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Special Issue "Inhibitors of Melanogenesis Related Processes: Application to Food, Agricultural and Cosmetic Industry-2014"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 November 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Manickam Sugumaran (Website)

Department of Biology, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA
Phone: +1 617-287-6598
Fax: +1 617 287 6650
Interests: enzymology; post translational modifications; aromatic metabolism; phenolic biochemistry; reactions of quinonoid compounds; invertebrate immunity; insect cuticular sclerotization; phenoloxidase; quinone isomerases; oxidative browning; melanin biosynthesis; catecholic antibiotics

Special Issue Information

Dear Colleagues,

Melanogenesis is a pigment-producing process that occurs ubiquitously in all animals, as well as in a wide variety of microorganisms and plants. The enzyme tyrosinase (also known as phenoloxidase) initiates melanogenesis by hydroxylating monophenols to create o-diphenols; these o-diphenols are further oxidized by tyrosinase into o-quinones. The unstable o-quinones undergo rapid transformations that are both nonenzymatic and enzyme catalyzed. Eventually, these transformations create different kinds of polymeric products.

Quinones in general are very reactive and tend to deplete cellular antioxidant pools. They also have deleterious effects on cellular macromolecules. In light of the above, inhibitors of melanogensis have great commercial potential.

For example, oxidative browning reactions reduce the nutritive values of plants. On the other hand, these reactions are advantageous for plants because they help fight off infection and invasion by other organisms. Nevertheless, oxidative browning certainly reduces the market value of food products.

The melanosis observed in crustaceans similarly reduces the market value of seafood drastically. In arthropods and especially insects, melanogenesis is used for wound healing and defense reactions (invertebrate immunity). A parallel process called sclerotization (which is initated through phenoloxidases), ensures the hardening of insect exoskeletons, so as to protect these soft-bodied animals from their environmental enemies. Arrest or even delay of sclerotization has devastating consequences for insects. Consequently, the inhibition of sclerotization provides a valuable tool for fighting noxious insects, and for developing new kinds of insecticides for future use.

Mammals use melanin mostly as skin, coat, and eye pigments. In recent years, dermal melanin production inhibitors have become a valuable tool for the cosmetic industry to produce lighter skin.

Thus, melanogenesis inhibitors have many useful applications. Naturally, lots of research groups have been engaged in discovering novel inhibitors of these enzymes. This Special Issue, which is the second of a series, will cover broad range topics, which include phenoloxidase/tyrosinase chemistry, biochemistry of inhibitors, and methods of either discovering or developing novel bioactive compounds (both natural and synthetic) that inhibit melanogenesis and related processes.  This new Special Issue aims to cover the most recent progress made in this area, and will include research papers and authoritative review articles.

Prof. Manickam Sugumaran
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).


Keywords

  • phenoloxidase inhibitors
  • tyrosinase inhibitors
  • inhibitors of melanogenesis
  • skin color lightening
  • prevention of oxidative browning
  • cuticular sclerotization
  • invertebrate immunity and melanin

Related Special Issue

Published Papers (9 papers)

