differences in hair color, melanin composition, and melanosome morphology. Male hair also tended to darken with age, but it was darker than female hair in those of younger ages. Although there was no age dependence of DHI mol% in male hair, as with female hair, the melanosomes’ sizes enlarged with age, the total melanin amount increased, and these findings were correlated with hair color. The analyses, considering age dependence, revealed that there were significant sex differences in the ratio of absorbance of dissolved melanin at the wavelength of 650 nm to 500 nm, in pheomelanin mol%, and in melanosome morphology parameters such as the minor axis. This may be the cause of the sex differences in hair color. Furthermore, the factors related to hair color were analyzed using all the data of the male and female hairs. The results suggested that total melanin amount, pheomelanin mol%, and DHI mol% correlated with hair color. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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18 pages, 7474 KiB

Open AccessArticle

A Novel Furocoumarin Derivative, 5-((diethylamino)me-13 thyl)-3-phenyl-7H-furo [3,2-g] chromen-7-one Upregulates Melanin Synthesis via the Activation of cAMP/PKA and MAPKs Signal Pathway: In Vitro and In Vivo Study

by Deng Zang, Chao Niu, Xueying Lu and Haji Akber Aisa

Int. J. Mol. Sci. 2022, 23(22), 14190; https://doi.org/10.3390/ijms232214190 - 16 Nov 2022

Cited by 4 | Viewed by 2257

Abstract

Psoralen, a major furocoumarin component of the Fructus Psoralen (FP), in combination with ultraviolet radiation, cures abnormal pigmentation disorder. In a previous study, we synthesized a series of linear furocoumarins with different substituents, out of which 5-((diethylamino)methyl)-3-phenyl-7H-furo [3,2-g] chromen-7-one (encoded as 5D3PC) showed [...] Read more.

Psoralen, a major furocoumarin component of the Fructus Psoralen (FP), in combination with ultraviolet radiation, cures abnormal pigmentation disorder. In a previous study, we synthesized a series of linear furocoumarins with different substituents, out of which 5-((diethylamino)methyl)-3-phenyl-7H-furo [3,2-g] chromen-7-one (encoded as 5D3PC) showed better pigmenting effect than others in B16 cells. In this study, we examined the mechanism underlying the melanogenic effect of 5D3PC both in vivo and in vitro. To examine the pigmentation effect, the B16 and human melanocyte cell lines, PIG1 and PIG3V melanocytes were incubated with 5D3PC. In animal experiments, C57BL/6 mice received 5% hydroquinone and were administrated with 5D3PC for 30 days. 5D3PC upregulated the melanin synthesis and tyrosinase in B16 cell, PIG1 and PIG3V. The expression level of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2), microphthalmia-associated transcription factor (MITF), cyclic adenosine monophosphate (cAMP), phosphorylation of cAMP-responsive element binding protein (p-CREB), phosphorylation of p38 mitogen-activated protein kinase (MAPK), c- phosphorylation of Jun N-terminal kinase (p-JNK) was significantly higher in 5D3PC-treated B16 cells. The oral administration of 5D3PC attenuated the depigmentation of the C57BL/6 vitiligo mice model by increasing the numbers of melanin-containing hair follicles, melanogenic protein, and melanogenesis-relative genes expression in skin tissues. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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10 pages, 1581 KiB

Open AccessArticle

Extraction and Concentration of Waste Pueraria lobata Stems with Antioxidants and Anti-Melanogenesis Activity as a Novel Skin Whitening Agent for Natural Cosmetic Prototypes

by Dan Gao, Chong-Woon Cho, Jin-Hyeok Kim, Cheong-Taek Kim, Won-Seok Jeong, Ye Wang, Xiwen Li and Jong-Seong Kang

Int. J. Mol. Sci. 2022, 23(18), 10352; https://doi.org/10.3390/ijms231810352 - 8 Sep 2022

Cited by 5 | Viewed by 2409

Abstract

The root of Pueraria lobata (Willd.) is used commercially in different products, including dietary supplements, cosmetics, and teas, but its stem part is rarely used and studied. Therefore, this study evaluated the antioxidant and anti-melanogenesis activities of the bioactive fraction of P. lobata [...] Read more.

The root of Pueraria lobata (Willd.) is used commercially in different products, including dietary supplements, cosmetics, and teas, but its stem part is rarely used and studied. Therefore, this study evaluated the antioxidant and anti-melanogenesis activities of the bioactive fraction of P. lobata stem and investigated whether the activated carbon decolorization technique would have an impact on its activity and chemical composition. We observed that the dichloromethane fraction of P. lobata stem (DCM-PLS) has excellent antioxidant and anti-melanin synthesis activity at a concentration of 50 μg/mL. For the investigation of the anti-melanogenesis mechanism, we evaluated the mRNA expression of tyrosinase, which was depressed by the DCM-PLS. Daidzin was identified as the main active ingredient in DCM-PLS by using a high-performance liquid chromatography-diode array detector-hyphenated with tandem mass spectrometry. In addition, the activated carbon decolorization technology has no negative impact on the main components and bioactivity of DCM-PLS. DCM-PLS also did not induce any skin response in the human skin safety test. Collectively, DCM-PLS could be used as a natural type of skin-whitening agent in skin care products. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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20 pages, 7732 KiB

Open AccessArticle

Study of Novel Furocoumarin Derivatives on Anti-Vitiligo Activity, Molecular Docking and Mechanism of Action

by Chao Niu, Deng Zang and Haji Akber Aisa

Int. J. Mol. Sci. 2022, 23(14), 7959; https://doi.org/10.3390/ijms23147959 - 19 Jul 2022

Cited by 11 | Viewed by 2668

Abstract

Vitiligo is a common chronic dermatological abnormality that afflicts tens of millions of people. Furocoumarins isolated from Uygur traditional medicinal material Psoralen corylifolia L. have been proven to be highly effective for the treatment of vitiligo. Although many furocoumarin derivatives with anti-vitiligo activity [...] Read more.

Vitiligo is a common chronic dermatological abnormality that afflicts tens of millions of people. Furocoumarins isolated from Uygur traditional medicinal material Psoralen corylifolia L. have been proven to be highly effective for the treatment of vitiligo. Although many furocoumarin derivatives with anti-vitiligo activity have been synthesized, their targets with respect to the disease are still ambiguous. Fortunately, the JAKs were identified as potential targets for the disease and its inhibitors have been proved to be effective in the treatment of vitiligo in many clinical trials. Thus, sixty-five benzene sulfonate and benzoate derivatives of furocoumarins (7a–7ad, 8a–8ag) with superior anti-vitiligo activity targeting JAKs were designed and synthesized based on preliminary research. The SAR was characterized after the anti-vitiligo-activity evaluation in B16 cells. Twenty-two derivatives showed more potent effects on melanin synthesis in B16 cells than the positive control (8-MOP). Among them, compounds 7y and 8 not only could increase melanin content, but they also improved the catecholase activity of tyrosinase in a concentration-dependent manner. The docking studies indicated that they were able to interact with amino acid residues in JAK1 and JAK2 via hydrogen bonds. Furthermore, candidate 8 showed a moderate inhibition of CXCL−10, which plays an important role in JAK–STAT signaling. The RT-PCR and Western blotting analyses illustrated that compounds 7y and 8 promoted melanogenesis by activating the p38 MAPK and Akt/GSK-3β/β-catenin pathways, as well as increasing the expressions of the MITF and tyrosinase-family genes. Finally, furocoumarin derivative 8 was recognized as a promising candidate for the fight against the disease and worthy of further research in vivo. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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19 pages, 3691 KiB

Open AccessArticle

Bamboo Lignin Fractions with In Vitro Tyrosinase Inhibition Activity Downregulate Melanogenesis in B16F10 Cells via PKA/CREB Signaling Pathway

by Moon-Hee Choi, Seung-Hwa Yang, Won-Keun Park and Hyun-Jae Shin

Int. J. Mol. Sci. 2022, 23(13), 7462; https://doi.org/10.3390/ijms23137462 - 5 Jul 2022

Cited by 2 | Viewed by 2782

Abstract

Cosmetic ingredients originating from natural resources have garnered considerable attention, and the demand for whitening ingredients is increasing, particularly in Asian countries. Lignin is a natural phenolic biopolymer significantly effective as a natural sunscreen, as its ultraviolet protection efficacy ranges from 250 to [...] Read more.

Cosmetic ingredients originating from natural resources have garnered considerable attention, and the demand for whitening ingredients is increasing, particularly in Asian countries. Lignin is a natural phenolic biopolymer significantly effective as a natural sunscreen, as its ultraviolet protection efficacy ranges from 250 to 400 nm. However, using different types of lignin as cosmetic ingredients is difficult owing to the heterogeneity of lignin and the lack of in vitro and in vivo safety and efficacy data. Thus, steam-exploded lignin (SEL) was prepared from bamboo, fractionated via successive organic solvent extraction, and sequentially fractionated using ethyl acetate, methanol, and acetone to investigate its potential as a natural whitening material. Gel permeation chromatography showed that the molecular weight of acetone-soluble and acetone-insoluble SEL fractions were the lowest and the highest, respectively. Monomer structures of the four lignin fractions were elucidated using ¹H, ¹³C, and 2D heteronuclear single quantum coherence nuclear magnetic resonance and pyrolysis gas chromatography/mass spectrometry. The antioxidant and tyrosinase inhibition activities of the four fractions were compared. The methanol-soluble SEL fraction (SEL-F2) showed the highest antioxidant activity (except 2,2-diphenyl-1-picrylhydrazyl scavenging activity), and the enzyme inhibition kinetics were confirmed. In this study, the expression pattern of the anti-melanogenic-related proteins by SEL-F2 was confirmed for the first time via the protein kinase A (PKA)/cAMP-response element-binding (CREB) protein signaling pathway in B16F10 melanoma cells. Thus, SEL may serve as a valuable cosmetic whitening ingredient. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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17 pages, 2450 KiB

Open AccessArticle

Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity

by Shosuke Ito, Hitomi Tanaka, Makoto Ojika, Kazumasa Wakamatsu and Manickam Sugumaran

Int. J. Mol. Sci. 2021, 22(21), 11751; https://doi.org/10.3390/ijms222111751 - 29 Oct 2021

Cited by 6 | Viewed by 2349

Abstract

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is [...] Read more.

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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18 pages, 2709 KiB

Open AccessArticle

Photoreactivity of Hair Melanin from Different Skin Phototypes—Contribution of Melanin Subunits to the Pigments Photoreactive Properties

by Krystian Mokrzynski, Shosuke Ito, Kazumasa Wakamatsu, Theodore G. Camenish, Tadeusz Sarna and Michal Sarna

Int. J. Mol. Sci. 2021, 22(9), 4465; https://doi.org/10.3390/ijms22094465 - 24 Apr 2021

Cited by 8 | Viewed by 3680

Abstract

Photoreactivity of melanin has become a major focus of research due to the postulated involvement of the pigment in UVA-induced melanoma. However, most of the hitherto studies were carried out using synthetic melanin models. Thus, photoreactivity of natural melanins is yet to be [...] Read more.

