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Melanogenesis
Selected AbstractsEnhancing the Growth of Natural Eyelashes: The Mechanism of Bimatoprost-Induced Eyelash GrowthDERMATOLOGIC SURGERY, Issue 9 20102Article first published online: 2 APR 2010, JOEL L. COHEN MD BACKGROUND Many women desire prominent eyelashes. In December 2008, bimatoprost ophthalmic solution 0.03% was approved for the treatment of hypotrichosis of the eyelashes in the United States. OBJECTIVE To review eyelash physiology and the proposed mechanisms by which the topical pros-tamide product bimatoprost enhances eyelash growth. METHODS AND MATERIALS Clinical and preclinical studies pertaining to the efficacy, safety, and mechanisms of action of bimatoprost are presented. RESULTS Treatment with bimatoprost increases the percentage of eyelash follicles in anagen at any one time. This probably accounts for its ability to lengthen lashes. Bimatoprost-induced stimulation of melanogenesis appears to result in darker lashes and, at the same time, appears to increase the size of the dermal papilla and hair bulb, affecting lash thickness and fullness. Such effects, largely demonstrated in animal studies, are consistent with the results of a recent Food and Drug Administration phase III clinical trial. The favorable safety profile of bimatoprost in human subjects is probably secondary to the limited exposure of ocular tissues resulting from topical application at the base of the upper lashes. CONCLUSION By influencing the eyelash hair cycle and follicles, bimatoprost ophthalmic solution 0.03% is a safe and effective means of enhancing eyelash growth. Dr. Cohen has served as a consultant and clinical trial participant for Allergan, Inc. [source] Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expressionEXPERIMENTAL DERMATOLOGY, Issue 6 2009Seo-Hyoung Park Abstract:, Previously, we reported that a fungal metabolite, terrein, decreases melanin synthesis via downregulation of microphthalmia-associated transcription factor (MITF). In the present study, we further investigated the long-term hypopigmenting action of terrein in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with terrein at a concentration of 50 ,m strongly decreased melanogenesis in a time-dependent manner. Interestingly, the decreased tyrosinase protein levels lasted for at least 7 days, even though the MITF protein levels were restored after 3 days of treatment. In accordance with the results of Western blot analyses, the tyrosinase mRNA levels were found to be continuously decreased for at least 7 days, even though recovery of the MITF mRNA levels began after 3 days of terrein treatment. Therefore, we evaluated tyrosinase downregulation to determine if it is caused by proteasomal degradation. We found that the reduction in tyrosinase levels that was induced by terrein was clearly recovered by MG-132, a proteasome inhibitor. Moreover, ubiquitination of tyrosinase increased following treatment with terrein in the presence of MG-132. Taken together, these results suggest that terrein decreases melanogenesis through ubiquitin-dependent proteasomal degradation as well as via decreased expression of its mRNA. [source] Antimelanogenesis effect of Tunisian herb Thymelaea hirsuta extract on B16 murine melanoma cellsEXPERIMENTAL DERMATOLOGY, Issue 12 2007Mitsuko Kawano Abstract:, Skin pigmentation is the result of melanogenesis that occurs in melanocytes and/or melanoma cells. Although melanogenesis is necessary for the prevention of DNA damage and cancer caused by UV irradiation, excessive accumulation of melanin can also cause melanoma. Thus, we focused on the antimelanogenesis effect of an extract from Thymelaea hirsuta, a Tunisian herb. Murine melanoma B16 cells were treated with T. hirsuta extract, and then cell viability and synthesized melanin content were measured. We found that the T. hirsuta extract decreased the synthesized melanin content in B16 cells without cytotoxicity. Tyrosinase is a key enzyme of melanogenesis and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation is known to be related to melanogenesis inhibition. To clarify its mechanism, we also determined ERK1/2 phosphorylation and tyrosinase expression level. ERK1/2 was immediately phosphorylated in cells just after treatment with the extract. The tyrosinase expression was inhibited after 24 h of stimulation with the extract. The T. hirsuta extract was fractionated, and we found that one fraction considerably decreased the melanin synthesis in B16 cells and that this fraction contains daphnanes as the main component. This indicates that our findings might be attributable to daphnanes. [source] Immunohistochemistry and in situ hybridization in the study of human skin melanocytesEXPERIMENTAL DERMATOLOGY, Issue 3 2007Thierry Passeron Abstract: Although keratinocytes are the most numerous type of cell in the skin, melanocytes are also key players as they produce and distribute melanin that protects the skin from ultraviolet (UV) radiation. In vitro experiments on melanocytic cell lines are useful to study melanogenesis and their progression towards melanoma. However, interactions of melanocytes with keratinocytes and with other types of cells in the skin, such as fibroblasts and Langerhans cells, are also crucial. We describe two techniques, immunohistochemistry (IHC) and tissue in situ hybridization (TISH), that can be used to identify and study melanocytes in the skin and their responses to UV or other stimuli in situ. We describe a practical method to localize melanocytic antigens on formalin-fixed, paraffin-embedded tissue sections and in frozen sections using indirect immunofluorescence with conjugated secondary antibodies. In addition, we detail the use of TISH and its combination with IHC to study mRNA levels of genes expressed in the skin at cellular resolution. This methodology, along with relevant tips and troubleshooting items, are important tools to identify and study melanocytes in the skin. [source] Influence of prostaglandin F2, and its analogues on hair regrowth and follicular melanogenesis in a murine modelEXPERIMENTAL DERMATOLOGY, Issue 5 2005S. Sasaki Abstract:, Latanoprost and isopropyl unoprostone, which are analogues of prostaglandin F2, (PGF2,), are promising drugs for the reduction of intra-ocular pressure. However, they have been reported to have side effects, including hypertrichosis and hyperpigmentation of the eyelashes and periocular skin, and occasionally poliosis. In order to investigate these