Human Melanogenesis Research Articles

Tranexamic Acid in the Treatment of Melasma: A Comprehensive Review of Topical, Intradermal, and Oral Administration

A malfunction in human melanogenesis called melasma causes the epidermis to become hyperpigmented in certain regions of the body gradually. It significantly affects physical appearance, results in psychological and physiological distress, and diminishes those impacted individuals' quality of living. In order to restrict blood loss, tranexamic acid (TA), a plasmin inhibitor, is used for stopping unusual fibrinolysis. It works by permanently inhibiting lysine binding sites on plasminogen molecules, which prohibits plasminogen activator (PA) from converting plasminogen to plasmin. It seems sense that tranexamic acid might have an impact on keratinocyte association and function because plasminogen is additionally found in human epidermis basal cells and owing to the fact that PA has been shown to be produced by cultivated human keratinocytes. A comprehensive review of the literature demonstrates that although TA is administered by topical, oral, and intradermal injection as well as utilized as an adjuvant therapy Added to the laser therapy to treat melasma, its effectiveness has not been sufficiently proved. To fully understand the function of TA in the management of melasma, additional investigation is required.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective.

The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin-lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation-related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from nonhuman species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responsesto melatonin are best interrogated in a physiological tissue context.Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis-inhibitory effects of melatonin may occur via activation of Nrf2-mediated PI3K/AKT signaling, estrogen receptor-mediated and/or melanocortin-1 receptor- and cAMP-dependent signaling, and/or via melatonin-regulated changes in peripheral clock genes that regulate human melanogenesis, namely Bmal1 and Per1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto- and senescence-protective as well as antioxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function.We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture-based observations translate into melatonin-induced pigmentary changes in a physiological tissue context, that is, in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models.

3,4,5-Trimethoxycinnamate thymol ester inhibits melanogenesis in normal human melanocytes and 3D human epidermal equivalents via the PGC-1α-independent PPARγ partial agonism

Background3,4,5-Trimethoxycinnamate thymol ester (TCTE), an anti-melanogenic cosmetic agent prescribed currently, promotes adiponectin synthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Adiponectin inhibits melanin biosynthesis and its biosynthesis is directly regulated by peroxisome proliferator-activated receptor (PPAR) γ. In this regard, TCTE may potentially affect PPARγ activity. However, contradicting effects of PPARγ agonists with different chemical structures on human melanogenesis have been reported. ObjectiveA molecular target of TCTE was investigated to elucidate the association of both adiponectin and PPARγ with anti-melanogenic activity. MethodsThe adiponectin secretion-promoting activity of TCTE was tested in an adipogenesis model of hBM-MSCs. A molecular target of TCTE for adiponectin secretion was evaluated via time-resolved fluorescence resonance energy transfer-based receptor binding and transactivation of PPARs. ResultsTCTE significantly promoted adiponectin secretion (EC50, 27.9 μM) during adipogenesis in hBM-MSCs and directly bound to PPARγ (Ki, 13.2 μM). The TCTE-bound PPARγ increased the recruitment of SRC-1, SRC-3, and TRAP220/DRIP-1 coactivator peptides without affecting PGC-1α coactivation. In the docking analysis, the optimal ligand binding mode of TCTE exhibited typical ligand-receptor interactions of PPARγ partial agonists. The PPARγ partial agonism of TCTE was established experimentally and the anti-melanogenic activity of TCTE was decreased by treatment with a PPARγ antagonist in cultured normal human melanocytes and a 3D model of human epidermis. ConclusionThe anti-melanogenic activity of TCTE was associated with a PGC-1α-independent PPARγ partial agonism.