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Research

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Open AccessArticle Cellular Anti-Melanogenic Effects of a Euryale ferox Seed Extract Ethyl Acetate Fraction via the Lysosomal Degradation Machinery
Int. J. Mol. Sci. 2015, 16(5), 9217-9235; doi:10.3390/ijms16059217
Received: 5 December 2014 / Revised: 17 April 2015 / Accepted: 20 April 2015 / Published: 23 April 2015
Cited by 1 | PDF Full-text (1486 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to investigate the effect of ethyl acetate fraction of Euryale ferox seed extracts (Efse-EA) on melanogenesis in immortalized mouse melanocyte cell line, melan-a. Efse-EA showed strong dose-dependent mushroom tyrosinase inhibitory activity. Treatment of melan-a cells with [...] Read more.
The aim of this study was to investigate the effect of ethyl acetate fraction of Euryale ferox seed extracts (Efse-EA) on melanogenesis in immortalized mouse melanocyte cell line, melan-a. Efse-EA showed strong dose-dependent mushroom tyrosinase inhibitory activity. Treatment of melan-a cells with 30 μg/mL Efse-EA produced strong inhibition of cellular tyrosinase and melanin synthesis. Efse-EA significantly reduced the levels of melanogenesis-related proteins, such as tyrosinase, tyrosinase-related proteins 1 and 2, and microphthalmia-associated transcription factor. Because Efse-EA treatment reduced tyrosinase protein levels without changing its mRNA expression, we investigated whether this decrease was related to proteasomal or lysosomal degradation of tyrosinase. We found that chloroquine, a lysosomal proteolysis inhibitor, almost completely abolished both the down-regulation of tyrosinase and the inhibition of melanin synthesis induced by Efse-EA. These results suggested that Efse-EA may contribute to the inhibition of melanogenesis by altering lysosomal degradation of tyrosinase, and that this extract may provide a new cosmetic skin-whitening agent. Full article
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Open AccessArticle The Potential of Minor Ginsenosides Isolated from the Leaves of Panax ginseng as Inhibitors of Melanogenesis
Int. J. Mol. Sci. 2015, 16(1), 1677-1690; doi:10.3390/ijms16011677
Received: 16 September 2014 / Accepted: 31 December 2014 / Published: 13 January 2015
Cited by 4 | PDF Full-text (991 KB) | HTML Full-text | XML Full-text
Abstract
Three minor ginsenosides, namely, ginsenoside Rh6 (1), vina-ginsenoside R4 (2) and vina-ginsenoside R13 (3), were isolated from the leaves of hydroponic Panax ginseng. The chemical structures were determined based on spectroscopic methods, including fast atom [...] Read more.
Three minor ginsenosides, namely, ginsenoside Rh6 (1), vina-ginsenoside R4 (2) and vina-ginsenoside R13 (3), were isolated from the leaves of hydroponic Panax ginseng. The chemical structures were determined based on spectroscopic methods, including fast atom bombardment mass spectroscopy (FAB-MS), 1D-nuclear magnetic resonance (NMR), 2D-NMR, and, infrared (IR) spectroscopy. The melanogenic inhibitory activity of compounds 1, 2 and 3 was 23.9%, 27.8% and 35.2%, respectively, at a concentration of 80 µM. Likewise, the three compounds showed inhibitory activity on body pigmentation on a zebrafish model, which is commonly used as a model for biomedical or cosmetic research. These results from in vitro and in vivo systems suggest that the three aforementioned compounds isolated from Panax ginseng may have potential as new skin whitening compounds. Full article
Open AccessArticle Hair Dyes Resorcinol and Lawsone Reduce Production of Melanin in Melanoma Cells by Tyrosinase Activity Inhibition and Decreasing Tyrosinase and Microphthalmia-Associated Transcription Factor (MITF) Expression
Int. J. Mol. Sci. 2015, 16(1), 1495-1508; doi:10.3390/ijms16011495
Received: 25 November 2014 / Accepted: 4 January 2015 / Published: 9 January 2015
Cited by 3 | PDF Full-text (3656 KB) | HTML Full-text | XML Full-text
Abstract
Hair coloring products are one of the most important cosmetics for modern people; there are three major types of hair dyes, including the temporary, semi-permanent and permanent hair dyes. The selected hair dyes (such as ammonium persulfate, sodium persulfate, resorcinol and lawsone) [...] Read more.