effects further, PGF2,, latanoprost and isopropyl unoprostone were applied to the dorsal skin of 7-week-old C57BL/6 mice, and hair length was measured during the treatment. The three molecules all showed stimulatory effects on the murine hair follicles and the follicular melanocytes in both the telogen and anagen stages, and stimulated conversion from the telogen to the anagen phase. PGE2 is known to act synergistically with PGF2,, and hence the influence of PGE2 was also examined. PGE2 did not induce distinct telogen-to-anagen conversion, but showed moderate growth stimulatory effects on early anagen hair follicles. In addition, we observed a case of hypertrichosis and trichomegaly with an excess of melanogenesis, leading to the emergence of white hair, suggesting that poliosis can occur as a side effect of eye treatment with solutions of PGF2, analogues. The stimulatory effects of PGF2,and PGE2 on hair growth have been discussed with regard to the role of protein kinase C and mast cells. [source] EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytomaGENES, CHROMOSOMES AND CANCER, Issue 12 2007Cristina R. Antonescu The molecular hallmark of angiomatoid fibrous histiocytoma (AFH) is not well defined, with only six cases with specific gene fusions reported to date, consisting of either FUS-ATF1 or EWSR1-ATF1. To address this, we investigated the presence of FUS-ATF1, EWSR1-ATF1, and the highly related EWSR1-CREB1 fusion in a group of nine AFHs. All cases were subjected to RT-PCR for EWSR1-ATF1 and EWSR1-CREB1. FISH for EWSR1 and FUS rearrangements was performed in most cases. Transcriptional profiling was performed in three tumors and their gene expression was compared to five clear cell sarcomas expressing either the EWSR1-ATF1 or EWSR1-CREB1 fusion. By RT-PCR, eight out of nine tumors showed the presence of the EWSR1-CREB1 fusion, while one had an EWSR1-ATF1 transcript. FISH showed evidence of EWSR1 rearrangement in seven out of eight cases. Karyotypic analysis performed in one tumor showed a t(2;22)(q33;q12). High transcript levels were noted for TFE3 in AFH tumors, while overexpression of genes involved in melanogenesis, such as MITF, GP100, and MET was noted in somatic clear cell sarcomas. We report for the first time the presence of EWSR1-CREB1 in AFH, which now appears to be the most frequent gene fusion in this tumor. EWSR1-CREB1 is a novel translocation recently described in clear cell sarcoma of the GI tract. EWSR1-ATF1, identified in some AFH cases, is the most common genetic abnormality in soft tissue clear cell sarcoma. Thus, identical fusions involving ATF1 and CREB1 are found in two distinct sarcomas, which may be able to transform two different types of mesenchymal precursor cells, unlike most other sarcoma gene fusions. © 2007 Wiley-Liss, Inc. [source] The inhibitory effect of the components of Cornus officinalis on melanogenesisINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 5 2008Yasuhiko Nawa Five known compounds were isolated from a Cornus officinalis 50% ethanol extract (C. officinalis extract) and a hot water extract. We investigated the photochemical and pharmacological active compounds of C. officinalis hot water extract and ethanol extract. We understood that C. officinalis is a medicinal plant with potent free-radical-scavenging activity not only against reactive oxygen species (H2O2, superoxiside anion, hydroxyl radical, etc.) in a narrow sense, but also against many other free radicals (peroxynitrate, peroxyradical). It is estimated that the reduction effect with C. officinalis extract can block oxidative reaction on melanogenesis. Loganin and cornuside, the components in C. officinalis, showed a significant free-radical-scavenging activity and inhibitory effects on melanogenesis. We report to prove the inhibitory effect of UVB-induced pigmentation in C. officinalis extract through its radical scavenging activity. [source] Influence of environmental stress on skin tone, color and melanogenesis in Japanese skinINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 1 2005K. Kikuchi Introduction It is needless to say that one of the most potent environmental stress for melanogenesis of the human skin is the effect of ultraviolet (UV) light from the sunlight. Characteristic skin aging as a result of this UV light is recognized as photoaging. Clinical features in photoaging are wrinkles, skin laxity, coarseness, leathery, yellowing, lentigenes, mottled pigmentation, telangiectasia, sebaceous hypertrophy and purpura. There is an apparent difference in clinical features in photoaging among different races, i.e. between Caucasians, African American and Asians that include Japanese. Not only photo skin type but also environmental factors, such as climate, latitude, altitude and their habit of sunbathing, smoking and skin care influence the characteristic development of their photoaging. Racial difference in photoaging Caucasians tend to develop skin laxity and fine wrinkles more than Asians [1]. Asians tend to produce coarser wrinkles than the Caucasians although their development is rather late in life. There is also a difference in the skin color. Pigmentation is an earliest and prominent skin changes in Asians [1] and it increases with age [2]. In contrast, pigmentation is not apparent in the Caucasians although redness probably because of an increase in cutaneous vascularization becomes prominent in middle aged Caucasians [2]. Chung reported that seborrheic keratosis is a major pigmentary lesion in men, whereas hyperpigmented macules are prominent features in women in Koreans [3]. Melanogenesis pigmentation disorders in Japanese Ephelides (freckles) are commonly found in those with photo skin type I who have fair skin and red eyes and blond hair. They are also found in the Japanese. Clinical feature reveals that multiple small pigmentary macules on sun-exposed areas mainly on the mid-portion of the face. These lesions seem to be familial, becoming apparent even in early childhood after sun exposure. Melasma is an acquired pigmentary disorder commonly found in middle aged Japanese women characterized by irregular brown macules and patches on the sun-exposed areas on the face typically as bilaterally present macules on the cheeks. An increase in sex hormones as a result of pregnancy and intake of contraceptive pills is one of the etiological factors to develop melasma. Sun exposure also worsens it. Nevus of Ota is also a common pigmentary disorder found in the Japanese. It is usually