REVIEW ARTICLE ON TREATMENT OPTIONS FOR MELASMA

Melasma is an acquired ,chronic pigmentary disorder that predominantly is seen over the sun exposed areas of the face[1]. It can be regarded as a dysfunction in human melanogenesis [2] and results from increased activity of melanocytes [3], increased melanocytes, melanin, melanosomes and increase in synthesis of tyrosinase[4]

Melanogenesis, Its Regulatory Process, and Insights on Biomedical, Biotechnological, and Pharmacological Potentials of Melanin as Antiviral Biochemical

Melanin is s most widely distributed pigment and is found in bacteria, fungi, plants, and animals. Melanogenesis is under complex regulatory control by multiple agents interacting through pathways activated by hormonal and receptor-dependent and -independent mechanisms. There are about 20 genes that are involved in the biochemical pathway of melanogenesis and its regulation, which include: tyrosinase, microphthalmia-associated transcription factor, melanocortin1 receptor, adenylate cyclase, protein kinase A. Human melanogenesis regulatory proteins such as MAPK1, CREB3, and CREBP, have binary interaction with the protein of herpesvirus, hepatitis C virus, Human immunodeficiency virus type 1, Simian virus 40, and Human adenovirus A and C. Melanin is a double-edged sword in host-pathogen interaction (e.g., human-bacteria and/or fungi interaction). The inducers of upregulation of melanogenesis include fluvoxamine, famotidine, terbutaline, heliotrine, sirolimus, dicoumarol, Prestwick-860, carbimazole, (-)-MK-801, rilmenidine, hydrastine hydrochloride, haloperidol, scopolamine N-oxide, raubasine, and dihydroergocristine. In melanogenesis, GSK3B, CSNK2A, MAPK1, MAPK3, MAPK14, ERK1, and HIPK2 were the major kinases, while RUNX1, GATA1, and REST, SUN12, and RCOR1 were the major transcription factors. This study has reviewed the melanogenesis pathway, its regulations as well as applications to viral infection. The antiviral activity of melanin and its complex in the presence of antibacterial and antifungal compounds should be investigated to further provide insight for biomedical, biotechnological, and pharmacological applications.

Oxyresveratrol-induced Activation of Nrf2/HO-1 Signaling Pathway Enhances Ability of Resveratrol to Inhibit UVB-induced Melanin

Abstract Objective: This study was performed to investigate the relationship between the human melanogenesis and antioxidant systems and to further confirm the synergistic effect of oxyresveratrol (OXYR) and resveratrol (RES) in human epidermal melanocyte cell line. Methods: The human epidermal melanocyte line PIG1 cells were divided into the UV groups and control group, treated with different doses of UVB and without UVB, respectively. MTT assay and flow cytometry were used to detect cell viability and apoptosis. The expression of Nrf2/HO-1 and melanogenesis-associated proteins/genes was measured by Western blotting and real-time qPCR (RT-qPCR). pCMV6-XL5-Nrf2 was used to upregulate the expression of Nrf2. Subsequently, the proteins/genes levels of Nrf2/HO-1 and tyrosinase (TYR), melanin/eumelanin content, and reactive oxygen species (ROS) were analyzed. Isobologram analysis and cell experiment were used to analyze whether OXYR and RES inhibit TYR synergistically. Western blotting, RT-qPCR, and NaOH splitting method were used to determine the Nrf2/HO-1 and melanogenesis-associated proteins/genes expression and melanin content to evaluate the efficacy of OXYR and RES. Results: The activated Nrf2 and HO-1 eliminated ROS produced by UVB irradiation. The melanogenesis-associated proteins/genes of melanocyte-inducing transcription factor (MITF, P < 0.01 on protein expression), TYR (both P < 0.01), TYR-related protein (TRP)-1 (both P < 0.05), and TRP2 (P < 0.05 on mRNA expression) were activated in PIG1 cells by UVB irradiation. Simultaneously, the upregulation of Nrf2 significantly reduced melanogenesis formation (P < 0.001) and TYR level (P < 0.01 on protein expression). Moreover, OXYR and RES synergistically inhibited TYR activity (P < 0.001) and reduced melanin content (P < 0.001). Conclusions: A microbalance exists between Nrf2/HO-1 signaling and melanogenesis production in the UVB-induced responses of melanocytes. Simultaneously, OXYR enhances the ability of RES to inhibit melanin production.