Photoreactivity of melanin has become a major focus of research due to the postulated involvement of the pigment in UVA-induced melanoma. However, most of the hitherto studies were carried out using synthetic melanin models. Thus, photoreactivity of natural melanins is yet to be systematically analyzed. Here, we examined the photoreactive properties of natural melanins isolated from hair samples obtained from donors of different skin phototypes (I, II, III, and V). X-band and W-band electron paramagnetic resonance (EPR) spectroscopy was used to examine the paramagnetic properties of the pigments. Alkaline hydrogen peroxide degradation and hydroiodic acid hydrolysis were used to determine the chemical composition of the melanins. EPR oximetry and spin trapping were used to examine the oxygen photoconsumption and photo-induced formation of superoxide anion, and time-resolved near infrared phosphorescence was employed to determine the singlet oxygen photogeneration by the melanins. The efficiency of superoxide and singlet oxygen photogeneration was related to the chemical composition of the studied melanins. Melanins from blond and chestnut hair (phototypes II and III) exhibited highest photoreactivity of all examined pigments. Moreover, melanins of these phototypes showed highest quantum efficiency of singlet oxygen photogeneration at 332 nm and 365 nm supporting the postulate of the pigment contribution in UVA-induced melanoma. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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15 pages, 2415 KiB

Open AccessArticle

Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone

by Ryo Kishida, Shosuke Ito, Manickam Sugumaran, Ryan Lacdao Arevalo, Hiroshi Nakanishi and Hideaki Kasai

Int. J. Mol. Sci. 2021, 22(3), 1373; https://doi.org/10.3390/ijms22031373 - 29 Jan 2021

Cited by 9 | Viewed by 3111

Abstract

Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the –SH group, [...] Read more.

Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the –SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys–S⁻) to DQ. Interestingly, the C2–S bonded intermediate was less energetically stable than the C6–S bonded case. Furthermore, the most preferred Cys–S⁻-attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3–C4 bridge site) but not on the C5 site. This structure allows the Cys–S⁻ to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5–S (and C2–S) intermediate into 5-S-cysteinyldopa (and 2-S-cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys–S⁻ to DQ proceeds via the following path: (i) coordination of Cys–S⁻ to C3–C4 bridge, (ii) migration of Cys–S⁻ to C5 (C2), (iii) proton rearrangement from cysteinyl –NH₃⁺ to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4). Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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16 pages, 1775 KiB

Open AccessArticle

Chemical Evaluation of Eumelanin Maturation by ToF-SIMS and Alkaline Peroxide Oxidation HPLC Analysis

by Martin Jarenmark, Peter Sjövall, Shosuke Ito, Kazumasa Wakamatsu and Johan Lindgren

Int. J. Mol. Sci. 2021, 22(1), 161; https://doi.org/10.3390/ijms22010161 - 26 Dec 2020

Cited by 8 | Viewed by 2789

Abstract

Residual melanins have been detected in multimillion-year-old animal body fossils; however, confident identification and characterization of these natural pigments remain challenging due to loss of chemical signatures during diagenesis. Here, we simulate this post-burial process through artificial maturation experiments using three synthetic and [...] Read more.

Residual melanins have been detected in multimillion-year-old animal body fossils; however, confident identification and characterization of these natural pigments remain challenging due to loss of chemical signatures during diagenesis. Here, we simulate this post-burial process through artificial maturation experiments using three synthetic and one natural eumelanin exposed to mild (100 °C/100 bar) and harsh (250 °C/200 bar) environmental conditions, followed by chemical analysis employing alkaline hydrogen peroxide oxidation (AHPO) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Our results show that AHPO is sensitive to changes in the melanin molecular structure already during mild heat and pressure treatment (resulting, e.g., in increased C-C cross-linking), whereas harsh maturation leads to extensive loss of eumelanin-specific chemical markers. In contrast, negative-ion ToF-SIMS spectra are considerably less affected by mild maturation conditions, and eumelanin-specific features remain even after harsh treatment. Detailed analysis of ToF-SIMS spectra acquired prior to experimental treatment revealed significant differences between the investigated eumelanins. However, systematic spectral changes upon maturation reduced these dissimilarities, indicating that intense heat and pressure treatment leads to the formation of a common, partially degraded, eumelanin molecular structure. Our findings elucidate the complementary nature of AHPO and ToF-SIMS during chemical characterization of eumelanin traces in fossilized organismal remains. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 3229 KiB

Open AccessArticle

Nonenzymatic Spontaneous Oxidative Transformation of 5,6-Dihydroxyindole

by Manickam Sugumaran, Jason Evans, Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2020, 21(19), 7321; https://doi.org/10.3390/ijms21197321 - 3 Oct 2020

Cited by 20 | Viewed by 3718

Abstract

Melanin is an important phenolic skin pigment found throughout the animal kingdom. Tyrosine and its hydroxylated product dopa provide the starting material for melanin biosynthesis in all animals. Through a set of well-established reactions, they are converted to 5,6-dihydroxyindole (DHI) and DHI-2-carboxylic acid [...] Read more.

Melanin is an important phenolic skin pigment found throughout the animal kingdom. Tyrosine and its hydroxylated product dopa provide the starting material for melanin biosynthesis in all animals. Through a set of well-established reactions, they are converted to 5,6-dihydroxyindole (DHI) and DHI-2-carboxylic acid (DHICA). Oxidative polymerization of these two indoles produces the brown to black eumelanin pigment. The steps associated with these transformations are complicated by the extreme instability of the starting materials and the transient and highly reactive nature of the intermediates. We have used mass spectral studies to explore the nonenzymatic mechanism of oxidative transformation of DHI in water. Our results indicate the facile production of not only dimeric and trimeric products but also higher oligomeric forms of DHI upon exposure to air in solution, even under nonenzymatic conditions. Such instantaneous polymerization of DHI avoids toxicity to self-matter and ensures the much-needed deposition of melanin at (a) the wound site and (b) the infection site in arthropods. The rapid deposition of DHI melanin is advantageous for arthropods given their open circulatory system; the process limits blood loss during wounding and prevents the spread of parasites by encapsulating them in melanin, limiting the damage. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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11 pages, 3781 KiB

Open AccessArticle

Oxidative Oligomerization of DBL Catechol, a potential Cytotoxic Compound for Melanocytes, Reveals the Occurrence of Novel Ionic Diels-Alder Type Additions

by Manickam Sugumaran, Kubra Umit, Jason Evans, Rachel Muriph, Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2020, 21(18), 6774; https://doi.org/10.3390/ijms21186774 - 15 Sep 2020

Cited by 4 | Viewed by 3560

Abstract

The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK is a carbonyl derivative of 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in skin of many consumers. These two phenolic compounds [...] Read more.

The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK is a carbonyl derivative of 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in skin of many consumers. These two phenolic compounds are oxidized by tyrosinase and the resultant products seem to cause cytotoxicity to melanocytes by producing reactive oxygen species and depleting cellular thiols through o-quinone oxidation products. Therefore, it is important to understand the biochemical mechanism of the oxidative transformation of these compounds. Earlier studies indicate that RK is initially oxidized to RK quinone by tyrosinase and subsequently converted to a side chain desaturated catechol called 3,4-dihydroxybenzalacetone (DBL catechol). In the present study, we report the oxidation chemistry of DBL catechol. Using UV–visible spectroscopic studies and liquid chromatography mass spectrometry, we have examined the reaction of DBL catechol with tyrosinase and sodium periodate. Our results indicate that DBL quinone formed in the reaction is extremely reactive and undergoes facile dimerization and trimerization reactions to produce multiple isomeric products by novel ionic Diels-Alder type condensation reactions. The production of a wide variety of complex quinonoid products from such reactions would be potentially more toxic to cells by causing not only oxidative stress, but also melanotoxicity through exhibiting reactions with cellular macromolecules and thiols. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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12 pages, 2238 KiB

Open AccessArticle

UP256 Inhibits Hyperpigmentation by Tyrosinase Expression/Dendrite Formation via Rho-Dependent Signaling and by Primary Cilium Formation in Melanocytes

by Min Cheol Kang, Jae-Wook Lee, Taek Hwan Lee, Lalita Subedi, Hussain M. Wahedi, Seon-Gil Do, Eunju Shin, Eun-Yi Moon and Sun Yeou Kim

Int. J. Mol. Sci. 2020, 21(15), 5341; https://doi.org/10.3390/ijms21155341 - 28 Jul 2020

Cited by 16 | Viewed by 4464

Abstract

Skin hyperpigmentation is generally characterized by increased synthesis and deposition of melanin in the skin. UP256, containing bakuchiol, is a well-known medication for acne vulgaris. Acne sometimes leaves dark spots on the skin, and we hypothesized that UP256 may be effective against hyperpigmentation-associated [...] Read more.

Skin hyperpigmentation is generally characterized by increased synthesis and deposition of melanin in the skin. UP256, containing bakuchiol, is a well-known medication for acne vulgaris. Acne sometimes leaves dark spots on the skin, and we hypothesized that UP256 may be effective against hyperpigmentation-associated diseases. UP256 was treated for anti-melanogenesis and melanocyte dendrite formation in cultured normal human epidermal melanocytes as well as in the reconstituted skin and zebrafish models. Western blot analysis and glutathione S-transferase (GST)-pull down assays were used to evaluate the expression and interaction of enzymes related in melanin synthesis and transportation. The cellular tyrosinase activity and melanin content assay revealed that UP256 decreased melanin synthesis by regulating the expression of proteins related on melanogenesis including tyrosinase, TRP-1 and -2, and SOX9. UP256 also decreased dendrite formation in melanocytes via regulating the Rac/Cdc42/α-PAK signaling proteins, without cytotoxic effects. UP256 also inhibited ciliogenesis-dependent melanogenesis in normal human epidermal melanocytes. Furthermore, UP256 suppressed melanin contents in the zebrafish and the 3D human skin tissue model. All things taken together, UP256 inhibits melanin synthesis, dendrite formation, and primary cilium formation leading to the inhibition of melanogenesis. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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12 pages, 3312 KiB

Open AccessArticle

Improved HPLC Conditions to Determine Eumelanin and Pheomelanin Contents in Biological Samples Using an Ion Pair Reagent

by Shosuke Ito, Sandra Del Bino, Tomohisa Hirobe and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2020, 21(14), 5134; https://doi.org/10.3390/ijms21145134 - 20 Jul 2020

Cited by 32 | Viewed by 4125

Abstract

Alkaline hydrogen peroxide oxidation (AHPO) of eumelanin and pheomelanin, two major classes of melanin pigments, affords pyrrole-2,3,5-tricarboxylic acid (PTCA), pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,4,5-tetracarboxylic acid (PTeCA) from eumelanin and thiazole-2,4,5-tricarboxylic acid (TTCA) and thiazole-4,5-dicarboxylic acid (TDCA) from pheomelanin. Quantification of these five markers [...] Read more.