unilateral, blue-brown to slate-gray pigmentary macules on the eyelid and cheek that appear in early childhood or in puberty. Acquired dermal melanocytosis is also a pigmentary disorder, in which dermal melanocytes are found as shown in nevus of Ota, characterized by bilateral brown to blue-gray macules on the forehead, temple, eyelid and malar areas in middle aged Japanese women. This tends to be misdiagnosed as melasma. Solar lentigo is an acquired pigmented macule induced by sun exposure. Solar lentigines are usually multiple, circumscribed brown macules. There are two types of solar lentigo. One is a small macular type, characterized by multiple, small brown macules whose diameter is less than 5 mm, being similar to ephelides (freckles). The other type is a large macular type, characterized by a few round to oval, brown macules whose diameter is beyond 1 cm. Some of their surface are hyperkeratotic and become elevated to produce seborrheic keratosis. Again, the early sign of photoaging in Japanese is pigmentated spots and these pigmentation disorders increase with age. Among the pigmentary changes, nevus of Ota, acquired dermal melanocytosis, melasma and large macular type of solar lentigo are characteristic skin changes found in the Japanese in addition to ephelides and small macular type of solar lentigo. Seasonal changes of the various functional properties of the skin including skin color assessed by non-invasive bioengineering techniques [4]. When we consider skin tone, color and melanogenesis, UV light from the sunlight is the most potent environmental stress, although we cannot forget also the important influence of environmental relative humidity affects our skin functions as well as its appearance. We investigated seasonal influences on the various properties of the skin in 39 healthy Japanese females consisting of different age groups. Their skin is thought to be affected by the UV light in summer, and by the exposure to the dry and cold air in winter. Materials and methods Biophysical, non-invasive measurements, including transepidermal water loss (TEWL) as a parameter for the barrier function of the stratum corneum (SC), high frequency conductance as a parameter for the hydration state of the SC, skin color and casual surface lipid levels, were conducted during late summer and winter months. Skin color was determined with a chromameter according to the L*a*b* CIE 1976 system, where L* is an attribute on the luminance scale, a* that on the red versus green scale and b* that on the yellow versus blue scale. All the measurements were conducted in an environment controlled-chamber (21 ± 1 °C room temperature, and 50 ± 3% relative humidity). Results The barrier function of the SC was found to be significantly impaired in winter on the cheek as compared with that measured in summer, whereas no such seasonal change was apparent both in the hydration state of the SC and sebum levels on the cheek. In the assessment of the skin color on the cheek, a significant increase in a* (redness) and a decrease in b* (yellowness) were observed in winter. In contrast, on the flexor forearm, the values of L* (luminescence) increased in winter, but no seasonal change was noted in the values of a* and b*. In this study, skin changes with aging were also found by the non-invasive bioengineering methods. The value of TEWL on the cheek tended to increase with age, whereas no significant change was observed in the value of TEWL on the forearm. In the assessment of skin color, b* value on the cheek significantly increased with age whereas a* and L* values on the cheek did not show any significant change with age. Summary of this study We think that such an increase in yellowness with aging of the cheek skin is a phenomenon unique to the Japanese (Asians) since an increase in b* value was not observed in Caucasians [2]. The facial skin that is always exposed shows barrier impairment in a dry and cold winter environment and demonstrates increased yellowness in skin color because of a prolonged exposure to the UV light from the sun in the summer season. The non-invasive bioengineering methods are useful to demonstrate even invisible seasonal changes occurring in the same individuals and changes with age occurring in the skin. References 1.,Goh, S.H. The treatment of visible signs of senescence: the Asian experience. Br. J. Dermatol.122, 105,109 (1990). 2.,LeFur, I., Numagami, K., Guinot, C. et al. Age-related reference values of skin color in Caucasian and Japanese healthy women according to skin site. Pigment Cell Res. 7, 67 (1999). 3.,Chung, J.H., Lee, S.H., Youn, C.S. et al. Cutaneous photodamage in Koreans: influence of sex, sun exposure, smoking, and skin color. Arch. Dermatol. 137, 1043,1051 (2001). 4.,Kikuchi, K., Kobayashi, H., Le Fur, I. et al. Winter season affects more severely the facial skin than the forearm skin: comparative biophysical studies conducted in the same Japanese females in later summer and winter. Exog. Dermatol. 1, 32,38 (2002). [source] A keratinocytes,melanocytes coculture system for the evaluation of active ingredients' effects on UV-induced melanogenesisINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 1-2 2003J.-F. Nicolaÿ Synopsis A new experimental design, more reliable for in vitro testing of active ingredients' effect on ultraviolet (UV)-induced melanogenesis has been carried out. It uses a bicompartmental coculture system where cell communication between keratinocytes and melanocytes can take place. Thus, this experimental situation enables to monitor the effect of biological agents released by both cell types on melanogenesis and the interference of tested compounds with this ,paracrine linkage'. Experiments with UVB-irradiated cocultures show the importance of cell communication in the melanogenic response. In this model, the endogenous mediator, nitric oxide (NO), increased melanin production. Different compounds were tested in the coculture system, and comparison with data obtained from irradiated monocultures of melanocytes enables to distinguish a specific effect on cell communication. In addition, this more close-to-reality experimental model proved to provide a valuable first approach for the assessment of the ,bioavailability' of the tested substances. Finally, the effect of an innovative photoprotective agent capable of ,boosting' UV-induced melanogenic cell communication is presented. Résumé Un nouveau concept expérimental, plus fiable pour l,évaluation in vitro de l,effet de principes actifs