A Comparative Study of Ingudi phalamajja Lepa and Ananatmul Ghan in The Management of Vyanga (Melasma)

The normal color of skin in human is largely due to melanin pigment. Melasma is most common disorder which is related to melanin. It is a human melanogenesis dysfunction that results in localized, chronic acquired hypermelanosis of the skin. In Ayurveda melasma can be correlated with Vyanga because of resemblance of its clinical features. According to Acharya Charak, it is caused due to vitiation of Pitta and Shonita but other Acharyas has depicted it due to the vitiation of Vāta and Pitta. This study is aimed to explore the Efficacy of Ingudi Phalmajja lepa with and without internal use of Anantamoola Ghana in Vyanga. Total 43 patients were registered and randomly divided into group A and group B by lottery method. Out of these, 40 patients have completed the treatment. All patients were examined by Wood’s Lamp to assess the depth of pigmentation (Dermal/Epidermal).. It is concluded that vyanga is frequent in females than males. It was found in madhyamavastha in which pitta dosha and Rajoguna is predominant. Mostly Centrofacial type of melasma is found in this study which is supported by other studies. Melasma Severity Index is improved in both the groups. Local application of Ingudi phalmajja is found to be effective in the severity of pigmentation. The action of Ingudi phalamajja in hyperpigmentation could not be evaluated. Further study can be conducted to find out the active principle of Ingudi.

Effect of sulfur mustard on melanogenesis in vitro

The chemical warfare agent sulfur mustard (SM) affects all cells in the epidermis including melanocytes which are responsible for melanin synthesis. After exposure to SM, pigment abnormalities like hypo- and hyperpigmentation can occur. The underlying molecular pathomechanisms of SM exposure on human melanogenesis have not been elucidated so far. In our study, we investigated the effect of SM on human melanocytes and melanogenesis. Normal human epidermal melanocytes (NHEM) were used as in vitro model and they were exposed to different concentrations of SM (4.5 μM–100 μM). Melanin production was analyzed by absorption measurements at 405 nm. In addition, quantitative real-time PCR (qPCR) and Western blot experiments were performed to determine the expression of essential melanogenesis-related proteins including tyrosinase (TYR), tyrosinase-related protein (TRP) 1 and 2 and microphthalmia transcription factor (MITF). Our findings demonstrated that exposure to low SM concentrations increased melanin synthesis accompanied with an increase in protein expression. In contrast, high SM concentrations led to decreased melanin content and a downregulation in expression of all investigated melanogenesis-associated proteins. We concluded that low SM concentrations may cause hyperpigmentation while high SM concentrations decreased melanin content which may explain hypopigmented skin areas in SM exposed patients.

Therapeutic effects of iNOS inhibition against vitiligo in an animal model.

Nitric oxide (NO) is involved in several biological processes, but its role in human melanogenesis and vitiligo need further studies. Previous studies revealed that exposure to UVA and UVB were capable of the inducing nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, whereas inducible nitric oxide synthase overexpression has been reported to play an important role in hyperpigmentary disorders. The aim of this study was to evaluate iNOS inhibitor aminoguanidine (AG) as a therapeutic agent in our mouse model of vitiligo. In this study, male C57BL/6J Ler-vit/vit mice were purchased to evaluate the effect of iNOS inhibitor (aminoguanidine) (50 and 100 mg/kg) and L-arginine (100 mg/kg) in a mouse model of vitiligo induced by monobenzone 40%. Moreover, we used phototherapy device to treat the mice with NBUVB as a gold standard.The findings revealed that monobenzone was capable of inducing depigmentation after 6 weeks. However, aminoguanidine in combination with monobenzone was decrease the effect of monobenzone, while L-arginine play a key role in promoting the effect of monobenzone (P<0.001). Based on the phototherapy, the efficacy of phototherapy significantly increased by adding L-arginine (P<0.05). Taken together, we suggest that iNOS inhibitor can be a novel treatment for the prevention and treatment of vitiligo by combination of NBUVB therapy, furthermore; NO agents like L-arginine could also increase the effectiveness of phototherapy. Taken together, this pilot study showed significant repigmentation of vitiligous lesions treated with iNOS inhibitor plus NBUVB therapy, where other aspect including expression of an inducible iNOS, NO and TNF levels remained to be evaluated in mice model.

TP53 Tumor-suppressor Gene Plays a Key Role in IGF1 Signaling Pathway Related to the Aging of Human Melanocytes.