Alkaline hydrogen peroxide oxidation (AHPO) of eumelanin and pheomelanin, two major classes of melanin pigments, affords pyrrole-2,3,5-tricarboxylic acid (PTCA), pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,4,5-tetracarboxylic acid (PTeCA) from eumelanin and thiazole-2,4,5-tricarboxylic acid (TTCA) and thiazole-4,5-dicarboxylic acid (TDCA) from pheomelanin. Quantification of these five markers by HPLC provides useful information on the quantity and structural diversity of melanins in various biological samples. HPLC analysis of these markers using the original method of 0.1 M potassium phosphate buffer (pH 2.1):methanol = 99:1 (85:15 for PTeCA) on a reversed-phase column had some problems, including the short lifetime of the column and, except for the major eumelanin marker PTCA, other markers were occasionally overlapped by interfering peaks in samples containing only trace levels of these markers. These problems can be overcome by the addition of an ion pair reagent for anions, such as tetra-n-butylammonium bromide (1 mM), to retard the elution of di-, tri- and tetra-carboxylic acids. The methanol concentration was increased to 17% (30% for PTeCA) and the linearity, reproducibility, and recovery of the markers with this improved method is good to excellent. This improved HPLC method was compared to the original method using synthetic melanins, mouse hair, human hair, and human epidermal samples. In addition to PTCA, TTCA, a major marker for pheomelanin, showed excellent correlations between both HPLC methods. The other markers showed an attenuation of the interfering peaks with the improved method. We recommend this improved HPLC method for the quantitative analysis of melanin markers following AHPO because of its simplicity, accuracy, and reproducibility. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 3518 KiB

Open AccessArticle

Tyrosinase-Targeting Gallacetophenone Inhibits Melanogenesis in Melanocytes and Human Skin- Equivalents

by Ji Young Lee, Jooyun Lee, Daejin Min, Juewon Kim, Hyoung-June Kim and Kyoung Tai No

Int. J. Mol. Sci. 2020, 21(9), 3144; https://doi.org/10.3390/ijms21093144 - 29 Apr 2020

Cited by 14 | Viewed by 4464

Abstract

Demands for safe depigmentation compounds are constantly increasing in the pharmaceutical and cosmetic industry, since the numerous relevant compounds reported to date have shown undesirable side effects or low anti-melanogenic effects. In this study, we reported three novel inhibitors of tyrosinase, which is [...] Read more.

Demands for safe depigmentation compounds are constantly increasing in the pharmaceutical and cosmetic industry, since the numerous relevant compounds reported to date have shown undesirable side effects or low anti-melanogenic effects. In this study, we reported three novel inhibitors of tyrosinase, which is the key enzyme in melanogenesis, identified using docking-based high throughput virtual screening of an in-house natural compound library followed by mushroom tyrosinase inhibition assay. Of the three compounds, gallacetophenone showed high anti-melanogenic effect in both human epidermal melanocytes and a 3D human skin model, MelanoDerm. The inhibitory effect of gallacetophenone on tyrosinase was elucidated by computational molecular modeling at the atomic level. Binding of gallacetophenone to the active site of tyrosinase was found to be stabilized by hydrophobic interactions with His367, Ile368, and Val377; hydrogen bonding with Ser380 and a water molecule bridging the copper ions. Thus, our results strongly suggested gallacetophenone as an anti-melanogenic ingredient that inhibits tyrosinase. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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17 pages, 3947 KiB

Open AccessArticle

Argania Spinosa Fruit Shell Extract-Induced Melanogenesis via cAMP Signaling Pathway Activation

by Rachida Makbal, Myra O. Villareal, Chemseddoha Gadhi, Abdellatif Hafidi and Hiroko Isoda

Int. J. Mol. Sci. 2020, 21(7), 2539; https://doi.org/10.3390/ijms21072539 - 6 Apr 2020

Cited by 18 | Viewed by 4286

Abstract

We have previously reported that argan oil and argan press-cake from the kernels of Argania spinosa have an anti-melanogenesis effect. Here, the effect of argan fruit shell ethanol extract (AFSEE) on melanogenesis in B16F10 cells was determined, and the mechanism underlying its effect [...] Read more.

We have previously reported that argan oil and argan press-cake from the kernels of Argania spinosa have an anti-melanogenesis effect. Here, the effect of argan fruit shell ethanol extract (AFSEE) on melanogenesis in B16F10 cells was determined, and the mechanism underlying its effect was elucidated. The proliferation of AFSEE-treated B16F10 cells was evaluated using the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, while the melanin content was quantified using a spectrophotometric method. The expression of melanogenesis-related proteins was determined by Western blot and real-time PCR, while global gene expression was determined using a DNA microarray. In vitro analysis results showed that the melanin content of B16F10 cells was significantly increased by AFSEE, without cytotoxicity, by increasing the melanogenic enzyme tyrosinase (TRY), tyrosinase related-protein 1 (TRP1), and dopachrome tautomerase (DCT) protein and mRNA expression, as well as upregulating microphthalmia-associated transcription factor (MITF) expression through mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38, and the cyclic adenosine monophosphate (cAMP) signaling pathway, as indicated by the microarray analysis results. AFSEE’s melanogenesis promotion effect is primarily attributed to its polyphenolic components. In conclusion, AFSEE promotes melanogenesis in B16F10 cells by upregulating the expression of the melanogenic enzymes through the cAMP–MITF signaling pathway.AFSEE may be used as a cosmetics product component to promote melanogenesis, or as a therapeutic against hypopigmentation disorders. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 5050 KiB

Open AccessArticle

Molecular and Potential Regulatory Mechanisms of Melanin Synthesis in Harmonia axyridis

by Da Xiao, Xu Chen, Renbin Tian, Mengmeng Wu, Fan Zhang, Liansheng Zang, James D. Harwood and Su Wang

Int. J. Mol. Sci. 2020, 21(6), 2088; https://doi.org/10.3390/ijms21062088 - 18 Mar 2020

Cited by 11 | Viewed by 4053

Abstract

Melanization is a common phenomenon in insects, and melanin synthesis is a conserved physiological process that occurs in epidermal cells. Moreover, a comprehensive understanding of the mechanisms of melanin synthesis influencing insect pigmentation are well-suited for investigating phenotype variation. The Asian multi-colored (Harlequin) [...] Read more.

Melanization is a common phenomenon in insects, and melanin synthesis is a conserved physiological process that occurs in epidermal cells. Moreover, a comprehensive understanding of the mechanisms of melanin synthesis influencing insect pigmentation are well-suited for investigating phenotype variation. The Asian multi-colored (Harlequin) ladybird beetle, Harmonia axyridis, exhibits intraspecific polymorphism based on relative levels of melanization. However, the specific characteristics of melanin synthesis in H. axyridis remains elusive. In this study, we performed gene-silencing analysis of the pivotal inverting enzyme, tyrosine hydroxylase (TH), and DOPA decarboxylase (DDC) in the tyrosine metabolism pathway to investigate the molecular and regulatory mechanism of melanin synthesis in H. axyridis. Using RNAi of TH and DDC genes in fourth instar larvae, we demonstrated that dopamine melanin was the primary contributor to the overall body melanization of H. axyridis. Furthermore, our study provides the first conclusive evidence that dopamine serves as a melanin precursor for synthesis in the early pupal stage. According to transcription factor Pannier, which is essential for the formation of melanic color on the elytra in H. axyridis, we further demonstrated that suppression of HaPnr can significantly decrease expression levels of HaTH and HaDDC. These results in their entirety lead to the conclusion that transcription factor Pannier can regulate dopamine melanin synthesis in the dorsal elytral epidermis of H. axyridis. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 3960 KiB

Open AccessArticle

Glucose Exerts an Anti-Melanogenic Effect by Indirect Inactivation of Tyrosinase in Melanocytes and a Human Skin Equivalent

by Sung Hoon Lee, Il-Hong Bae, Eun-Soo Lee, Hyoung-June Kim, Jongsung Lee and Chang Seok Lee

Int. J. Mol. Sci. 2020, 21(5), 1736; https://doi.org/10.3390/ijms21051736 - 3 Mar 2020

Cited by 19 | Viewed by 5860

Abstract

Sugars are ubiquitous in organisms and well-known cosmetic ingredients for moisturizing skin with minimal side-effects. Glucose, a simple sugar used as an energy source by living cells, is often used in skin care products. Several reports have demonstrated that sugar and sugar-related compounds [...] Read more.

Sugars are ubiquitous in organisms and well-known cosmetic ingredients for moisturizing skin with minimal side-effects. Glucose, a simple sugar used as an energy source by living cells, is often used in skin care products. Several reports have demonstrated that sugar and sugar-related compounds have anti-melanogenic effects on melanocytes. However, the underlying molecular mechanism by which glucose inhibits melanin synthesis is unknown, even though glucose is used as a whitening as well as moisturizing ingredient in cosmetics. Herein, we found that glucose significantly reduced the melanin content of α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells and darkly pigmented normal human melanocytes with no signs of cytotoxicity. Furthermore, topical treatment of glucose clearly demonstrated its whitening efficacy through photography, Fontana-Masson (F&M) staining, and multi-photon microscopy in a pigmented 3D human skin model, MelanoDerm. However, glucose did not alter the gene expression or protein levels of major melanogenic proteins in melanocytes. While glucose potently decreased intracellular tyrosinase activity in melanocytes, it did not reduce mushroom tyrosinase activity in a cell-free experimental system. However, glucose was metabolized into lactic acid, which can powerfully suppress tyrosinase activity. Thus, we concluded that glucose indirectly inhibits tyrosinase activity through conversion into lactic acid, explaining its anti-melanogenic effects in melanocytes. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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18 pages, 4090 KiB

Open AccessArticle

The Surprising Effect of Phenformin on Cutaneous Darkening and Characterization of Its Underlying Mechanism by a Forward Chemical Genetics Approach

by Kei Takano, Akira Hachiya, Daiki Murase, Akiko Kawasaki, Hirokazu Uda, Shinya Kasamatsu, Yoshiya Sugai, Yoshito Takahashi, Tadashi Hase, Atsushi Ohuchi and Tamio Suzuki

Int. J. Mol. Sci. 2020, 21(4), 1451; https://doi.org/10.3390/ijms21041451 - 20 Feb 2020

Cited by 3 | Viewed by 3883

Abstract

Melanin in the epidermis is known to ultimately regulate human skin pigmentation. Recently, we exploited a phenotypic-based screening system composed of ex vivo human skin cultures to search for effective materials to regulate skin pigmentation. Since a previous study reported the potent inhibitory [...] Read more.

Melanin in the epidermis is known to ultimately regulate human skin pigmentation. Recently, we exploited a phenotypic-based screening system composed of ex vivo human skin cultures to search for effective materials to regulate skin pigmentation. Since a previous study reported the potent inhibitory effect of metformin on melanogenesis, we evaluated several biguanide compounds. The unexpected effect of phenformin, once used as an oral anti-diabetic drug, on cutaneous darkening motivated us to investigate its underlying mechanism utilizing a chemical genetics approach, and especially to identify alternatives to phenformin because of its risk of severe lactic acidosis. Chemical pull-down assays with phenformin-immobilized beads were performed on lysates of human epidermal keratinocytes, and subsequent mass spectrometry identified 7-dehydrocholesterol reductase (DHCR7). Consistent with this, AY9944, an inhibitor of DHCR7, was found to decrease autophagic melanosome degradation in keratinocytes and to intensely darken skin in ex vivo cultures, suggesting the involvement of cholesterol biosynthesis in the metabolism of melanosomes. Thus, our results validated the combined utilization of the phenotypic screening system and chemical genetics as a new approach to develop promising materials for brightening/lightening and/or tanning technologies. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 3971 KiB

Open AccessArticle

Rhododenol Activates Melanocytes and Induces Morphological Alteration at Sub-Cytotoxic Levels

by Minjeong Kim, Chang-Seok Lee and Kyung-Min Lim

Int. J. Mol. Sci. 2019, 20(22), 5665; https://doi.org/10.3390/ijms20225665 - 12 Nov 2019

Cited by 10 | Viewed by 3757

Abstract

Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but [...] Read more.

Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but the features are different from vitiligo, a skin hypopigmentary disorder, alluding to events more complex than simple melanocyte cytotoxicity. Here, we discovered that rhododenol treatment reduced the number of melanocytes in a pigmented 3D human skin model, Melanoderm™, confirming the melanocyte toxicity of RD. Of note, melanocytes that survived in the RD treated tissues exhibited altered morphology, such as extended dendrites and increased cell sizes. Consistently with this, sub-cytotoxic level of RD increased cell size and elongated dendrites in B16 melanoma cells. Morphological changes of B16 cells were further confirmed in the immunocytochemistry of treated cells for actin and tubulin. Even more provoking, RD up-regulated the expression of tyrosinase and TRP1 in the survived B16 cells. Evaluation of mRNA expression of cytoskeletal proteins suggests that RD altered the cytoskeletal dynamic favoring cell size expansion and melanosome maturation. Collectively, these results suggest that RD not only induces cytotoxicity in melanocytes but also can lead to a profound perturbation of melanocyte integrity even at sub-cytotoxic levels. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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13 pages, 2335 KiB

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The Organogermanium Compound THGP Suppresses Melanin Synthesis via Complex Formation with L-DOPA on Mushroom Tyrosinase and in B16 4A5 Melanoma Cells

by Junya Azumi, Tomoya Takeda, Yasuhiro Shimada, Hisashi Aso and Takashi Nakamura

Int. J. Mol. Sci. 2019, 20(19), 4785; https://doi.org/10.3390/ijms20194785 - 26 Sep 2019

Cited by 17 | Viewed by 7700

Abstract

The organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) has various biological activities. We previously reported that THGP forms a complex with cis-diol structures. L-3,4-Dihydroxyphenylalanine (L-DOPA), a precursor of melanin, contains a cis-diol structure in its catechol skeleton, and excessive melanin production causes skin [...] Read more.

The organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) has various biological activities. We previously reported that THGP forms a complex with cis-diol structures. L-3,4-Dihydroxyphenylalanine (L-DOPA), a precursor of melanin, contains a cis-diol structure in its catechol skeleton, and excessive melanin production causes skin darkening and staining. Thus, the cosmetic field is investigating substances that suppress melanin production. In this study, we investigated whether THGP inhibits melanin synthesis via the formation of a complex with L-DOPA using mushroom tyrosinase and B16 4A5 melanoma cells. The ability of THGP to interact with L-DOPA was analyzed by ¹H-NMR, and the influence of THGP and/or kojic acid on melanin synthesis was investigated. We also examined the effect of THGP on cytotoxicity, tyrosinase activity, and gene expression and found that THGP interacted with L-DOPA, a precursor of melanin with a cis-diol structure. The results also showed that THGP inhibited melanin synthesis, exerted a synergistic effect with kojic acid, and did not affect tyrosinase activity or gene expression. These results suggest that THGP is a useful substrate that functions as an inhibitor of melanogenesis and that its effect is enhanced by combination with kojic acid. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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15 pages, 2497 KiB

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Effects of Aging on Hair Color, Melanosome Morphology, and Melanin Composition in Japanese Females

by Takashi Itou, Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2019, 20(15), 3739; https://doi.org/10.3390/ijms20153739 - 31 Jul 2019

Cited by 23 | Viewed by 8725

Abstract

In a previous study, we showed that the size of melanosomes isolated from Japanese female hairs enlarges with age, and this affects the hair color. In this study, we analyzed the age-dependent changes in hair melanin in order to further explore the factors [...] Read more.

In a previous study, we showed that the size of melanosomes isolated from Japanese female hairs enlarges with age, and this affects the hair color. In this study, we analyzed the age-dependent changes in hair melanin in order to further explore the factors related to hair color changing by aging. A significant positive correlation with age was found in the total melanin amount (TM) and the mol% of 5,6-dihydroxyindole (DHI) units, while no correlation was found in pheomelanin mol%. TM showed significant correlations with hair color parameters and the melanosome volume, suggesting that hair color darkening by aging is caused by the increase in TM due to the enlargement of the size of melanosome. From the measurement of absorbance spectra on synthetic eumelanins with different ratios of DHI and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), we found that the increase in DHI mol% also contributes to the darkening of hair color by aging. In addition, the level of pyrrole-2,3-dicarboxylic acid (PDCA), a marker of DHI melanin, showed a significant negative correlation with the aspect ratio of melanosome, suggesting a contribution of DHI melanin to the change in melanosome morphology by aging. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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18 pages, 3335 KiB

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The Oxidative Pathway to Dopamine–Protein Conjugates and Their Pro-Oxidant Activities: Implications for the Neurodegeneration of Parkinson’s Disease

by Kazumasa Wakamatsu, Kenta Nakao, Hitomi Tanaka, Yuki Kitahori, Yui Tanaka, Makoto Ojika and Shosuke Ito

Int. J. Mol. Sci. 2019, 20(10), 2575; https://doi.org/10.3390/ijms20102575 - 25 May 2019

Cited by 17 | Viewed by 5060

Abstract

Neuromelanin (NM) is a dark brown pigment found in dopaminergic neurons of the substantia nigra (SN) and in norepinephrinergic neurons of the locus coeruleus (LC). Although NM is thought to be involved in the etiology of Parkinson’s disease (PD) because its content decreases [...] Read more.

Neuromelanin (NM) is a dark brown pigment found in dopaminergic neurons of the substantia nigra (SN) and in norepinephrinergic neurons of the locus coeruleus (LC). Although NM is thought to be involved in the etiology of Parkinson’s disease (PD) because its content decreases in neurodegenerative diseases such as PD, details are still unknown. In this study, we characterized the biosynthetic pathway of the oxidation of dopamine (DA) by tyrosinase in the presence of thiol peptides and proteins using spectroscopic and high-performance liquid chromatography (HPLC) methods and we assessed the binding of DA via cysteine residues in proteins by oxidation catalyzed by redox-active metal ions. To examine whether the protein-bound DA conjugates exhibit pro-oxidant activities, we measured the depletion of glutathione (GSH) with the concomitant production of hydrogen peroxide. The results suggest that the fate of protein-bound DA conjugates depends on the structural features of the proteins and that DA-protein conjugates produced in the brain possess pro-oxidant activities, which may cause neurodegeneration due to the generation of reactive oxygen species (ROS) and the depletion of antioxidants. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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10 pages, 2260 KiB

Open AccessArticle

Rice Bran Ash Mineral Extract Increases Pigmentation through the p-ERK Pathway in Zebrafish (Danio rerio)

by Yu-Mi Kim, Eun-Cheol Lee, Han-Moi Lim and Young-Kwon Seo

Int. J. Mol. Sci. 2019, 20(9), 2172; https://doi.org/10.3390/ijms20092172 - 2 May 2019

Cited by 12 | Viewed by 3950

Abstract

The purpose of the present study is to evaluate the effect of rice bran ash mineral extract (RBM) on pigmentation in zebrafish (Danio rerio). Melanin has the ability to block ultraviolet (UV) radiation and scavenge free oxygen radicals, thus protecting the [...] Read more.

The purpose of the present study is to evaluate the effect of rice bran ash mineral extract (RBM) on pigmentation in zebrafish (Danio rerio). Melanin has the ability to block ultraviolet (UV) radiation and scavenge free oxygen radicals, thus protecting the skin from their harmful effects. Agents that increase melanin synthesis in melanocytes may reduce the risk of photodamage and skin cancer. The present study investigates the effect of RBM on pigmentation in zebrafish and the underlying mechanism. RBM was found to significantly increase the expression of microphthalmia-associated transcription factor (MITF), a key transcription factor involved in melanin production. RBM also suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), which negatively regulates zebrafish pigmentation. Together, these results suggest that RBM promotes melanin biosynthesis in zebrafish. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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10 pages, 1842 KiB

Open AccessArticle

Pulsed Electromagnetic Fields Increase Pigmentation through the p-ERK/p-p38 Pathway in Zebrafish (Danio rerio)

by Yu-Mi Kim, Han-Moi Lim, Hyang-Seon Ro, Ga-Eun Ki and Young-Kwon Seo

Int. J. Mol. Sci. 2018, 19(10), 3211; https://doi.org/10.3390/ijms19103211 - 17 Oct 2018

Cited by 13 | Viewed by 4538

Abstract

Melanogenesis is a biological process resulting in the production of melanin pigment, which plays an important role in the prevention of sun-induced skin injury, and determines hair and skin color. So, a wide variety of approaches have been proposed to increase the synthesis [...] Read more.

Melanogenesis is a biological process resulting in the production of melanin pigment, which plays an important role in the prevention of sun-induced skin injury, and determines hair and skin color. So, a wide variety of approaches have been proposed to increase the synthesis of melanin. This study evaluated the effects of pulsed electromagnetic fields (PEMFs) on the pigmentation of zebrafish (Danio rerio) in vivo. We stimulated pigmentation in zebrafish by using specific frequencies and intensities of PEMFs. This study focuses on pigmentation using PEMFs, and finds that PEMFs, at an optimal intensity and frequency, upregulate pigmentation by the stimulated expression of tyrosinase-related protein 1 (TRP1), dopachrome tautomerase (DCT) through extracellular signal-regulated kinase(ERK) phosphorylation, and p38 phosphorylation signaling pathways in zebrafish. These results suggest that PEMFs, at an optimal intensity and frequency, are a useful tool in treating gray hair, with reduced melanin synthesis in the hair shaft or hypopigmentation-related skin disorders. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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17 pages, 2314 KiB

Open AccessArticle

Zerumbone, a Tropical Ginger Sesquiterpene of Zingiber officinale Roscoe, Attenuates α-MSH-Induced Melanogenesis in B16F10 Cells

by Taek-In Oh, Hye-Jeong Jung, Yoon-Mi Lee, Sujin Lee, Geon-Hee Kim, Sang-Yeon Kan, Hyeji Kang, Taerim Oh, Hyun Myung Ko, Keun-Chang Kwak and Ji-Hong Lim

Int. J. Mol. Sci. 2018, 19(10), 3149; https://doi.org/10.3390/ijms19103149 - 13 Oct 2018

Cited by 29 | Viewed by 8036

Abstract

Zerumbone (ZER), an active constituent of the Zingiberaceae family, has been shown to exhibit several biological activities, such as anti-inflammatory, anti-allergic, anti-microbial, and anti-cancer; however, it has not been studied for anti-melanogenic properties. In the present study, we demonstrate that ZER and Zingiber [...] Read more.