sur la mélanogénèse induite par les UV, a été mis en ,uvre. Il utilise un système de co-culture à double compartiment dans lequel une communication cellulaire entre les kératinocytes et les mélanocytes peut s,établir. Ainsi, ce système expérimental permet de suivre l,effet des agents biologiques libérés par les deux types de cellules sur la mélanogénèse, et les interférences des composés testés avec ce ,lien paracrine'. Les essais avec des co-cultures irradiées aux UV montrent l,importance de la communication cellulaire dans la réponse mélanogénique. Avec ce modèle, le médiateur oxyde nitrique endogène (NO) augmente la production de mélanine. Différents composés ont été testés avec ce système de co-culture, et une comparaison avec les données obtenues à partir de monocultutres de mélanocytes irradiées permet de distinguer un effet spécifique sur la communication cellulaire. En outre, ce modèle expérimental plus proche de la réalité s,est avéré apporter une première approche valable de l,évaluation de la ,biodisponibilité' des substances testées. Enfin, l,effet d,un agent protecteur innovant capable de stimuler la communication cellulaire mélanogénique induite par les UV est décrit. [source] Genetic mapping of dominant white (W), a homozygous lethal condition in the horse (Equus caballus)JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2004C. Mau Summary Dominant white coat colour (W) is a depigmentation syndrome, known in miscellaneous species. When homozygous in the horse (similar in mice), the mutation responsible for the white phenotype is lethal in a very early stage of gestation. It seems, that the action of the dominant white allele is not always fully penetrant, resulting occasionally in spotted look alike offspring. These horses resemble a coat colour pattern known as sabino spotting. So far, it is not known whether dominant white (W) and sabino spotting (S) share a common genetic background. In this study, a pedigree consisting of 87 horses segregating for dominant white (W) was used to genetically localize the horse (W)-locus. Microsatellite ASB23 was found linked to (W), which allowed us to map dominant white to a region on horse chromosome 3q22. Tyrosine kinase receptor (KIT) was previously mapped to this same chromosome region (3q21,22). KIT and its ligand (KITLG) are responsible for the normal function of melanogenesis, haematopoiesis and gametogenesis. So far, sequence analysis of different KIT gene fragments did not lead to new polymorphisms, except for a SNP detected in KIT intron 3 (KITSNPIn3). Additional microsatellites from ECA3q (TKY353 and LEX7), together with KITSNPIn3 allowed us to state more precisely the (W)-mutation. The positional results and comparative functional data strongly suggest that KIT encodes for the horse (W)-locus. Zusammenfassung Die dominant weisse Fellfarbe (W) ist eine Form der Depigmentierung, die bei vielen Spezies auftritt. Beim Pferd wirkt die Mutation für Dominant Weiss (W) in homozygoter Form (analog zur Maus), bereits in einem sehr frühen Stadium der Trächtigkeit letal. Es scheint, dass die Wirkung des dominant weissen Allels nicht immer mit vollständiger Penetranz erfolgt. Dies führt gelegentlich zu Nachkommen mit einer Art Schecken-Fellzeichnung. Solche Pferde sind phänotypisch mit den sogenannten ,,Sabino-Schecken,, vergleichbar. Es ist bis jetzt nicht bekannt ob Dominant Weiss (W) und Sabino-Scheckung (S) einen gemeinsamen genetischen Hintergrund besitzen. Mittels eines Pedigrees aus 87 Pferden, in dem Dominant Weiss (W) segregiert, konnte in der vorliegenden Studie der equine (W)-Locus genetisch lokalisiert werden. Der Mikrosatellit ASB23 erwies sich als gekoppelt mit (W) und ermöglichte die Zuweisung des (W)-Locus auf eine Region von Chromosom ECA 3q22. Das Gen für den Tyrosinkinaserezeptor (KIT) liegt ebenfalls in dieser Chromosomenregion (3q21,22). Das KIT -Gen ist zusammen mit dem KIT -Liganden (KITLG) verantwortlich für einen normal funktionierenden Ablauf der Melanogenese, Hämatopoese und Gametogenese. Die direkte Sequenzierung von KIT -Genfragmenten führte bis jetzt zu keinen neuen Polymorphismen, ausser einem SNP in KIT Intron 3 (KITSNPIn3). Mittels weiterer Mikrosatelliten von ECA3q (TKY353 and LEX7) sowie KITSNPIn3 gelang es, die (W)-Mutation genauer zu positionieren. Die vorliegenden Lokalisierungsresultate und vergleichende funktionelle Erkenntnisse deuten stark darauf hin, dass KIT für den Pferde (W)-Locus kodiert. [source] Inhibitory effects of 5-chloroacetyl-2-piperidino-1,3-selenazole, a novel selenium-containing compound, on skin melanin biosynthesisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2010Eunjoo H. Lee Abstract Objectives Increased production and accumulation of melanin leads to many hyperpigmentation disorders such as melasma, freckles and geriatric pigment spots. Thus, there is a need for the development of depigmenting agents. Based on our previous reports, selenium derivatives as anti-melanogenic lead compounds could be very important. The aim of this study was to investigate the depigmenting effect of novel selenium-containing compounds. Methods The inhibitory effects of 5-chloroacetyl-2-piperidino-1,3-selenazole (CS1), a novel selenium-containing compound, on melanogenesis were investigated in B16F10 melanoma cells and cultured brownish guinea pig skin tissue with ,-melanocyte-stimulating hormone stimulation. Key findings We found that CS1 inhibited melanin production in B16F10 cells by suppressing tyrosinase activity and its protein expression. In addition, Western blotting analysis revealed that CS1 suppressed the expression of tyrosinase-related protein (TRP)-1 and TRP-2. Therefore, the depigmenting effect of CS1 might have been due to inhibition of tyrosinase activity and expression of melanogenic enzymes. Furthermore, CS1 had inhibitory effects on melanin biosynthesis of primary cultured skin of brownish guinea pig. Conclusions The results suggested that CS1 could be a useful candidate for the treatment of skin hyperpigmentation. [source] Inhibitory effects of 1,3-thiazine derivatives on melanogenesisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2009Sang Keun Ha Abstract Objectives The aim of this study was to identify a novel skin-depigmenting agent from synthetic 1,3-thiazine derivatives. Methods We investigated the inhibitory effects of six kinds of 1,3-thiazine derivative on melanogenesis by examining their effects on tyrosinase activity and melanin biosynthesis in melan-a cells and the zebrafish model. Key