The insulin-like growth factor 1 (IGF1) signaling pathway as an aging mechanism related to p53 in human melanogenesis remains unclear. The aim of this study was to investigate the relationship between p53 and IGF1 signaling pathway in young, senescent and H2O2-treated cells. The protein and gene expression in young, senescent and H2O2-treated cells were analyzed using western blot and reverse transcription polymerase chain reaction (RT-PCR) assays, respectively. The expression levels of (phosphoinositide 3-kinases) PI3K, v-akt murine thymoma viral oncogene homolog 1 (AKT1), mammalian target of rapamycin, β-catenin (CTNNB1), acetylated p53 (ac-p53), p53 and p-p21 proteins, related to IGF1 and p53 signaling pathways, were higher in senescent and H2O2-treated cells than those of young cells. Furthermore, AKT reduced melanogenesis through microphthalmia-associated transcription factor (MITF) inactivation by the inhibition of CTNNB1. The gene expression levels of PI3K, TP53 and catalase (CAT) in senescent and H2O2-treated cells were increased compared to young cells. p53 protein plays a key role in the aging of melanocytes via IGF1 signaling pathways.

Editorial introductions

Current Opinion in Oncology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of psychiatry is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Véronique del MarmolVéronique del MarmolProfessor Véronique del Marmol is the Head of the Department of Dermatology at Hôspital Erasme, Université Libre de Bruxelles, Belgium. Professor del Marmol graduated as a bachelor in philosophy in 1983 and as an MD in 1987 at the Université de Louvain, Belgium. She graduated as an MSc in molecular biology in 1991 and received her PhD in 1995 for her work on “Contribution to the study of the regulation of human melanogenesis”. She graduated as a specialist in dermato-venerology in 1996 at the Université Libre de Bruxelles. Skin cancer, skin pigmentation, melanoma and non-melanoma skin cancer and non-invasive imaging are the main areas of interest for Professor del Marmol. In recognition of her work in these fields, she has been awarded several scholarships and grants, including the Major Roche Dermatology Fundamental Research Award. She authored and co-authored more than 116 peer reviewed articles and seven books (H index 36), particularly in Journal of Investigative Dermatology, Experimental Dermatology, Journal of the European Academy of Dermatology and Venereology (JEADV), Nature and New England Journal of Medicine. She is a founding member for the European skin cancer prevention campaign EUROMELANOMA and since 2009 led its European campaign. She is board member of the European Dermatology Forum (EDF), the Academy of Dermatology and Venerology (EADV), the European Academy of Dermato-oncology (EADO) and the European Pigment Cell Society (ESPCR). She is vice-president of the Belgian Society of Dermatology and was elected in 2014 as member of the Belgian Royal Academy of Medicine. Pierre HainautPierre HainautPierre Hainaut (born 1958, Belgium) is PhD in Biology, University of Liège, Belgium, 1987. After postdocs in France and in the UK (1988–1994), he joined the International Agency for Research on Cancer (IARC, World Health Organization) in 1994, where he held the post of head of Molecular Carcinogenesis from 1999 to 2011. In 2012, he joined the International Prevention Research Institute (iPRI) as Research Director. Since 2014, he has been appointed as Professor of Cancer Biology and Chair of Excellence in Translational Research at Université Grenoble Alpes, France. Since October 2014, he is Director of the Institute of Advanced Biosciences (formerly Institut Albert Bonniot), a multi-thematic research center supported dedicated to epigenetics, chronic diseases and cancer (17 research groups). He is also responsible for Molecular Diagnosis of Cancer at the University Hospital (CHU) of Grenoble, France. His research focuses on TP53 mutations and on biomarkers of transition from chronic diseases to cancer. From 1994 to 2011, he led the development of the international IARC database of TP53 mutations, a source of information on the causes and consequences of mutations affecting the p53 suppressor protein in cancer. His current research focuses on gain-of-function effects in lung cancer and on biomarkers for early detection of liver and lung cancers, in particular in low-resource countries. Pierre Hainaut is author of over 400 publications and 50 book chapters (h index: 83, Google Scholar). He has co-edited two books on p53 (25 Years of p53 Research 2005, 2007, p53 in the Clinics, Springer) and a textbook of molecular epidemiology (Molecular Epidemiology: Principle and Practice, IARC Press, 2011).

