Human Skin Pigmentation Research Articles

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

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

Traditional Chinese Herbal Medicine for Whitening

Melanin is the chief pigment responsible for the pigmentation of human skin. Increasing evidence indicates that traditional Chinese drugs with skin-whitening effects are attracting the attention of consumers and researchers because they are perceived to be milder, safer, and healthier than synthetic alternatives. This commentary summarizes the current research on Chinese herbal medicines that inhibit melanin and their biological activities. The findings presented in this study suggest that these traditional Chinese herbal medicines might be potential candidates for novel skin-whitening agents.

Topical treatment strategies to manipulate human skin pigmentation.

Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e., "tanning pathway"). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway ("sunless tanning") represents a potential strategy for skin cancer prevention, particularly in those with light skin or the "red hair" phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway.

564 Melasolv, a skin lightening compound with different mechanisms to regulate skin pigmentation

The pigmentation of human skin (nevi, senile lentigines, melasma, etc) is regulated by a complex process involving the synthesis and distribution of melanin. Overexpression of melanin is induced by the off-balance between the signals which regulates melanin synthesis, this can be caused due to a response to external or internal stimulus that often affects the genes related to melanogenesis. To date, many studies have focused on developing direct enzymatic inhibitors of tyrosinase in order to achieve a skin-lightening effect. However, it was also reported that these direct inhibitors could be converted to quinone derivatives by tyrosinase-catalyzed oxidation, which lead to undesirable outcomes. Therefore, we have studied intrinsic inhibitory factors of melanogenesis in skin with the objective to achieve a lightening effect without the undesirable potential side effects. It was reported that non-coding RNAs including H19, miR125b and WIF1 were decreased in hyper-pigmented skin such as melasma and nevi. And it was found out that melanogenesis could be inhibited by increasing these lightening genes expression in normal human epidermal melanocytes and keratinocytes. Our group showed that the 3, 4, 5-trimethoxy cinnamate thymol ester (TCTE, Melasolv®), synthesized from gallic acid, is a lightening active which decreases tyrosinase protein formation by regulating the MITF. Likewise, we have also observed that Melasolv significantly decreased melanogenesis by increasing expression of the lightening genes H19, miR125b and WIF1 in the skin cells. Finally, we have confirmed the lightening effect of Melasolv in 3D human skin equivalent. Nonetheless, since Melasolv is not a direct inhibitor of tyrosinase enzymatic activity, it is extremely unlikely that nocive quinone derivatives conversions occur. From these results, we have proposed Melasolv as an active for lightening effects with a safer profile, when considering undesirable effects, to treat pigmentary disorder and uneven skin color.

525 Identification of a new gene involved in human skin pigmentation: CLEC12B

525 Identification of a new gene involved in human skin pigmentation: CLEC12B

571 Identifying a novel mechanism of human skin pigmentation

571 Identifying a novel mechanism of human skin pigmentation

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti- tyrosinase agents. A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

The vitamin D-folate hypothesis in human vascular health.

The vitamin D-folate hypothesis has been proposed as an explanation for the evolution of human skin pigmentation. According to this hypothesis, a darkened skin pigment was adapted by early human populations living in equatorial Africa to protect against photodegradation of bioavailable folate by ultraviolet radiation (UVR). As humans moved away from the equator to more northern latitudes and occupied regions of lower UVR exposure and greater seasonal variation, however, depigmentation occurred to allow for adequate biosynthesis of vitamin D. Vitamin D and folate are both recognized for their evolutionary importance in healthy pregnancy and early childhood development. More recently, evidence has emerged demonstrating the importance of both vitamin D and folate in vascular health via their effects in reducing oxidative stress and improving nitric oxide (NO) bioavailability. Thus, populations with darkened skin pigmentation may be at elevated risk of vascular dysfunction and cardiovascular disease in low UVR environments due to hypovitaminosis D; particularly important as darkly-pigmented African-Americans represent an at-risk population for cardiovascular disease. Conversely, lightly pigmented populations in high UVR environments may be at risk of deleterious vascular effects of UVR-induced folate degradation. The focus of this review is to explore the currently available literature regarding the potential role of UVR in vascular health via its differential effects on vitamin D and folate metabolism, as well as the interaction between skin pigmentation, genetics, and environment in modulating the vascular influence of UVR exposure.

The Genetics of Human Skin and Hair Pigmentation.

Human skin and hair color are visible traits that can vary dramatically within and across ethnic populations. The genetic makeup of these traits-including polymorphisms in the enzymes and signaling proteins involved in melanogenesis, and the vital role of ion transport mechanisms operating during the maturation and distribution of the melanosome-has provided new insights into the regulation of pigmentation. A large number of novel loci involved in the process have been recently discovered through four large-scale genome-wide association studies in Europeans, two large genetic studies of skin color in Africans, one study in Latin Americans, and functional testing in animal models. The responsible polymorphisms within these pigmentation genes appear at different population frequencies, can be used as ancestry-informative markers, and provide insight into the evolutionary selective forces that have acted to create this human diversity.