findings Of the six compounds, 4-hydroxy-2,6-dimethyl-5,6-dihydro-4H -1,3-thiazine (TZ-6) had the strongest anti-melanogenic effects in cultured melan-a cells (30.4% inhibition at 100 ,M). In addition, TZ-6 exhibited an inhibitory effect on mushroom and cellular tyrosinase. Based on the results of Western blotting, TZ-6 reduced the expression of tyrosinase at 100 mM. Additionally, TZ-6 reduced body pigmentation and inhibited tyrosinase activity in the zebrafish model. Conclusions The results have provided useful information for the development of a skin whitening agent. [source] Standardization of In Vitro Macrophotography for Assessment of Cutaneous ResponsesPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2009Sergio G. Coelho The increased popularity of commercially available three-dimensional human skin equivalents in recent years has allowed for assessment of melanogenesis modulated by compounds topically applied to the skin or directly incorporated from the medium. These skin equivalents provide a suitable model for elucidating the mechanisms of action of various factors that modulate skin pigmentation or other properties of the skin. As such, researchers need to objectively quantify cutaneous responses at the macroscopic level. A simple method to standardize macrophotography images is reported that can quantify cutaneous responses in human skin equivalents of Asian, Black or African American, and Caucasian or White racial/ethnic origin. Macrophotographs are analyzed using the Commission Internationale de l'Eclairage L*a*b* color space system in combination with a personal computer and image editing software. Pigmentation changes monitored over a 9 day period showed a high correlation with melanin content evaluated in Fontana,Masson-stained sections. These results indicate the feasibility of using a macrophotography setup in a sterile tissue culture environment to objectively assess in vitro cutaneous responses in human skin equivalents. This serves as an adjunct tool to biochemical and morphological methods to effectively quantify changes in pigmentation over time. [source] Molecular Responses to Stress Induced in Normal Human Caucasian Melanocytes in Culture by Exposure to Simulated Solar UV,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Laurent Marrot ABSTRACT Melanocytes play a central role in the response of skin to sunlight exposure. They are directly involved in UV-induced pigmentation as a defense mechanism. However, their alteration can lead to melanoma, a process where the role of sun overexposure is highly probable. The transformation process whereby UV damage may result in melanoma initiation is poorly understood, especially in terms of UV-induced genotoxicity in pigmented cells, where melanin can act either as a sunscreen or as a photosensitizer. The aim of this study was to analyze the behavior of melanocytes from fair skin under irradiation mimicking environmental sunlight in terms of spectral power distribution. To do this, normal human Caucasian melanocytes in culture were exposed to simulated solar UV (SSUV, 300,400 nm). Even at relatively high doses (until 20 min exposure, corresponding to 12 kJ/m2 UV-B and 110 kJ/m2 UV-A), cell death was limited, as shown by cell viability and low occurrence of apoptosis (caspase-3 activation). Moreover, p53 accumulation was three times lower in melanocytes than in unpigmented cells such as fibroblasts after SSUV exposure. However, an important fraction of melanocyte population was arrested in G2-M phase, and this correlated well with a high induction level of the gene GADD45, 4 h after exposure. Among the genes involved in DNA repair, gene XPC was the most inducible because its expression increased more than two-fold 15 h after a 20 min exposure, whereas expression of P48 was only slightly increased. In addition, an early induction of Heme Oxygenase 1 (HO1) gene, a typical response to oxidative stress, was also observed for the first time in melanocytes. Interestingly, this induction remained significant when melanocytes were exposed to UV-A radiation only (320,400 nm), and stimulation of melanogenesis before irradiation further increased HO1 induction. These results were obtained with normal human cells after exposure to SSUV radiation, which mimicked natural sunlight. They provide new data related to gene expression and suggest that melanin in light skin could contribute to sunlight-induced genotoxicity and maybe to melanocyte transformation. [source] Melanin Offers Protection Against Induction of Cyclobutane Pyrimidine Dimers and 6,4 Photoproducts by UVB in Cultured Human Melanocytes,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2001Nico P. M. Smit ABSTRACT The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals synthesized less melanin and produced more cyclobutane pyrimidine dimers and 6,4 photoproducts upon UVB exposure than did melanocytes from black skin. Tyrosine-stimulated melanogenesis provided protection against DNA damage in both cell types. In another set of pigmented cell lines a ratio between eumelanin and pheomelanin was determined. The assessment of association between DNA damage induction and the quantity and quality of melanin revealed that eumelanin concentration correlated better with DNA protection than pheomelanin. Skin type,I and skin type,VI melanocytes, congenital nevus (CN)-derived cells and skin type,II melanocytes from a multiple-melanoma patient were grown in media with low or high l -tyrosine concentration. The cells were irradiated with 200 J/m2 UVB, and the levels of the photoproducts were determined immediately and after 6 and 24 h. Once again the induction of the photoproducts was mitigated by increased melanogenesis, and it was inversely correlated with the skin type. No significant differences were found for the removal of photoproducts in the cultures of skin types I and VI and CN cells. No indications of a delay in the removal of photoproducts in the melanocytes from the multiple-melanoma patient were found either. [source] Inhibitory effects of Hoelen extract on melanogenesis in B16/F1 melanoma cellsPHYTOTHERAPY RESEARCH, Issue 9 2010Mun Seog Chang Abstract Melanin synthesis is regulated by melanogenic proteins, such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and TRP-2. The effects of Hoelen extract on melanogenesis were investigated in B16Fl murine melanoma cells. Specifically, tyrosinase activity, cell viability and melanin content were assayed, and western blotting and RT-PCR for tyrosinase, TRP-1 