Zerumbone (ZER), an active constituent of the Zingiberaceae family, has been shown to exhibit several biological activities, such as anti-inflammatory, anti-allergic, anti-microbial, and anti-cancer; however, it has not been studied for anti-melanogenic properties. In the present study, we demonstrate that ZER and Zingiber officinale (ZO) extract significantly attenuate melanin accumulation in α-melanocyte-stimulating hormone (α-MSH)-stimulated mouse melanogenic B16F10 cells. Further, to elucidate the molecular mechanism by which ZER suppresses melanin accumulation, we analyzed the expression of melanogenesis-associated transcription factor, microphthalmia-associated transcription factor (MITF), and its target genes, such as tyrosinase, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2), in B16F10 cells that are stimulated by α-MSH. Here, we found that ZER inhibits the MITF-mediated expression of melanogenic genes upon α-MSH stimulation. Additionally, cells treated with different concentrations of zerumbone and ZO showed increased extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, which are involved in the degradation mechanism of MITF. Pharmacological inhibition of ERK1/2 using U0126 sufficiently reversed the anti-melanogenic effect of ZER, suggesting that increased phosphorylation of ERK1/2 is required for its anti-melanogenic activity. Taken together, these results suggest that ZER and ZO extract can be used as active ingredients in skin-whitening cosmetics because of their anti-melanogenic effect. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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15 pages, 5963 KiB

Open AccessArticle

Antimelanogenic Effects of Polygonum tinctorium Flower Extract from Traditional Jeju Fermentation via Upregulation of Extracellular Signal-Regulated Kinase and Protein Kinase B Activation

by You Chul Chung, Ji-Hye Ko, Hyun-Kyu Kang, Seoyeon Kim, Choon Il Kang, Jung No Lee, Sung-Min Park and Chang-Gu Hyun

Int. J. Mol. Sci. 2018, 19(10), 2895; https://doi.org/10.3390/ijms19102895 - 24 Sep 2018

Cited by 22 | Viewed by 4596

Abstract

This study was carried out to investigate the antimelanogenic effects of a Polygonum tinctorium flower extract obtained using red nuruk, a traditional Jeju barley-based fermentation starter. We also studied the mechanism of action of the P. tinctorium fermented flower extract (PTFFE) in mouse [...] Read more.

This study was carried out to investigate the antimelanogenic effects of a Polygonum tinctorium flower extract obtained using red nuruk, a traditional Jeju barley-based fermentation starter. We also studied the mechanism of action of the P. tinctorium fermented flower extract (PTFFE) in mouse melanoma cells (B16F10). Cells were treated with various concentrations (62.5, 125 and 250 μg/mL) of PTFFE and the results showed that PTFFE significantly decreased the melanin content and tyrosinase activity without being cytotoxic. In addition, PTFFE strongly inhibited the expression of tyrosinase and tyrosinase-related protein 2 by decreasing the expression of the microphthalmia-associated transcription factor, as shown by a western blot assay. Furthermore, PTFFE inhibited melanogenesis via upregulation of the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B, also known as AKT. We also used inhibitors such as PD98059 (a specific ERK inhibitor) or LY294002 (an AKT inhibitor) to determine whether the signaling pathways are involved. High-performance liquid chromatography fingerprinting showed the presence of a quercetin glucoside (isoquercitrin) and quercetin in PTFFE. To test the potential for PTFFE application as a cosmetic material, we also performed a primary skin irritation test on human skin. In this assay, PTFFE did not induce any adverse reactions at the treatment dose. Based on these results, we suggest that PTFFE may be considered a potential antimelanogenesis candidate for topical applications. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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14 pages, 1682 KiB

Open AccessArticle

Conjugation with Dihydrolipoic Acid Imparts Caffeic Acid Ester Potent Inhibitory Effect on Dopa Oxidase Activity of Human Tyrosinase

by Raffaella Micillo, Julia Sirés-Campos, José Carlos García-Borrón, Lucia Panzella, Alessandra Napolitano and Conchi Olivares

Int. J. Mol. Sci. 2018, 19(8), 2156; https://doi.org/10.3390/ijms19082156 - 24 Jul 2018

Cited by 14 | Viewed by 5185

Abstract

Caffeic acid derivatives represent promising lead compounds in the search for tyrosinase inhibitors to be used in the treatment of skin local hyperpigmentation associated to an overproduction or accumulation of melanin. We recently reported the marked inhibitory activity of a conjugate of caffeic [...] Read more.

Caffeic acid derivatives represent promising lead compounds in the search for tyrosinase inhibitors to be used in the treatment of skin local hyperpigmentation associated to an overproduction or accumulation of melanin. We recently reported the marked inhibitory activity of a conjugate of caffeic acid with dihydrolipoic acid, 2-S-lipoylcaffeic acid (LCA), on the tyrosine hydroxylase (TH) and dopa oxidase (DO) activities of mushroom tyrosinase. In the present study, we evaluated a more lipophilic derivative, 2-S-lipoyl caffeic acid methyl ester (LCAME), as an inhibitor of tyrosinase from human melanoma cells. Preliminary analysis of the effects of LCAME on mushroom tyrosinase indicated more potent inhibitory effects on either enzyme activities (IC₅₀ = 0.05 ± 0.01 μM for DO and 0.83 ± 0.09 μM for TH) compared with LCA and the reference compound kojic acid. The inhibition of DO of human tyrosinase was effective (Ki = 34.7 ± 1.1 μM) as well, while the action on TH was weaker. Lineweaver–Burk analyses indicated a competitive inhibitor mechanism. LCAME was not substrate of tyrosinase and proved nontoxic at concentrations up to 50 μM. No alteration of basal tyrosinase expression was observed after 24 h treatment of human melanoma cells with the inhibitor, but preliminary evidence suggested LCAME might impair the induction of tyrosinase expression in cells stimulated with α-melanocyte-stimulating hormone. All these data point to this compound as a valuable candidate for further trials toward its use as a skin depigmenting agent. They also highlight the differential effects of tyrosinase inhibitors on the human and mushroom enzymes. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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22 pages, 15912 KiB

Open AccessArticle

Structural Requirements of Alkylglyceryl-l-Ascorbic Acid Derivatives for Melanogenesis Inhibitory Activity

by Norihisa Taira, Yushi Katsuyama, Masato Yoshioka, Osamu Muraoka and Toshio Morikawa

Int. J. Mol. Sci. 2018, 19(4), 1144; https://doi.org/10.3390/ijms19041144 - 10 Apr 2018

Cited by 10 | Viewed by 8079

Abstract

l-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin production, and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-l-ascorbic acid derivatives, highly stable vitamin C–alkylglycerol conjugates, would [...] Read more.

l-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin production, and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-l-ascorbic acid derivatives, highly stable vitamin C–alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-l-ascorbic acid derivatives (1–28) on theophylline-stimulated B16 melanoma 4A5 cells to determine if they inhibit melanogenesis and establish any structure–function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid (6, IC₅₀ = 81.4 µM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid (20, IC₅₀ = 117 µM) are deemed the best candidate derivatives based on their inhibitory activities and low toxicities. These derivatives are also found to be more stable than l-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-l-ascorbic acid derivatives are also determined: (i) alkylation of glyceryl-l-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivatives (2–14) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivatives (16–28); and (iii) derivatives with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that l-ascorbic acid derivatives exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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14 pages, 14760 KiB

Open AccessArticle

Sesamol Inhibited Melanogenesis by Regulating Melanin-Related Signal Transduction in B16F10 Cells

by Po-Yuan Wu, Ya-Jhen You, Yi-Jung Liu, Chien-Wei Hou, Chin-Sheng Wu, Kuo-Ching Wen, Chien-Yih Lin and Hsiu-Mei Chiang

Int. J. Mol. Sci. 2018, 19(4), 1108; https://doi.org/10.3390/ijms19041108 - 7 Apr 2018

Cited by 48 | Viewed by 9601

Abstract

Melanin is synthesized through a series of interactions catalyzed by melanogenic enzymes such as tyrosinase, dopachrome tautomerase (tyrosinase-related protein-2; TRP-2), and tyrosinase-related protein-1 (TRP-1). Tyrosinase plays a key role in catalysing the initial and limiting steps of melanogenesis. The melanin that results from [...] Read more.

Melanin is synthesized through a series of interactions catalyzed by melanogenic enzymes such as tyrosinase, dopachrome tautomerase (tyrosinase-related protein-2; TRP-2), and tyrosinase-related protein-1 (TRP-1). Tyrosinase plays a key role in catalysing the initial and limiting steps of melanogenesis. The melanin that results from melanogenesis has the protective effect of absorbing ultraviolet radiation. However, overproduction of melanin, in addition to altering the appearance of skin, may lead to skin disorders such as melasma, solar lentigo, and postinflammatory hyperpigmentation. Previous studies have revealed that sesamol is a strong antioxidant and a free radical scavenger. In this study, we investigated the effects of sesamol on the regulation of melanogenesis and related mechanisms in B16F10 cells. The results indicated that sesamol inhibited tyrosinase activity and melanogenesis induced by α-melanocyte-stimulating hormone (α-MSH) in B16F10 melanoma cells. Sesamol decreased the protein level of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, and TRP-1 by downregulating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathways that had been activated by α-MSH. Sesamol increased glycogen synthase kinase 3 beta (GSK3β), protein kinase B (AKT), and extracellular signal-related kinase (ERK) phosphorylation, thus inhibiting the transcription of MITF. Sesamol also inhibited melanin synthesis and tyrosinase expression by modulating ERK, phosphoinositide 3-kinase (PI3K)/AKT, p38, and c-Jun amino-terminal kinase (JNK) signalling pathways. These results indicate that sesamol acted as a potent depigmenting agent. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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12 pages, 8877 KiB

Open AccessArticle

Novel (1E,3E,5E)-1,6-bis(Substituted phenyl)hexa-1,3,5-triene Analogs Inhibit Melanogenesis in B16F10 Cells and Zebrafish

by Jisun Oh, Jungeun Kim, Jin Ho Jang, Sangwoo Lee, Chul Min Park, Woo-Keun Kim and Jong-Sang Kim

Int. J. Mol. Sci. 2018, 19(4), 1067; https://doi.org/10.3390/ijms19041067 - 3 Apr 2018

Cited by 10 | Viewed by 4976

Abstract

The present study aimed to evaluate the anti-melanogenic activity of 1,6-diphenyl-1,3,5-hexatriene and its derivatives in B16F10 murine melanoma cells and zebrafish embryos. Twenty five (1E,3E,5E)-1,6-bis(substituted phenyl)hexa-1,3,5-triene analogs were synthesized and their non-cytotoxic effects were predictively [...] Read more.

The present study aimed to evaluate the anti-melanogenic activity of 1,6-diphenyl-1,3,5-hexatriene and its derivatives in B16F10 murine melanoma cells and zebrafish embryos. Twenty five (1E,3E,5E)-1,6-bis(substituted phenyl)hexa-1,3,5-triene analogs were synthesized and their non-cytotoxic effects were predictively analyzed using three-dimensional quantitative structure-activity relationship approach. Inhibitory activities of these synthetic compounds against melanin synthesis were determined by evaluating melanin content and melanogenic regulatory enzyme expression in B16F10 cells. The anti-melanogenic activity was verified by observing body pigmentation in zebrafishes treated with these compounds. Compound #2, #4, and #6 effectively decreased melanogenesis induced by α-melanocyte-stimulating hormone. In particular, compound #2 remarkably lowered the mRNA and protein expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and TYRP2 in B16F10 cells and substantially reduced skin pigmentation in the developed larvae of zebrafish. These findings suggest that compound #2 may be used as an anti-melanogenic agent for cosmetic purpose. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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11 pages, 2996 KiB

Open AccessArticle

Antimelanogenic Effect of an Oroxylum indicum Seed Extract by Suppression of MITF Expression through Activation of MAPK Signaling Protein

by Peijun Zhao, Md Badrul Alam, Hongyan An, Hee-Jeong Choi, Yeong Ho Cha, Chi-Yeol Yoo, Hyo-Hyun Kim and Sang-Han Lee

Int. J. Mol. Sci. 2018, 19(3), 760; https://doi.org/10.3390/ijms19030760 - 7 Mar 2018

Cited by 10 | Viewed by 5215

Abstract

In this study, the antimelanogenic effect of an ethyl acetate fraction of Oroxylum indicum Vent. seeds (OISEA) and its underlying mechanisms in melan-a cells were investigated. Antimelanogenesis activity was confirmed by assessing inhibition of tyrosinase activity and melanin content in the cells. Both [...] Read more.