Hair coloring products are one of the most important cosmetics for modern people; there are three major types of hair dyes, including the temporary, semi-permanent and permanent hair dyes. The selected hair dyes (such as ammonium persulfate, sodium persulfate, resorcinol and lawsone) are the important components for hair coloring products. Therefore, we analyzed the effects of these compounds on melanogenesis in B16-F10 melanoma cells. The results proved that hair dyes resorcinol and lawsone can reduce the production of melanin. The results also confirmed that resorcinol and lawsone inhibit mushroom and cellular tyrosinase activities in vitro. Resorcinol and lawsone can also downregulate the protein levels of tyrosinase and microphthalmia-associated transcription factor (MITF) in B16-F10 cells. Thus, we suggest that frequent use of hair dyes may have the risk of reducing natural melanin production in hair follicles. Moreover, resorcinol and lawsone may also be used as hypopigmenting agents to food, agricultural and cosmetic industry in the future. Full article
Open AccessCommunication Inhibitory Effects of Adlay Extract on Melanin Production and Cellular Oxygen Stress in B16F10 Melanoma Cells
Int. J. Mol. Sci. 2014, 15(9), 16665-16679; doi:10.3390/ijms150916665
Received: 6 January 2014 / Revised: 12 September 2014 / Accepted: 15 September 2014 / Published: 19 September 2014
Cited by 6 | PDF Full-text (853 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to determine the effects of adlay extract on melanin production and the antioxidant characteristics of the extract. The seeds were extracted by the supercritical fluid CO2 extraction (SFE) method. The effect of adlay extract on [...] Read more.
The aim of this study was to determine the effects of adlay extract on melanin production and the antioxidant characteristics of the extract. The seeds were extracted by the supercritical fluid CO2 extraction (SFE) method. The effect of adlay extract on melanin production was evaluated using mushroom tyrosinase activity assay, intracellular tyrosinase activity, antioxidant properties and melanin content. Those assays were performed spectrophotometrically. In addition, the expression of melanogenesis-related proteins was determined by western blotting. The results revealed that the adlay extract suppressed intracellular tyrosinase activity and decreased the amount of melanin in B16F10 cells. The adlay extract decreased the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase related protein-1 (TRP-1) and tyrosinase related protein-2 (TRP-2). The extract also exhibited antioxidant characteristics such as free radical scavenging capacity and reducing power. It effectively decreased intracellular reactive oxygen species (ROS) levels in B16F10 cells. We concluded that the adlay extract inhibits melanin production by down-regulation of MITF, tyrosinase, TRP-1 and TRP-2. The antioxidant properties of the extract may also contribute to the inhibition of melanogenesis. The adlay extract can therefore be applied as an inhibitor of melanogenesis and could also act as a natural antioxidant in skin care products. Full article
Open AccessArticle Mechanistic Studies of Anti-Hyperpigmentary Compounds: Elucidating Their Inhibitory and Regulatory Actions
Int. J. Mol. Sci. 2014, 15(8), 14649-14668; doi:10.3390/ijms150814649
Received: 29 June 2014 / Revised: 28 July 2014 / Accepted: 13 August 2014 / Published: 21 August 2014
Cited by 2 | PDF Full-text (1414 KB) | HTML Full-text | XML Full-text
Abstract
Searching for depigmenting agents from natural sources has become a new direction in the cosmetic industry as natural products are generally perceived as relatively safer. In our previous study, selected Chinese medicines traditionally used to treat hyperpigmentation were tested for anti-hyperpigmentary effects [...] Read more.
Searching for depigmenting agents from natural sources has become a new direction in the cosmetic industry as natural products are generally perceived as relatively safer. In our previous study, selected Chinese medicines traditionally used to treat hyperpigmentation were tested for anti-hyperpigmentary effects using a melan-a cell culture model. Among the tested chemical compounds, 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were found to possess hypopigmentary effects. Western blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR), cyclic adenosine monophosphate (cAMP) assay, protein kinase A (PKA) activity assay, tyrosinase inhibition assay and lipid peroxidation inhibition assay were performed to reveal the underlying cellular and molecular mechanisms of the hypopigmentary effects. 4-Ethylresorcinol and 4-ethylphenol attenuated mRNA and protein expression of tyrosinase-related protein (TRP)-2, and possessed antioxidative effect by inhibiting lipid peroxidation. 1-Tetradecanol was able to attenuate protein expression of tyrosinase. The hypopigmentary actions of 4-ethylresorcinol, 4-ethylphenol and 1-tetradecanol were associated with regulating downstream proteins along the PKA pathway. 4-Ethylresorcinol was more effective in inhibiting melanin synthesis when compared to 4-ethylphenol and 1-tetradecanol. Full article