and TRP-2 conducted. The results show that Hoelen significantly inhibited melanin synthesis through inhibition of TRP-2 expression, while it did not affect tyrosinase activity or its expression. Taken together, RT-PCR results showed that the depigmentation effect of Hoelen may be due to inhibition of TRP-2 gene transcription. These results suggest that Hoelen may be a useful inhibitor for the attenuation of melanogenesis and hyperpigmentation in skin cells. Copyright © 2010 John Wiley & Sons, Ltd. [source] Fifteen-year quest for microphthalmia-associated transcription factor target genesPIGMENT CELL & MELANOMA RESEARCH, Issue 1 2010Yann Cheli Summary Microphthalmia-associated transcription factor (MITF) was initially shown to play a key role in melanocyte differentiation through the direct transcriptional control of TYROSINASE, TYRP1 and DCT genes, encoding the three enzymes involved in melanin synthesis or melanogenesis. Sixteen years after the first description of MITF, more than 40 direct MITF target genes have been described. They play a key role in melanocyte, osteoclast and mast cell specific functions. Furthermore, several MITF target genes, e.g. BCL2, CDK2, CDKN1A, CDKN2A, MET and HIF1A, link MITF to general cellular processes such as growth or survival. In this review, we provide an overview of the MITF-regulated genes. We pay special attention to the MITF target genes in melanocytes and raise questions about target specificity. [source] Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanomaPIGMENT CELL & MELANOMA RESEARCH, Issue 6 2009Kevin G. Chen Summary Because melanomas are intrinsically resistant to conventional radiotherapy and chemotherapy, many alternative treatment approaches have been developed such as biochemotherapy and immunotherapy. The most common cause of multidrug resistance (MDR) in human cancers is the expression and function of one or more ATP- binding cassette (ABC) transporters that efflux anticancer drugs from cells. Melanoma cells express a group of ABC transporters (such as ABCA9, ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, and ABCD1) that may be associated with the resistance of melanoma cells to a broad range of anticancer drugs and/or of melanocytes to toxic melanin intermediates and metabolites. In this review, we propose a model (termed the ABC-M model) in which the intrinsic MDR of melanoma cells is at least in part because of the transporter systems that may also play a critical role in reducing the cytotoxicity of the melanogenic pathway in melanocytes. The ABC-M model suggests molecular strategies to reverse MDR function in the context of the melanogenic pathway, which could open therapeutic avenues towards the ultimate goal of circumventing clinical MDR in patients with melanoma. [source] NDRG2 gene expression in B16F10 melanoma cells restrains melanogenesis via inhibition of Mitf expressionPIGMENT CELL & MELANOMA RESEARCH, Issue 6 2008Aeyung Kim Summary NDRG2 (N-myc downstream-regulated gene 2) is a candidate tumor suppressor implicated in control of glioblastoma proliferation and dendritic cell differentiation. The microphthalmia-associated transcription factor (Mitf) plays a crucial role in the melanocyte lineage and in melanoma by controlling survival, differentiation, cell cycle entry and exit, and melanoma metastasis. Identifying upstream regulators of Mitf expression, therefore, remains a key issue. In this study, we aimed to assess whether the candidate tumor suppressor NDRG2 can modulate Mitf expression. Here, we show that NDRG2 acts to prevent cAMP and ,-catenin-mediated activation of the Mitf promoter, thereby blocking melanogenesis via the downstream Mitf target genes Tyrosinase, Tyrp1 and Dct. The data suggest that NDRG2 impairs melanogenesis by interfering with both the TCF/,-catenin and cAMP/CREB pathways that are known to stimulate Mitf expression in melanocytes and have major implications for the role of NDRG2 in pigmentation and melanoma progression. Taken together, the results not only identify NDRG2 as a novel regulator of pigmentation, but also potentially a key factor in regulating melanoma progression via Mitf. [source] Correlation between melanogenic and catalase activity in in vitro human melanocytes: a synergic strategy against oxidative stressPIGMENT CELL & MELANOMA RESEARCH, Issue 2 2008Vittoria Maresca Summary UV-induced DNA damage can lead to melanoma, the most dangerous form of skin cancer. Understanding the mechanisms employed by melanocytes to protect against UV is therefore a key issue. In melanocytes, catalase is the main enzyme responsible for degrading hydrogen peroxide and we have previously shown that that low basal levels of catalase activity are associated with the light phototype in in vitro and ex vivo models. Here we investigate the possible correlation between its activity and melanogenesis in primary cultures of human melanocytes. We show that while the total melanin concentration is directly correlated to the level of pigmentation, the more the degree of pigmentation increased, the lower the proportion of pheomelanin present. Moreover, in human melanocytes in vitro, catalase-specific mRNA, protein and enzymatic activity were all directly correlated with total cellular melanin content. We also observed that immediately after a peroxidative treatment, the increase in reactive oxygen species was inversely associated with pigmentation level. Darkly pigmented melanocytes therefore possess two protective strategies represented by melanins and catalase activity that are likely to act synergistically to counteract the deleterious effects of UV radiation. By contrast, lightly pigmented melanocytes possess lower levels of melanogenic and catalase activity and are therefore more susceptible to accumulate damage after UV exposition. [source] Quercetin Enhances Melanogenesis By Increasing the Activity and Synthesis of Tyrosinase in Human Melanoma Cells and in Normal Human MelanocytesPIGMENT CELL & MELANOMA RESEARCH, Issue 1 2004Hidetaka Nagata Quercetin (3,3,,4,,5,7-pentahydroxyflavone) is a diphenyl propanoid widely distributed in edible plants. In this study, we examined the effect of quercetin on melanogenesis in human HMVII melanoma cells and in normal human epidermal melanocytes (NHEM) in the absence of ultraviolet radiation. Upon the addition of quercetin to the culture medium, the melanin content in melanoma cells (HMVII) increased remarkably in time- and dose-dependent manners. In addition, quercetin induced melanogenesis in