In this study, the antimelanogenic effect of an ethyl acetate fraction of Oroxylum indicum Vent. seeds (OISEA) and its underlying mechanisms in melan-a cells were investigated. Antimelanogenesis activity was confirmed by assessing inhibition of tyrosinase activity and melanin content in the cells. Both transcriptional and translational expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase related protein-1 and 2 (TYRP-1 and TYRP-2), were also examined. The results depicted that pretreatment of OISEA significantly inhibits not only tyrosinase activity, but melanin production and intracellular tyrosinase activity. By repressing the expression of tyrosinase, TYRP-1, TYRP-2, and MITF, OISEA interrupted melanin production. Additionally, OISEA interfered with the phosphorylation of p38, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK), with the reversal of OISEA-induced melanogenesis inhibition after treatment with the specific inhibitors SB239063, U0126, and SP600125. Overall, these results suggest that OISEA can stimulate p38, ERK1/2, JNK phosphorylation, and subsequent suppression of melanin, leading to the inhibition of melanogenic enzymes and melanin production, possibly owing to the presence of polyphenolic compounds. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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19 pages, 4229 KiB

Open AccessArticle

Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3β/β-Catenin Signaling Pathways

by Chao Niu, Li Yin and Haji Akber Aisa

Int. J. Mol. Sci. 2018, 19(3), 746; https://doi.org/10.3390/ijms19030746 - 6 Mar 2018

Cited by 37 | Viewed by 6860

Abstract

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter [...] Read more.

The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a–8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration-dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3β (glycogen synthase kinase 3 beta), which inhibited the degradation of β-catenin were observed through Western blot analysis. The accumulation of β-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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14 pages, 13463 KiB

Open AccessArticle

Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase

by Tobias Mann, Cathrin Scherner, Klaus-Heinrich Röhm and Ludger Kolbe

Int. J. Mol. Sci. 2018, 19(3), 690; https://doi.org/10.3390/ijms19030690 - 28 Feb 2018

Cited by 41 | Viewed by 9794

Abstract

Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4-resorcinylthiazol-2-amines and -amides) [...] Read more.

Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4-resorcinylthiazol-2-amines and -amides) are both selective and efficacious inhibitors of hTyr in vitro and in vivo. Here, we measured dose-activity profiles of a large number of thiazolyl resorcinols and analogous compounds to better understand the molecular basis of their interaction with hTyr. We show that both the resorcinyl moiety and the thiazole ring must be intact to allow efficient inhibition of hTyr, while the substituents at the thiazole 2-amino group confer additional inhibitory activity, depending on their size and polarity. The results of molecular docking simulations were in excellent agreement with the experimental data, affording a rationale for the structural importance of either ring. We further propose that a special type of interaction between the thiazole sulfur and a conserved asparagine residue is partially responsible for the superior inhibitory activity of thiazolyl resorcinols against hTyr. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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14 pages, 1513 KiB

Open AccessArticle

Nanomechanical Phenotype of Melanoma Cells Depends Solely on the Amount of Endogenous Pigment in the Cells

by Michal Sarna, Andrzej Zadlo, Barbara Czuba-Pelech and Krystyna Urbanska

Int. J. Mol. Sci. 2018, 19(2), 607; https://doi.org/10.3390/ijms19020607 - 18 Feb 2018

Cited by 29 | Viewed by 4730

Abstract

Cancer cells have unique nanomechanical properties, i.e., they behave as if they were elastic. This property of cancer cells is believed to be one of the main reasons for their facilitated ability to spread and metastasize. Thus, the so-called nanomechanical phenotype of cancer [...] Read more.

Cancer cells have unique nanomechanical properties, i.e., they behave as if they were elastic. This property of cancer cells is believed to be one of the main reasons for their facilitated ability to spread and metastasize. Thus, the so-called nanomechanical phenotype of cancer cells is viewed as an important indicator of the cells’ metastatic behavior. One of the most highly metastatic cancer cells are melanoma cells, which have a very unusual property: they can synthesize the pigment melanin in large amounts, becoming heavily pigmented. So far, the role of melanin in melanoma remains unclear, particularly the impact of the pigment on metastatic behavior of melanoma cells. Importantly, until recently the potential mechanical role of melanin in melanoma metastasis was completely ignored. In this work, we examined melanoma cells isolated from hamster tumors containing endogenous melanin pigment. Applying an array of advanced microscopy and spectroscopy techniques, we determined that melanin is the dominating factor responsible for the mechanical properties of melanoma cells. Our results indicate that the nanomechanical phenotype of melanoma cells may be a reliable marker of the cells’ metastatic behavior and point to the important mechanical role of melanin in the process of metastasis of melanoma. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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10 pages, 2181 KiB

Open AccessCommunication

AP-1/KIF13A Blocking Peptides Impair Melanosome Maturation and Melanin Synthesis

by Cécile Campagne, Léa Ripoll, Floriane Gilles-Marsens, Graça Raposo and Cédric Delevoye

Int. J. Mol. Sci. 2018, 19(2), 568; https://doi.org/10.3390/ijms19020568 - 14 Feb 2018

Cited by 11 | Viewed by 9024

Abstract

Melanocytes are specialized cells that generate unique organelles called melanosomes in which melanin is synthesized and stored. Melanosome biogenesis and melanocyte pigmentation require the transport and delivery of melanin synthesizing enzymes, such as tyrosinase and related proteins (e.g., TYRP1), from endosomes to maturing [...] Read more.

Melanocytes are specialized cells that generate unique organelles called melanosomes in which melanin is synthesized and stored. Melanosome biogenesis and melanocyte pigmentation require the transport and delivery of melanin synthesizing enzymes, such as tyrosinase and related proteins (e.g., TYRP1), from endosomes to maturing melanosomes. Among the proteins controlling endosome-melanosome transport, AP-1 together with KIF13A coordinates the endosomal sorting and trafficking of TYRP1 to melanosomes. We identify here β1-adaptin AP-1 subunit-derived peptides of 5 amino acids that block the interaction of KIF13A with AP-1 in cells. Incubating these peptides with human MNT-1 cells or 3D-reconstructed pigmented epidermis decreases pigmentation by impacting the maturation of melanosomes in fully pigmented organelles. This study highlights that peptides targeting the intracellular trafficking of melanocytes are candidate molecules to tune pigmentation in health and disease. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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18 pages, 1649 KiB

Open AccessArticle

Antioxidative and Anti-Melanogenic Activities of Bamboo Stems (Phyllostachys nigra variety henosis) via PKA/CREB-Mediated MITF Downregulation in B16F10 Melanoma Cells

by Moon-Hee Choi, Han-Gyo Jo, Ji Hye Yang, Sung Hwan Ki and Hyun-Jae Shin

Int. J. Mol. Sci. 2018, 19(2), 409; https://doi.org/10.3390/ijms19020409 - 30 Jan 2018

Cited by 57 | Viewed by 8530

Abstract

Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. [...] Read more.

Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. The anti-melanogenic and antioxidative activities of the EtOAc fraction (PN3) of a P. nigra stem extract were investigated in a cell-free system and in B16F10 melanoma cells. PN3 consisted of a mixture of flavonoids, such as catechin, chlorogenic acid, caffeic acid, and p-coumaric acid. The antioxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)), and hydroxyl radical scavenging) was evaluated, as well as the inhibition of reactive oxygen species (ROS) produced by the Fenton reaction. PN3 showed in vitro tyrosinase inhibition activity with the half maximal inbihitory concentration (IC₅₀) values of 240 μg/mL, and in vivo cytotoxic concentration ranges > 100 μg/mL. The protein expression levels and mRNA transcription levels of TYR, TRP-1, and MITF were decreased in a dose-dependent manner by the treatment with PN3. PN3 interfered with the phosphorylation of intracellular protein kinase A (PKA)/cAMP response element-binding protein (CREB), demonstrating potent anti-melanogenic effects. PN3 could inhibit PKA/CREB and the subsequent degradation of microphthalmia-associated transcription factor (MITF), resulting in the suppression of melanogenic enzymes and melanin production, probably because of the presence of flavonoid compounds. These properties make it a candidate as an additive to whitening cosmetics. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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4551 KiB

Open AccessArticle

Selection on the Major Color Gene Melanocortin-1-Receptor Shaped the Evolution of the Melanocortin System Genes

by Linda Dib, Luis M. San-Jose, Anne-Lyse Ducrest, Nicolas Salamin and Alexandre Roulin

Int. J. Mol. Sci. 2017, 18(12), 2618; https://doi.org/10.3390/ijms18122618 - 5 Dec 2017

Cited by 22 | Viewed by 6672

Abstract

Modular genetic systems and networks have complex evolutionary histories shaped by selection acting on single genes as well as on their integrated function within the network. However, uncovering molecular coevolution requires the detection of coevolving sites in sequences. Detailed knowledge of the functions [...] Read more.

Modular genetic systems and networks have complex evolutionary histories shaped by selection acting on single genes as well as on their integrated function within the network. However, uncovering molecular coevolution requires the detection of coevolving sites in sequences. Detailed knowledge of the functions of each gene in the system is also necessary to identify the selective agents driving coevolution. Using recently developed computational tools, we investigated the effect of positive selection on the coevolution of ten major genes in the melanocortin system, responsible for multiple physiological functions and human diseases. Substitutions driven by positive selection at the melanocortin-1-receptor (MC1R) induced more coevolutionary changes on the system than positive selection on other genes in the system. Contrarily, selection on the highly pleiotropic POMC gene, which orchestrates the activation of the different melanocortin receptors, had the lowest coevolutionary influence. MC1R and possibly its main function, melanin pigmentation, seems to have influenced the evolution of the melanocortin system more than functions regulated by MC2-5Rs such as energy homeostasis, glucocorticoid-dependent stress and anti-inflammatory responses. Although replication in other regulatory systems is needed, this suggests that single functional aspects of a genetic network or system can be of higher importance than others in shaping coevolution among the genes that integrate it. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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Open AccessArticle

Effects of Extremely Low Frequency Electromagnetic Fields on Melanogenesis through p-ERK and p-SAPK/JNK Pathways in Human Melanocytes

by Yu-Mi Kim, Sang-Eun Cho, Soo-Chan Kim, Hyun-Joon Jang and Young-Kwon Seo

Int. J. Mol. Sci. 2017, 18(10), 2120; https://doi.org/10.3390/ijms18102120 - 11 Oct 2017

Cited by 15 | Viewed by 6588

Abstract

This study evaluated frequency-dependent effects of extremely low frequency electromagnetic fields (ELF-EMFs) on melanogenesis by melanocytes in vitro. Melanocytes were exposed to 2 mT EMFs at 30–75 Hz for 3 days before melanogenesis was examined. Exposure to ELF-EMFs at 50 and 60 Hz [...] Read more.