Method for identification of sensitive nodes in Boolean models of biological networks.

Biological systems are often represented as Boolean networks and analysed to identify sensitive nodes which on perturbation disproportionately change a predefined output. There exist different kinds of perturbation methods: perturbation of function, perturbation of state and perturbation in update scheme. Nodes may have defects in interpretation of the inputs from other nodes and calculation of the node output. To simulate these defects and systematically assess their effect on the system output, two new function perturbations, referred to as ‘not of function’ and ‘function of not’, are introduced. In the former, the inputs are assumed to be correctly interpreted but the output of the update rule is perturbed; and in the latter, each input is perturbed but the correct update rule is applied. These and previously used perturbation methods were applied to two existing Boolean models, namely the human melanogenesis signalling network and the fly segment polarity network. Through mathematical simulations, it was found that these methods successfully identified nodes earlier found to be sensitive using other methods, and were also able to identify sensitive nodes which were previously unreported.

Differential Expression of Nitric Oxide Synthase Isoforms nNOS and iNOS in Patients with Non-Segmental Generalized Vitiligo.

Nitric oxide (NO) is involved in several biological processes, but its role in human melanogenesis is still not well understood. Exposure to UVA and UVB induces nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, increasing tyrosinase activity and melanin synthesis, whereas inducible nitric oxide synthase over expression might be involved in hypopigmentary disorders. The aim of this study was to evaluate whether inducible nitric oxide synthase and neuronal nitric oxide synthase expression were modified in vitiligo skin compared to healthy controls. Skin biopsies were obtained from inflammatory/lesional and white/lesional skin in 12 patients with active, non-segmental vitiligo; site-matched biopsies of normal skin from eight patients were used as controls. Nitric oxide synthase isoforms expression was evaluated by confocal laser scanning microscopy and Western Blot analysis. Inducible nitric oxide synthase expression was significantly increased in inflammatory/lesional skin compared to healthy skin; melanocytes showed a moderate neuronal nitric oxide synthase expression in white/lesional skin, demonstrating that metabolic function still goes on. The obtained data demonstrated that vitiligo lesions were characterized by modifications of nitric oxide synthase isoforms, thus confirming the hypothesis that nitric oxide imbalance is involved in vitiligo and supporting the idea that nitric oxide synthase inhibitors might be used as a possible therapeutic approach for the management of vitiligo.

Tranexamic acid in treatment of melasma: A comprehensive review of clinical studies.

Melasma is a human melanogenesis dysfunction that results in localized, chronic acquired hyperpigmentation of the skin. It has a significant impact on appearance, causing psychosocial and emotional distress, and reducing the quality of life of the affected patients. Tranexamic acid (TA) is a plasmin inhibitor used to prevent abnormal fibrinolysis to reduce blood loss and exerts its effect by reversibly blocking lysine binding sites on plasminogen molecules, thus inhibiting plasminogen activator (PA) from converting plasminogen to plasmin. As plasminogen also exists in human epidermal basal cells and cultured human keratinocyte are known to produce PA, there is basic rationale that TA will affect keratinocyte function and interaction. A thorough literature review indicates that while TA is used through various route of administration including oral, topical, and intradermal injection and as adjutant therapy with laser to treat melasma, its efficacy is not established adequately. Further studies are needed to clarify the role of TA in treatment of melasma.

Melasma: Through the eye of a dermoscope

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Melasma is a human melanogenesis dysfunction that results in localized, chronic acquired hypermelanosis of the skin. Dermoscopy is a new non-invasive tool which is used to visualise the pigment colour and distribution. This study was undertaken to explore the usefulness of dermoscope in comparison to Wood’s lamp in melasma.&lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A total of 50 patients of melasma were examined clinically, under Wood’s lamp and with dermoscope. All the findings were recorded, described and analysed.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; The data was compared using SPSS software and the degree of agreement between Wood’s lamp and dermoscopy was found to be substantial (K =0.833, p =&amp;lt;0.001)&lt;span lang="EN-IN"&gt;. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Dermoscopy is better tool in determining the depth of pigmentation. It gives an additional advantage to visualize the vasculature.&lt;/span&gt;&lt;/p&gt;

Stress chaperone mortalin regulates human melanogenesis.