Open AccessArticle S-(−)-10,11-Dihydroxyfarnesoic Acid Methyl Ester Inhibits Melanin Synthesis in Murine Melanocyte Cells
Int. J. Mol. Sci. 2014, 15(7), 12750-12763; doi:10.3390/ijms150712750
Received: 31 March 2014 / Revised: 1 July 2014 / Accepted: 8 July 2014 / Published: 18 July 2014
Cited by 3 | PDF Full-text (5097 KB) | HTML Full-text | XML Full-text
Abstract
The development of antimelanogenic agents is important for the prevention of serious aesthetic problems such as melasmas, freckles, age spots, and chloasmas. In the course of screening for melanin synthesis inhibitors, we found that the culture broth from an insect morphopathogenic fungus, [...] Read more.
The development of antimelanogenic agents is important for the prevention of serious aesthetic problems such as melasmas, freckles, age spots, and chloasmas. In the course of screening for melanin synthesis inhibitors, we found that the culture broth from an insect morphopathogenic fungus, Beauveria bassiana CS1029, exhibits potent antimelanogenic activity. We isolated and purified an active metabolite and identified it as S-(−)-10,11-dihydroxyfarnesoic acid methyl ester (dhFAME), an insect juvenile hormone. To address whether dhFAME inhibits melanin synthesis, we first measured the size of the melanin biosynthesis inhibition zone caused by dhFAME. dhFAME also showed inhibitory activity against mushroom tyrosinase in Melan-a cells. Intracellular, dose-dependent tyrosinase inhibition activity was also confirmed by zymography. In addition, we showed that dhFAME strongly inhibits melanin synthesis in Melan-a cells. Furthermore, we compared levels of TYR, TRP-1, TRP-2, MITF, and MC1R mRNA expression by reverse-transcription polymerase chain reaction and showed that treatment of Melan-a cells with 35 μM dhFAME led to an 11-fold decrease in TYR expression, a 6-fold decrease in TRP-2 expression, and a 5-fold decrease in MITF expression. Together, these results indicate that dhFAME is a potent inhibitor of melanin synthesis that can potentially be used for cosmetic biomaterial(s). Full article
Open AccessCommunication Novel Inhibitory Effect of N-(2-Hydroxycyclohexyl)valiolamine on Melanin Production in a Human Skin Model
Int. J. Mol. Sci. 2014, 15(7), 12188-12195; doi:10.3390/ijms150712188
Received: 30 April 2014 / Revised: 24 June 2014 / Accepted: 26 June 2014 / Published: 9 July 2014
Cited by 2 | PDF Full-text (1378 KB) | HTML Full-text | XML Full-text
Abstract
Hyper-pigmentation causes skin darkness and medical disorders, such as post-inflammatory melanoderma and melasma. Therefore, the development of anti-melanogenic agents is important for treating these conditions and for cosmetic production. In our previous paper, we demonstrated that the anti-diabetic drug voglibose, a valiolamine [...] Read more.
Hyper-pigmentation causes skin darkness and medical disorders, such as post-inflammatory melanoderma and melasma. Therefore, the development of anti-melanogenic agents is important for treating these conditions and for cosmetic production. In our previous paper, we demonstrated that the anti-diabetic drug voglibose, a valiolamine derivative, is a potent anti-melanogenic agent. In addition, we proposed an alternative screening strategy to identify valiolamine derivatives with high skin permeability that act as anti-melanogenic agents when applied topically. In this study, we synthesized several valiolamine derivatives with enhanced lipophilicity and examined their inhibitory effects in a human skin model. N-(2-hydroxycyclohexyl)valiolamine (HV) possesses a stronger inhibitory effect on melanin production than voglibose in a human skin model, suggesting that HV is a more potent anti-melanogenic agent for the skin. Full article

Review

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Open AccessReview Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies
Int. J. Mol. Sci. 2014, 15(8), 13768-13801; doi:10.3390/ijms150813768
Received: 3 July 2014 / Revised: 31 July 2014 / Accepted: 5 August 2014 / Published: 8 August 2014
Cited by 32 | PDF Full-text (1378 KB) | HTML Full-text | XML Full-text
Abstract
Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on [...] Read more.
Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs. Full article
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Open AccessReview Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents
Int. J. Mol. Sci. 2014, 15(5), 8293-8315; doi:10.3390/ijms15058293
Received: 14 March 2014 / Revised: 17 April 2014 / Accepted: 29 April 2014 / Published: 12 May 2014
Cited by 2 | PDF Full-text (5096 KB) | HTML Full-text | XML Full-text
Abstract
Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at [...] Read more.
Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation. Full article

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