This study evaluated frequency-dependent effects of extremely low frequency electromagnetic fields (ELF-EMFs) on melanogenesis by melanocytes in vitro. Melanocytes were exposed to 2 mT EMFs at 30–75 Hz for 3 days before melanogenesis was examined. Exposure to ELF-EMFs at 50 and 60 Hz induced melanogenic maturation without cell damage, without changing cell proliferation and mitochondrial activity. Melanin content and tyrosinase activity of cells exposed to 50 Hz were higher than in controls, and mRNA expression of tyrosinase-related protein-2 was elevated relative to controls at 50 Hz. Phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) levels were higher than controls in cells exposed to ELF-EMFs at 50–75 Hz. Immunohistochemical staining showed that melanocyte-specific markers (HMB45, Melan-A) were strongly expressed in cells exposed to EMFs at 50 and 60 Hz compared to controls. Thus, exposure to ELF-EMFs at 50 Hz could stimulate melanogenesis in melanocytes, through activation of p-CREB and p-p38 and inhibition of phosphorylated extracellular signal-regulated protein kinase and phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase. The results may form the basis of an appropriate anti-gray hair treatment or be applied in a therapeutic device for inducing repigmentation in the skin of vitiligo patients. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression

by Taek-In Oh, Yoon-Mi Lee, Beong-Ou Lim and Ji-Hong Lim

Int. J. Mol. Sci. 2017, 18(9), 1924; https://doi.org/10.3390/ijms18091924 - 7 Sep 2017

Cited by 37 | Viewed by 8483

Abstract

N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable. Using a small molecule or small interfering RNA targeting NAT10, we examined [...] Read more.

N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable. Using a small molecule or small interfering RNA targeting NAT10, we examined the effect of NAT10 inhibition on melanogenesis and melanoma growth in human and mouse melanoma cells. Genetic silencing or chemical inhibition of NAT10 resulted in diminished melanin synthesis through the suppression of melanogenesis-stimulating genes such as those encoding dopachrome tautomerase (DCT) and tyrosinase in B16F10 melanoma cells. In addition, NAT10 inhibition significantly increased cell cycle arrest in S-phase, thereby suppressing the growth and proliferation of malignant melanoma cells in vitro and in vivo. These results demonstrate the potential role of NAT10 in melanogenesis and melanoma growth through the regulation of microphthalmia-associated transcription factor (MITF) expression and provide a promising strategy for the treatment of various skin diseases (melanoma) and pigmentation disorders (chloasma and freckles). Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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2020 KiB

Open AccessArticle

Protocatechuic Acid from Pear Inhibits Melanogenesis in Melanoma Cells

by Xuan T. Truong, Seo-Hee Park, Yu-Geon Lee, Hang Yeon Jeong, Jae-Hak Moon and Tae-Il Jeon

Int. J. Mol. Sci. 2017, 18(8), 1809; https://doi.org/10.3390/ijms18081809 - 21 Aug 2017

Cited by 37 | Viewed by 12148

Abstract

Despite the critical role of melanin in the protection of skin against UV radiation, excess production of melanin can lead to hyperpigmentation and skin cancer. Pear fruits are often used in traditional medicine for the treatment of melasma; therefore, we investigated the effects [...] Read more.

Despite the critical role of melanin in the protection of skin against UV radiation, excess production of melanin can lead to hyperpigmentation and skin cancer. Pear fruits are often used in traditional medicine for the treatment of melasma; therefore, we investigated the effects of pear extract (PE) and its component, protocatechuic acid (PCA), on melanogenesis in mouse melanoma cells. We found that PE and PCA significantly suppressed melanin content and cellular tyrosinase activity through a decrease in the expression of melanogenic enzymes and microphthalmia-associated transcription factor (Mitf) in α-melanocyte stimulating hormone-stimulated mouse melanoma cells. Moreover, PCA decreased cyclic adenosine monophosphate (cAMP) levels and cAMP-responsive element-binding protein phosphorylation, which downregulated Mitf promoter activation and subsequently mediated the inhibition of melanogenesis. These results suggested that pear may be an effective skin lightening agent that targets either a tyrosinase activity or a melanogenic pathway. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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Review

Jump to: Editorial, Research

20 pages, 383 KiB

Open AccessReview

Plants as Modulators of Melanogenesis: Role of Extracts, Pure Compounds and Patented Compositions in Therapy of Pigmentation Disorders

by Anna Merecz-Sadowska, Przemysław Sitarek, Joanna Stelmach, Karolina Zajdel, Ewa Kucharska and Radosław Zajdel

Int. J. Mol. Sci. 2022, 23(23), 14787; https://doi.org/10.3390/ijms232314787 - 26 Nov 2022

Cited by 7 | Viewed by 4081

Abstract

The kingdom of plants as a “green biofabric” of valuable bioactive molecules has long been used in many ailments. Currently, extracts and pure compounds of plant origin are used to aid in pigmentation skin problems by influencing the process of melanogenesis. Melanin is [...] Read more.

The kingdom of plants as a “green biofabric” of valuable bioactive molecules has long been used in many ailments. Currently, extracts and pure compounds of plant origin are used to aid in pigmentation skin problems by influencing the process of melanogenesis. Melanin is a very important pigment that protects human skin against ultraviolet radiation and oxidative stress. It is produced by a complex process called melanogenesis. However, disturbances in the melanogenesis mechanism may increase or decrease the level of melanin and generate essential skin problems, such as hyperpigmentation and hypopigmentation. Accordingly, inhibitors or activators of pigment formation are desirable for medical and cosmetic industry. Such properties may be exhibited by molecules of plant origin. Therefore, that literature review presents reports on plant extracts, pure compounds and compositions that may modulate melanin production in living organisms. The potential of plants in the therapy of pigmentation disorders has been highlighted. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

36 pages, 9632 KiB

Open AccessReview

Chemical Reactivities of ortho-Quinones Produced in Living Organisms: Fate of Quinonoid Products Formed by Tyrosinase and Phenoloxidase Action on Phenols and Catechols

by Shosuke Ito, Manickam Sugumaran and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2020, 21(17), 6080; https://doi.org/10.3390/ijms21176080 - 24 Aug 2020

Cited by 82 | Viewed by 8846

Abstract

Tyrosinase catalyzes the oxidation of phenols and catechols (o-diphenols) to o-quinones. The reactivities of o-quinones thus generated are responsible for oxidative browning of plant products, sclerotization of insect cuticle, defense reaction in arthropods, tunichrome biochemistry in tunicates, production of [...] Read more.

Tyrosinase catalyzes the oxidation of phenols and catechols (o-diphenols) to o-quinones. The reactivities of o-quinones thus generated are responsible for oxidative browning of plant products, sclerotization of insect cuticle, defense reaction in arthropods, tunichrome biochemistry in tunicates, production of mussel glue, and most importantly melanin biosynthesis in all organisms. These reactions also form a set of major reactions that are of nonenzymatic origin in nature. In this review, we summarized the chemical fates of o-quinones. Many of the reactions of o-quinones proceed extremely fast with a half-life of less than a second. As a result, the corresponding quinone production can only be detected through rapid scanning spectrophotometry. Michael-1,6-addition with thiols, intramolecular cyclization reaction with side chain amino groups, and the redox regeneration to original catechol represent some of the fast reactions exhibited by o-quinones, while, nucleophilic addition of carboxyl group, alcoholic group, and water are mostly slow reactions. A variety of catecholamines also exhibit side chain desaturation through tautomeric quinone methide formation. Therefore, quinone methide tautomers also play a pivotal role in the fate of numerous o-quinones. Armed with such wide and dangerous reactivity, o-quinones are capable of modifying the structure of important cellular components especially proteins and DNA and causing severe cytotoxicity and carcinogenic effects. The reactivities of different o-quinones involved in these processes along with special emphasis on mechanism of melanogenesis are discussed. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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37 pages, 4406 KiB

Open AccessReview

From Extraction to Advanced Analytical Methods: The Challenges of Melanin Analysis

by Ioana-Ecaterina Pralea, Radu-Cristian Moldovan, Alina-Maria Petrache, Maria Ilieș, Simona-Codruța Hegheș, Irina Ielciu, Raul Nicoară, Mirela Moldovan, Mihaela Ene, Mihai Radu, Alina Uifălean and Cristina-Adela Iuga

Int. J. Mol. Sci. 2019, 20(16), 3943; https://doi.org/10.3390/ijms20163943 - 13 Aug 2019

Cited by 168 | Viewed by 12256

Abstract

The generic term “melanin“ describes a black pigment of biological origin, although some melanins can be brown or even yellow. The pigment is characterized as a heterogenic polymer of phenolic or indolic nature, and the classification of eu-, pheo- and allo- melanin is [...] Read more.

The generic term “melanin“ describes a black pigment of biological origin, although some melanins can be brown or even yellow. The pigment is characterized as a heterogenic polymer of phenolic or indolic nature, and the classification of eu-, pheo- and allo- melanin is broadly accepted. This classification is based on the chemical composition of the monomer subunit structure of the pigment. Due to the high heterogeneity of melanins, their analytical characterization can be a challenging task. In the present work, we synthesized the current information about the analytical methods which can be applied in melanin analysis workflow, from extraction and purification to high-throughput methods, such as matrix-assisted laser desorption/ionization mass-spectrometry or pyrolysis gas chromatography. Our thorough comparative evaluation of analytical data published so far on melanin analysis has proven to be a difficult task in terms of finding equivalent results, even when the same matrix was used. Moreover, we emphasize the importance of prior knowledge of melanin types and properties in order to select a valid experimental design using analytical methods that are able to deliver reliable results and draw consistent conclusions. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)

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44 pages, 3421 KiB

Open AccessReview

Clinical and Biological Characterization of Skin Pigmentation Diversity and Its Consequences on UV Impact

by Sandra Del Bino, Christine Duval and Françoise Bernerd

Int. J. Mol. Sci. 2018, 19(9), 2668; https://doi.org/10.3390/ijms19092668 - 8 Sep 2018

Cited by 175 | Viewed by 25722

Abstract

Skin color diversity is the most variable and noticeable phenotypic trait in humans resulting from constitutive pigmentation variability. This paper will review the characterization of skin pigmentation diversity with a focus on the most recent data on the genetic basis of skin pigmentation, [...] Read more.

Skin color diversity is the most variable and noticeable phenotypic trait in humans resulting from constitutive pigmentation variability. This paper will review the characterization of skin pigmentation diversity with a focus on the most recent data on the genetic basis of skin pigmentation, and the various methodologies for skin color assessment. Then, melanocyte activity and amount, type and distribution of melanins, which are the main drivers for skin pigmentation, are described. Paracrine regulators of melanocyte microenvironment are also discussed. Skin response to sun exposure is also highly dependent on color diversity. Thus, sensitivity to solar wavelengths is examined in terms of acute effects such as sunburn/erythema or induced-pigmentation but also long-term consequences such as skin cancers, photoageing and pigmentary disorders. More pronounced sun-sensitivity in lighter or darker skin types depending on the detrimental effects and involved wavelengths is reviewed. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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16 pages, 814 KiB

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MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA Repair

by Viki B. Swope and Zalfa A. Abdel-Malek

Int. J. Mol. Sci. 2018, 19(9), 2667; https://doi.org/10.3390/ijms19092667 - 8 Sep 2018

Cited by 78 | Viewed by 11489

Abstract

Melanin, the pigment produced by specialized cells, melanocytes, is responsible for skin and hair color. Skin pigmentation is an important protective mechanism against the DNA damaging and mutagenic effects of solar ultraviolet radiation (UV). It is acknowledged that exposure to UV is the [...] Read more.

