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      Melanogenic Inhibition and Toxicity Assessment of Flavokawain A and B on B16/F10 Melanoma Cells and Zebrafish ( Danio rerio)

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          Abstract

          Excessive production of melanin implicates hyperpigmentation disorders. Flavokawain A (FLA) and flavokawain B (FLB) have been reported with anti-melanogenic activity, but their melanogenic inhibition and toxicity effects on the vertebrate model of zebrafish are still unknown. In the present study, cytotoxic as well as melanogenic effects of FLA and FLB on cellular melanin content and tyrosinase activity were evaluated in α-MSH-induced B16/F10 cells. Master regulator of microphthalmia-associated transcription factor ( Mitf) and the other downstream melanogenic-related genes were verified via quantitative real time PCR (qPCR). Toxicity assessment and melanogenesis inhibition on zebrafish model was further observed. FLA and FLB significantly reduced the specific cellular melanin content by 4.3-fold and 9.6-fold decrement, respectively in α-MSH-induced B16/F10 cells. Concomitantly, FLA significantly reduced the specific cellular tyrosinase activity by 7-fold whilst FLB by 9-fold. The decrement of melanin production and tyrosinase activity were correlated with the mRNA suppression of Mitf which in turn down-regulate Tyr, Trp-1 and Trp-2. FLA and FLB exhibited non-toxic effects on the zebrafish model at 25 and 6.25 µM, respectively. Further experiments on the zebrafish model demonstrated successful phenotype-based depigmenting activity of FLA and FLB under induced melanogenesis. To sum up, our findings provide an important first key step for both of the chalcone derivatives to be further studied and developed as potent depigmenting agents.

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          Microphthalmia Gene Product as a Signal Transducer in cAMP-Induced Differentiation of Melanocytes

          Melanocyte differentiation characterized by an increased melanogenesis, is stimulated by α-melanocyte–stimulating hormone through activation of the cAMP pathway. During this process, the expression of tyrosinase, the enzyme that controls melanin synthesis is upregulated. We previously showed that cAMP regulates transcription of the tyrosinase gene through a CATGTG motif that binds microphthalmia a transcription factor involved in melanocyte survival. Further, microphthalmia stimulates the transcriptional activity of the tyrosinase promoter and cAMP increases the binding of microphthalmia to the CATGTG motif. These observations led us to hypothesize that microphthalmia mediates the effect of cAMP on the expression of tyrosinase. The present study was designed to elucidate the mechanism by which cAMP regulates microphthalmia function and to prove our former hypothesis, suggesting that microphthalmia is a key component in cAMP-induced melanogenesis. First, we showed that cAMP upregulates the transcription of microphthalmia gene through a classical cAMP response element that is functional only in melanocytes. Then, using a dominant-negative mutant of microphthalmia, we demonstrated that microphthalmia is required for the cAMP effect on tyrosinase promoter. These findings disclose the mechanism by which cAMP stimulates tyrosinase expression and melanogenesis and emphasize the critical role of microphthalmia as signal transducer in cAMP-induced melanogenesis and pigment cell differentiation.
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            Chemical and instrumental approaches to treat hyperpigmentation.

            Many modalities of treatment for acquired skin hyperpigmentation are available including chemical agents or physical therapies, but none are completely satisfactory. Depigmenting compounds should act selectively on hyperactivated melanocytes, without short- or long-term side-effects, and induce a permanent removal of undesired pigment. Since 1961 hydroquinone, a tyrosinase inhibitor, has been introduced and its therapeutic efficacy demonstrated, and other whitening agents specifically acting on tyrosinase by different mechanisms have been proposed. Compounds with depigmenting activity are now numerous and the classification of molecules, based on their mechanism of action, has become difficult. Systematic studies to assess both the efficacy and the safety of such molecules are necessary. Moreover, the evidence that bleaching compounds are fairly ineffective on dermal accumulation of melanin has prompted investigations on the effectiveness of physical therapies, such as lasers. This review which describes the different approaches to obtain depigmentation, suggests a classification of whitening molecules on the basis of the mechanism by which they interfere with melanogenesis, and confirms the necessity to apply standardized protocols to evaluate depigmenting treatments.
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              Enzymatic control of pigmentation in mammals.

              Visible pigmentation in mammals results from the synthesis and distribution of melanin in the skin, hair bulbs, and eyes. The melanins are produced in melanocytes and can be of two basic types: eumelanins, which are brown or black, and phaseomelanins, which are red or yellow. In mammals typically there are mixtures of both types. The most essential enzyme in this melanin biosynthetic pathway is tyrosinase and it is the only enzyme absolutely required for melanin production. However, recent studies have shown that mammalian melanogenesis is not regulated solely by tyrosinase at the enzymatic level, and have identified additional melanogenic factors that can modulate pigmentation in either a positive or negative fashion. In addition, other pigment-specific genes that are related to tyrosinase have been cloned which encode proteins that apparently work together at the catalytic level to specify the quantity and quality of the melanins synthesized. Future research should provide a greater understanding of the enzymatic interactions, processing, and tissue specificity that are important to pigmentation in mammals.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                28 July 2020
                August 2020
                : 25
                : 15
                : 3403
                Affiliations
                [1 ]Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, UPM Serdang, Serdang 43400, Selangor, Malaysia; shafikams@ 123456gmail.com (N.M.S.); najwabiochem@ 123456gmail.com (N.N.M.R.); farahidayu1991@ 123456gmail.com (F.I.M.M.); nazrischolar@ 123456gmail.com (M.N.A.B.); naimah_latif@ 123456yahoo.com (N.L.); zettynorhana@ 123456upm.edu.my (Z.N.B.Y.)
                [2 ]Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Gambang, Kuantan 26300, Pahang, Malaysia; nadeem@ 123456ump.edu.my
                Author notes
                [* ]Correspondence: syahida@ 123456upm.edu.my ; Tel.: +603-89466699; Fax: +603-89467590
                Author information
                https://orcid.org/0000-0003-1624-3026
                https://orcid.org/0000-0002-8565-5609
                Article
                molecules-25-03403
                10.3390/molecules25153403
                7436045
                32731323
                89dc75fd-798c-45ad-8e14-0a47b71bbd38
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 May 2020
                : 02 July 2020
                Categories
                Article

                α-msh,b16/f10 melanoma,chalcone,flavokawain,melanogenesis,zebrafish

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