cultured NHEM. As compared with controls, melanin content was increased about sevenfold by treatment with 20 ,M (HMVII) or 1 ,M (NHEM) quercetin for 7 d. Tyrosinase activity was also increased, to 61.8-fold higher than the control. The expression of tyrosinase protein was slightly increased by the addition of quercetin. However, quercetin did not affect the expression of tyrosinase mRNA. Tyrosinase activation by quercetin was blocked by actinomycin-D or by cycloheximide demonstrating that its actions in stimulating melanogenesis may involve both transcriptional and translational events. Tyrosinase activity was increased dramatically whereas the level of melanogenic inhibitor was remarkably decreased following quercetin treatment. Taken together, these results demonstrate that in human melanoma cells and in NHEM, quercetin stimulates melanogenesis by increasing tyrosinase activity and decreasing other factors such as melanogenic inhibitors. [source] Keratinocytes Control the Pheo/Eumelanin Ratio in Cultured Normal Human MelanocytesPIGMENT CELL & MELANOMA RESEARCH, Issue 6 2002Christine Duval The pheo/eumelanin ratio of cultured normal human melanocytes is distinct from the ratio observed for the same cells in vivo where they are in close contact with keratinocytes. To study the possible involvement of keratinocytes in the control of melanogenesis, we compared quantitatively and qualitatively the melanin production in melanocyte mono-cultures, in melanocyte,keratinocyte co-cultures and in pigmented reconstructed epidermis. Pheomelanin and eumelanin contents were assessed by high-performance liquid chromatography with electrochemical and fluorometric detection of their specific degradation products and revealed striking differences in the presence of keratinocytes. In the absence of keratinocytes (melanocyte mono-cultures), we observed a very limited eumelanin production and a very high pheomelanin synthesis. The pheo/eumelanin ratio in mono-cultures could be slightly influenced by changing the composition of the culture medium, however, the very strong imbalance in favor of pheomelanin remained unchanged. An induction of eumelanin synthesis accompanied by an important reduction of pheomelanin formation was only observed in the presence of keratinocytes. The pheo/eumelanin ratio in melanocyte mono-culture dropped from 1043 down to about 25 in the presence of keratinocytes (co-cultures). The same observations were made when the melanocytes were integrated into a reconstructed human epidermis. Interestingly, under co-culture conditions resulting in only a partial contact between melanocytes and keratinocytes, the reduction of the pheo/eumelanin ratio were less pronounced. From these results we conclude that keratinocytes play an important role in the melanin production, affecting the melanogenic pathways. [source] Rac and Rho: The Story Behind Melanocyte Dendrite FormationPIGMENT CELL & MELANOMA RESEARCH, Issue 5 2002Glynis Scott Melanocyte dendrites are hormonally responsive actin and microtubule containing structures whose primary purpose is to transport melanosomes to the dendrite tip. Melanocyte dendrites have been an area of intense interest for melanocyte biologists, but it was not until recently that we began to understand the mechanisms underlying their formation. In contrast with melanogenesis, for which numerous mutations in pigment producing genes and mouse models have been identified, a genetic defect resulting in impaired dendrite formation has not been found. Therefore, much of the insight into melanocyte dendrites has come from electron microscopy or in vitro culture systems of normal human and murine melanocytes as well as melanoma cell lines. The growth factors that regulate the formation of melanocyte dendrites have been thoroughly studied and it is clear that multiple signalling systems are able to stimulate, and in some cases inhibit, dendrite formation. Recent data points to the Rho family of small guanosine triphosphate (GTP)-binding proteins as master regulators of dendrite formation, particularly Rac and Rho. In this review I will summarize the progress scientists have made in understanding the structure, hormonal regulation and molecular mediators of melanocyte dendrite formation. [source] Comparative Biochemistry of Eumelanogenesis and the Protective Roles of Phenoloxidase and Melanin in InsectsPIGMENT CELL & MELANOMA RESEARCH, Issue 1 2002Manickam Sugumaran The phenolic biopolymer eumelanin is an important skin pigment found throughout the animal kingdom. The enzyme, tyrosinase, initiates melanogenesis in mammals. The biogenesis is assisted by a number of mammalian protein factors including dopachrome tautomerase and 5,6-dihydroxyindole-2-carboxylate oxidase. Invertebrates, such as insects, employ phenoloxidase and dopachrome (decarboxylating) isomerase for melanin biosynthesis. Recently generated molecular biological and biochemical data indicate that tyrosinase and phenoloxidase are distinctly different enzymes in spite of possessing both monophenol monooxygenase activity as well as o -diphenoloxidase activity. Similarly, insect dopachrome isomerase also differs significantly from its mammalian counterpart in several of its properties including the nature of the enzymatic reaction. In addition, there are considerable differences in the eumelanogenic pathways of these two animal groups that include the utility of substrates, use of dihydroxyindoles and the nature of eumelanin pigment. Thus, the biochemistry and molecular biology of melanogenesis in mammals and insects are significantly different. The advantages of generating different eumelanin pigments and intermediates by the insects are discussed. [source] Mutational Analysis of the Modulation of Tyrosinase by Tyrosinase-Related Proteins 1 and 2 In VitroPIGMENT CELL & MELANOMA RESEARCH, Issue 5 2000PRASHIELA MANGA The albino (tyrosinase, Tyrc), brown (tyrosinase-related protein 1, Tyrp1b) and slaty (tyrosinase-related protein 2, tyrp2slt) loci are all involved in the regulation of melanogenesis. Phenotypes of inbred mice mutant at two or more of these loci are not always explicable by simple summation of the established or suspected catalytic functions of the gene products. These phenotypes suggest that relationships among the proteins extend beyond the obvious fact that they catalyze different steps in the same melanogenic pathway, and that they may also interact intimately in such a way that a mutation in one impacts the function of the other(s). Previous