Melanin, the pigment produced by specialized cells, melanocytes, is responsible for skin and hair color. Skin pigmentation is an important protective mechanism against the DNA damaging and mutagenic effects of solar ultraviolet radiation (UV). It is acknowledged that exposure to UV is the main etiological environmental factor for all forms of skin cancer, including melanoma. DNA repair capacity is another major factor that determines the risk for skin cancer. Human melanocytes synthesize eumelanin, the dark brown form of melanin, as well as pheomelanin, which is reddish-yellow in color. The relative rates of eumelanin and pheomelanin synthesis by melanocytes determine skin color and the sensitivity of skin to the drastic effects of solar UV. Understanding the complex regulation of melanocyte function and how it responds to solar UV has a huge impact on developing novel photoprotective strategies to prevent skin cancer, particularly melanoma, the most fatal form, which originates from melanocytes. This review provides an overview of the known differences in the photoprotective effects of eumelanin versus pheomelanin, how these two forms of melanin are regulated genetically and biochemically, and their impact on the DNA damaging effects of UV exposure. Additionally, this review briefly discusses the role of paracrine factors, focusing on α-melanocortin (α-melanocyte stimulating hormone; α-MSH), in regulating melanogenesis and the response of melanocytes to UV, and describes a chemoprevention strategy based on targeting the melanocortin 1 receptor (MC1R) by analogs of its physiological agonist α-MSH. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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16 pages, 1076 KiB

Open AccessReview

The Late Stages of Melanogenesis: Exploring the Chemical Facets and the Application Opportunities

by Lucia Panzella, Atsuko Ebato, Alessandra Napolitano and Kenzo Koike

Int. J. Mol. Sci. 2018, 19(6), 1753; https://doi.org/10.3390/ijms19061753 - 13 Jun 2018

Cited by 51 | Viewed by 7178

Abstract

In the last decade, the late stages of melanin biosynthesis involving the oxidative polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) have been extensively investigated. Most of the information derived from a biomimetic approach in which the oxidation of melanogenic indoles was carried [...] Read more.

In the last decade, the late stages of melanin biosynthesis involving the oxidative polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) have been extensively investigated. Most of the information derived from a biomimetic approach in which the oxidation of melanogenic indoles was carried out under conditions mimicking those occurring in the biological environment. Characterization of the early oligomers allowed for drawing a structural picture of DHI and DHICA melanins, providing also an interpretative basis for the different properties exhibited by these pigments, e.g., the chromophore and the antioxidant ability. The improved knowledge has opened new perspectives toward the exploitation of the unique chemistry of melanins and its precursors in cosmetic and health care applications. A noticeable example is the development of an innovative hair dyeing system that is based on the marked ease of DHI to give rise to black melanin on air oxidation under slightly alkaline conditions. The advantage of this method for a step-wise coverage of gray hair with a natural shade pigmentation on repeated treatment with a DHI-based formulation with respect to traditional dyes is presented. A variant of DHICA melanin combining solubility in water-miscible organic solvents, an intense chromophore in the UltraViolet-A UV-A region, and a marked antioxidant potency was evaluated as an ingredient for cosmetic formulations. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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15 pages, 255 KiB

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Clinical and Molecular Aspects of Vitiligo Treatments

by Anuradha Bishnoi and Davinder Parsad

Int. J. Mol. Sci. 2018, 19(5), 1509; https://doi.org/10.3390/ijms19051509 - 18 May 2018

Cited by 56 | Viewed by 9194

Abstract

Vitiligo is an asymptomatic but cosmetically disfiguring disorder that results in the formation of depigmented patches on skin and/or mucosae. Vitiligo can be segmental or non-segmental depending upon the morphology of the clinical involvement. It can also be classified as progressing or stable [...] Read more.

Vitiligo is an asymptomatic but cosmetically disfiguring disorder that results in the formation of depigmented patches on skin and/or mucosae. Vitiligo can be segmental or non-segmental depending upon the morphology of the clinical involvement. It can also be classified as progressing or stable based on the activity of the disease. Further, the extent of involvement can be limited (localized disease) or extensive (generalized disease). The treatment of vitiligo therefore depends on the clinical classification/characteristics of the disease and usually comprises of 2 strategies. The first involves arresting the progression of active disease (to provide stability) in order to limit the area involved by depigmentation. The second strategy aims at repigmentation of the depigmented area. It is also important to maintain the disease in a stable phase and to prevent relapse. Accordingly, a holistic treatment approach for vitiligo should be individualistic and should take care of all these considerations. In this review, we shall discuss the vitiligo treatments and their important clinical and molecular aspects. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

17 pages, 852 KiB

Open AccessReview

On the Metal Cofactor in the Tyrosinase Family

by Francisco Solano

Int. J. Mol. Sci. 2018, 19(2), 633; https://doi.org/10.3390/ijms19020633 - 23 Feb 2018

Cited by 81 | Viewed by 8122

Abstract

The production of pigment in mammalian melanocytes requires the contribution of at least three melanogenic enzymes, tyrosinase and two other accessory enzymes called the tyrosinase-related proteins (Trp1 and Trp2), which regulate the type and amount of melanin. The last two proteins are paralogues [...] Read more.

The production of pigment in mammalian melanocytes requires the contribution of at least three melanogenic enzymes, tyrosinase and two other accessory enzymes called the tyrosinase-related proteins (Trp1 and Trp2), which regulate the type and amount of melanin. The last two proteins are paralogues to tyrosinase, and they appeared late in evolution by triplication of the tyrosinase gene. Tyrosinase is a copper-enzyme, and Trp2 is a zinc-enzyme. Trp1 has been more elusive, and the direct identification of its metal cofactor has never been achieved. However, due to its enzymatic activity and similarities with tyrosinase, it has been assumed as a copper-enzyme. Recently, recombinant human tyrosinase and Trp1 have been expressed in enough amounts to achieve for the first time their crystallization. Unexpectedly, it has been found that Trp1 contains a couple of Zn(II) at the active site. This review discusses data about the metal cofactor of tyrosinase and Trps. It points out differences in the studied models, and it proposes some possible points accounting for the apparent discrepancies currently appearing. Moreover, some proposals about the possible flexibility of the tyrosinase family to uptake copper or zinc are discussed. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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16 pages, 1389 KiB

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Biochemical Mechanism of Rhododendrol-Induced Leukoderma

by Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2018, 19(2), 552; https://doi.org/10.3390/ijms19020552 - 12 Feb 2018

Cited by 31 | Viewed by 8801

Abstract

RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))—a skin-whitening ingredient—was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic [...] Read more.

RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))—a skin-whitening ingredient—was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products. Subsequently, we confirmed that human tyrosinase is able to oxidize both enantiomers of RD. We then showed that B16 cells exposed to RD produce high levels of RD-pheomelanin and protein-SH adducts of RD-quinone. Our recent studies showed that RD-eumelanin—an oxidation product of RD—exhibits a potent pro-oxidant activity that is enhanced by ultraviolet-A radiation. In this review, we summarize our biochemical findings on the tyrosinase-dependent metabolism of RD and related studies by other research groups. The results suggest two major mechanisms of cytotoxicity to melanocytes. One is the cytotoxicity of RD-quinone through binding with sulfhydryl proteins that leads to the inactivation of sulfhydryl enzymes and protein denaturation that leads to endoplasmic reticulum stress. The other mechanism is the pro-oxidant activity of RD-derived melanins that leads to oxidative stress resulting from the depletion of antioxidants and the generation of reactive oxygen radicals. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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11 pages, 2214 KiB

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Melanins in Fossil Animals: Is It Possible to Infer Life History Traits from the Coloration of Extinct Species?

by Juan J. Negro, Clive Finlayson and Ismael Galván

Int. J. Mol. Sci. 2018, 19(2), 230; https://doi.org/10.3390/ijms19020230 - 23 Jan 2018

Cited by 14 | Viewed by 8888

Abstract

Paleo-colour scientists have recently made the transition from describing melanin-based colouration in fossil specimens to inferring life-history traits of the species involved. Two such cases correspond to counter-shaded dinosaurs: dark-coloured due to melanins dorsally, and light-coloured ventrally. We believe that colour reconstruction of [...] Read more.

Paleo-colour scientists have recently made the transition from describing melanin-based colouration in fossil specimens to inferring life-history traits of the species involved. Two such cases correspond to counter-shaded dinosaurs: dark-coloured due to melanins dorsally, and light-coloured ventrally. We believe that colour reconstruction of fossils based on the shape of preserved microstructures—the majority of paleo-colour studies involve melanin granules—is not without risks. In addition, animals with contrasting dorso-ventral colouration may be under different selection pressures beyond the need for camouflage, including, for instance, visual communication or ultraviolet (UV) protection. Melanin production is costly, and animals may invest less in areas of the integument where pigments are less needed. In addition, melanocytes exposed to UV radiation produce more melanin than unexposed melanocytes. Pigment economization may thus explain the colour pattern of some counter-shaded animals, including extinct species. Even in well-studied extant species, their diversity of hues and patterns is far from being understood; inferring colours and their functions in species only known from one or few specimens from the fossil record should be exerted with special prudence. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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Neural Stem Cells and Its Derivatives as a New Material for Melanin Inhibition

by Insik Hwang and Sunghoi Hong

Int. J. Mol. Sci. 2018, 19(1), 36; https://doi.org/10.3390/ijms19010036 - 22 Dec 2017

Cited by 12 | Viewed by 6000

Abstract

The pigment molecule, melanin, is produced from melanosomes of melanocytes through melanogenesis, which is a complex process involving a combination of chemical and enzymatically catalyzed reactions. The synthesis of melanin is primarily influenced by tyrosinase (TYR), which has attracted interest as a target [...] Read more.

The pigment molecule, melanin, is produced from melanosomes of melanocytes through melanogenesis, which is a complex process involving a combination of chemical and enzymatically catalyzed reactions. The synthesis of melanin is primarily influenced by tyrosinase (TYR), which has attracted interest as a target molecule for the regulation of pigmentation or depigmentation in skin. Thus, direct inhibitors of TYR activity have been sought from various natural and synthetic materials. However, due to issues with these inhibitors, such as weak or permanent ability for depigmentation, allergy, irritant dermatitis and rapid oxidation, in vitro and in vivo, the development of new materials that inhibit melanin production is essential. A conditioned medium (CM) derived from stem cells contains many cell-secreted factors, such as cytokines, chemokines, growth factors and extracellular vesicles including exosomes. In addition, the secreted factors could negatively regulate melanin production through stimulation of a microenvironment of skin tissue in a paracrine manner, which allows the neural stem cell CM to be explored as a new material for skin depigmentation. In this review, we will summarize the current knowledge regulating depigmentation, and discuss the potential of neural stem cells and their derivatives, as a new material for skin depigmentation. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)

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