In order to identify the cellular factors involved in human melanogenesis, we carried out shRNA-mediated loss-of-function screening in conjunction with induction of melanogenesis by 1-oleoyl-2-acetyl-glycerol (OAG) in human melanoma cells using biochemical and visual assays. Gene targets of the shRNAs (that caused loss of OAG-induced melanogenesis) and their pathways, as determined by bioinformatics, revealed involvement of proteins that regulate cell stress response, mitochondrial functions, proliferation, and apoptosis. We demonstrate, for the first time, that the mitochondrial stress chaperone mortalin is crucial for melanogenesis. Upregulation of mortalin was closely associated with melanogenesis in in vitro cell-based assays and clinical samples of keloids with hyperpigmentation. Furthermore, its knockdown resulted in compromised melanogenesis. The data proposed mortalin as an important protein that may be targeted to manipulate pigmentation for cosmetic and related disease therapeutics.

The Peripheral Clock Regulates Human Pigmentation

Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.

RAC1 and Melanoma

RAC1 is a GTPase member of the RAS superfamily, and RAC1P29S was recently identified as the third most common recurrent mutation in melanomas, affecting 4-7% of the patients. This is an oncogenic mutation, because the mutant protein remains mostly in its active GTP-bound form, and its ectopic expression increases the rate of normal melanocytes proliferation and migration. There is limited information regarding the functional role of RAC1P29S as a “driver” in human melanogenesis and as a cause for drug resistance. This commentary describes the latest data and provides evidence that supports the notion that RAC1 is activated even in melanoma cells that do not carry the mutation rendering it a good target for therapy. On the other hand, its role in conferring resistance to BRAF or MEK inhibitors is still in question.

Potent low toxicity inhibition of human melanogenesis by novel indole-containing octapeptides

BackgroundAbnormal production and accumulation of melanin are characteristics of a number of skin disorders, including postinflammatory hyperpigmentation and melasma. Our objective was to develop and validate novel oligopeptides with potent inhibitory activity against mushroom and human tyrosinase with minimal toxicity toward melanocytes, keratinocytes, and fibroblasts. MethodsA library of short sequence oligopeptides was docked against the crystal structure of mushroom tyrosinase to screen for favorable binding free energies and direct interaction with the catalytic pocket. The inhibitory activity of the octapeptides and hydroquinone (HQ) was assessed using mushroom and human tyrosinase and melanin content via human primary melanocytes. Effects on cell viability and proliferation were determined using the MTT assay and cytotoxicity via trypan blue exclusion. ResultsOctapeptides P16–18 outperformed HQ, the benchmark of hypopigmenting agents, in all tested categories. Prolonged incubation of human keratinocytes, fibroblasts, or melanocytes with 30–3000μM HQ led to 8- to 65-fold greater cell death than with octapeptides. After 6d of incubation with 30μM HQ, we observed 70±3% and 60±2% cell death in melanocytes and fibroblasts, respectively, versus minimal toxicity up to an octapeptide concentration of 3mM. ConclusionOctapeptides P16–18 are potent competitive tyrosinase inhibitors with minimal toxicity toward the major cell types of human skin. General significanceThe findings in our study suggest that all three novel octapeptides may serve as safe and efficacious replacements of HQ for the treatment of pigmentary disorders.

The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis

Skin cancer, chloracne and hyperpigmentation have been associated with the exposure to environmental contaminants such as polychlorinated biphenyls, dioxins or polycyclic aromatic hydrocarbons. These compounds are xenobiotic high-affinity ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with important physiological roles in, for example, the control of cell proliferation and inflammation. We show here that exposure of normal human melanocytes to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), results in activation of the AHR signaling pathway and an AHR-dependent induction of tyrosinase activity, the key enzyme of the melanogenic pathway. In accordance with the upregulation of tyrosinase enzyme activity, total melanin content was also elevated in TCDD-exposed melanocytes. Neither the induction of tyrosinase enzyme activity or of total melanin could be attributed to enhanced cell proliferation, but was rather due to the induction of tyrosinase and tyrosinase-related protein 2 gene expression. Thus, the AHR is able to modulate melanogenesis by controlling the expression of melanogenic genes.