studies have attributed catalytic activities to each member of this trio; however, it has been difficult to study the proteins individually, either in vivo or in tissues or cells. Therefore, we undertook to transfect the genes, in revealing combinations, into COS-7 cells (which have no melanogenic apparatus of their own) to clarify the interacting functions of their encoded proteins. Specifically, we attempted to evaluate the effects of Tyrp1 and Tyrp2 proteins on tyrosinase protein. We report evidence that Tyrp1 stabilizes tyrosinase, confirming previous observations, and, in addition, demonstrate that Tyrp1 decreases tyrosinase activity. By contrast, Tyrp2 increases tyrosinase activity by stabilizing the protein. We conclude that both Tyrp1 and Tyrp2, in addition to other catalytic functions they may possess, act together to modulate tyrosinase activity. [source] Spontaneous Redox Reactions of Dopaquinone and the Balance between the Eumelanic and Phaeomelanic PathwaysPIGMENT CELL & MELANOMA RESEARCH, Issue 4 2000E.J. LAND Eumelanogenesis and phaeomelanogenesis diverge at an early stage in pigment formation, namely at the point where dopaquinone, the initial product of tyrosine oxidation by tyrosinase, undergoes one of two types of reaction: either (1) a reductive endocyclisation in which a Michael addition of the side-chain amino group takes place; or (2) a reductive addition of cysteine to give cysteinyldopa. In the former case, the product cyclodopa, is known rapidly to undergo a redox exchange reaction with dopaquinone to yield dopachrome, the precursor of the eumelanogenic pathway. In the second instance, cysteinyldopa is regarded as leading to the formation of benzothiazoles, which are characteristic of phaeomelanin. The precursor molecule of the phaeomelanic pathway is cysteinyldopaquinone. We have examined quantitatively the role of dopaquinone in the non-enzymatic oxidation of 5-S-cysteinyldopa using pulse radiolysis and have demonstrated that the redox exchange reaction between dopaquinone and 5-S-cysteinyldopa occurs spontaneously with a rate constant of 8.8×105 M,1 sec,1. This study has also enabled an improved estimate of ,4×107 M,1sec,1 to be obtained for the rate constant of the reaction of dopaquinone with cyclodopa. Calculations utilising these figures and estimates of the rate constants for the other reactions in early melanogenesis, demonstrate that, whilst similar pathways are invoked, the phaeomelanic pathway predominates in the presence of cysteine, irrespective of the availability of dopaquinone and thus independently of the rate of tyrosinase-catalysed oxidation. This suggests that the balance between the formation of eumelanin and phaeomelanin is regulated principally by the availability of cysteine at the site of melanogenesis. [source] Molecular Bases of Congenital Hypopigmentary Disorders in Humans and Oculocutaneous Albinism 1 in JapanPIGMENT CELL & MELANOMA RESEARCH, Issue 2000YASUSHI TOMITA The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented. [source] Regulation of the Murine Silver Locus Product (gp87) by the Hypopigmenting Cytokines TGF-,1 and TNF-,PIGMENT CELL & MELANOMA RESEARCH, Issue 2 2000MARÍA MARTÍNEZ-ESPARZA The melanosomal proteins encoded by the silver (si, SILV, or PMEL17) locus play important roles in melanogenesis and are actively investigated as targets for melanoma immunotherapy. The human silver locus yields two proteins, gp100 and PMEL17, by alternative splicing of a common mRNA precursor. Mouse melanocytes exclusively express the gp100 orthologue, here termed gp87, thus providing a simpler model with which to study the silver locus products. We have analyzed the effects of [Nle4, d -Phe7]-, melanocyte-stimulating hormone (,MSH) and two hypopigmenting cytokines, tumor necrosis factor (TNF)-, and transforming growth factor (TGF)-,1, on the expression of gp87 in B16 mouse melanoma cells. TNF-, and TGF-,1 (at saturating doses for 48 hr) decreased gp87 mRNA by 50%. The gp87 protein was almost undetectable by Western immunoblotting after TNF-, treatment, but was not affected by TGF-,1. ,MSH increased the mRNA and the gp87 protein ,2-fold. Moreover, the amount of gp87 was not reduced by TNF-, in the presence of the hormone, in spite of a 50% decrease in its mRNA. Therefore, the levels of mRNA and gp87 protein did not correlate after treatment with the cytokines. Overall, our data suggest that the silver locus product is not regulated exclusively at the transcriptional level, and highlight the importance of still-uncharacterized regulatory translational and/or post-translational events. [source] Co-localization of inducible nitric oxide synthase and phosphorylated Akt in the lesional skins of patients with melasmaTHE JOURNAL OF DERMATOLOGY, Issue 1 2009Ho-Youn JO ABSTRACT Activation of the inducible nitric oxide synthase (iNOS)/nitric oxide (NO) pathway in keratinocytes has been reported to be associated with the pathogenesis of melanogenesis. Akt activation plays an important role in the activation of the transcription factor nuclear factor (NF)-,B and subsequent elevation of iNOS expression. In the present study, we highly detected both iNOS protein and Akt phosphorylation in keratinocytes of the basal layer of the epidermis at the junction with the dermis of melasma skin biopsy specimens, but not in normal skin tissues, from nine patients using immunohistological analysis. iNOS protein and phosphorylated Akt were co-localized in the lesional skins, and their levels were highly correlated (R2 = 0.69). Furthermore, iNOS mRNA was also detected in an additional three skin biopsy specimens, but not in normal skin, by reverse transcription polymerase chain reaction. Our results describe that iNOS expression is elevated in human melasma lesions, probably via activation of the Akt/NF-,B pathway, indicating that NO production plays an important role in the mechanism of hyperpigmentation in human facial melasma. [source] Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivativesBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2008S. Chawla Summary Background, Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin. Objectives, The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ). Methods, The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays. Results, dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver,Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate. Conclusions, Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin. [source] | |||||||||||||