Skin color variation: A study on Eastern and North East India

Background: Skin pigmentation is one of the most variable phenotypic traits and most noticeable of human polymorphisms. Skin pigmentation in humans is largely determined by the quantity and distribution of the pigment melanin. The literature review on skin color variation revealed a few works on skin pigmentation variation has been conducted in India from Southern, Western and Northern part.
 Aims and Objectives: To best of the knowledge, the present discourse is the first attempt to understand skin color variation from Eastern and North Eastern part of India among three populations.
 Materials and Methods: The present study consisted of 312 participants from Chakma and Tripuri groups of Tripura, North East India, and participants from Bengalee Hindu caste population from West Bengal. Skin color was measured by Konica Minolta CR-10 spectrophotometer which measures and quantifies the colors with a 3D color space (CIELAB) color space created by 3 axes. All the skin color measurements from each participant were taken from unexposed (underarm) left and right to get a mean and exposed (forehead) to sunlight.
 Results: The distribution of skin color variation among the three populations demonstrated significant (p<0.05) difference in lightness for unexposed and exposed indicating lightness in unexposed area. Furthermore, the present study revealed significant difference (p<0.05) in skin color among the ethnic groups across the body location and all three attributes (lightness, redness and yellowness).
 Conclusion: Generally, skin color variation may be elucidated by two main factors: individual differences in lightness and yellowness and by and large due to ethnicity, where diversity in redness is due to primarily due to different body locations. Variation in lightness have more characteristic probability. The present study first time reports the wide range of quantitative skin color variation among the three ethnic groups from Eastern and North East India and highest yellowness (b*) among the population from North East India.

Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study.

Human skin pigmentation is a result of constitutive and facultative pigmentation. Facultative pigmentation is frequently stimulated by UV radiation, pharmacologic drugs, and hormones whereby leads to the development of abnormal skin hyperpigmentation. To date, many state-of-art depigmenting compounds have been studied using in vitro model to treat hyperpigmentation problems for cosmetic dermatological applications; little attention has been made to compare the effectiveness of these depigmenting compounds and their mode of actions. In this present article, new and recent depigmenting compounds, their melanogenic pathway targets, and modes of action are reviewed. This article compares the effectiveness of these new depigmenting compounds to modulate several melanogenesis-regulatory enzymes and proteins such as tyrosinase (TYR), TYR-related protein-1 (TRP1), TYR-related protein-2 (TRP2), microphthalmia-associated transcription factor (MITF), extracellular signal-regulated kinase (ERK) and N-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38 MAPK). Other evidences from in vitro assays such as inhibition on melanosomal transfer, proteasomes, nitric oxide, and inflammation-induced melanogenesis are also highlighted. This article also reviews analytical techniques in different assays performed using in vitro model as well as their advantages and limitations. This article also provides an insight on recent finding and re-examination of some protocols as well as their effectiveness and reliability in the evaluation of depigmenting compounds. Evidence and support from related patents are also incorporated in this present article to give an overview on current patented technology, latest trends, and intellectual values of some depigmenting compounds and protocols, which are rarely highlighted in the literatures.

Meta-analysis and prioritization of human skin pigmentation-associated GWAS-SNPs using ENCODE data-based web-tools.

Skin pigmentation in human is a complex trait, which varies widely, both within and between human populations. The exact players governing the trait of skin pigmentation remain elusive till date. Various Genome Wide Association Studies (GWAS) have shown the association of different genomic variants with normal human skin pigmentation, often indicating genes with no direct implications in melanin biosynthesis or distribution. Little has been explained in terms of the functionality of the associated Single-Nucleotide Polymorphisms (SNPs) with respect to modulating the skin pigmentation phenotype. In the present study, which, to our knowledge, is the first of its kind, we tried to analyze and prioritize 519 non-coding SNPs and 24 3'UTR SNPs emerging from 14 different human skin pigmentation-related GWAS, primarily using several ENCODE-based web-tools like rSNPBase, RegulomeDB, HaploReg, etc., most of which incorporate experimentally validated evidences in their predictions. Using this comprehensive, in-silico, analytical approach, we successfully prioritized all the pigmentation-associated GWAS-SNPs and tried to annotate pigmentation-related functionality to them, which would pave the way for deeper understanding of the molecular basis of human skin pigmentation variations.

Photoprotection against visible light-induced pigmentation.

This paper presents invivo an invitro studies demonstrating the induction of pigmentation in human skin by visible light which can be blocked by using formulation containing the correct amount of yellow iron oxide (YIO). An invitro absorption method was developed to determine the protection provided by a test formulation containing 4.5% YIO using an IPD UVA-VIS action spectrum. Following the development of the invitro method and invivo study with 10 normal healthy volunteers with Fitzpatrick skin phototypes IV to VI was conducted to verify if the predictive model. The invitro model for visible light protection provided a protection factor of 2.5 using the invitro absorption spectrum of 4.5% of YIO with a very similar result from the invivo study with a protection factor of 3.0. Multiple daily exposures of visible light have shown increase in skin pigmentation and the application of YIO provide less development of pigmentation when compared to unprotected skin. In vitro testing of the absorbance of the pigmented formulation using a proposed action spectrum for immediate pigment darkening (IPD) response in the visible light range supports the invivo protection observations for persistent pigment darkening (PPD) and can be used as predictor for skin pigmentation induced by visible light.

The effect of sexual selection on phenotypic diversification among human populations: A simulation study

Despite the generally low level of inter-population genetic differentiation in humans as compared with great apes, it has long been acknowledged that there is a considerable amount of geographic variations in human phenotypes, for example, skin pigmentation, cranial morphology, and soft-tissue facial morphology, to name but a few. Indeed, recent studies have suggested that the extent of inter-population diversity in some human phenotypes is greater than expected from random drift alone. Such an excess of phenotypic diversity is often attributed to adaptation to local environment. However, this account is valid only if populations differ in some ecological aspects that elicit differential selection acting on a given phenotypic feature. Another long-standing hypothesis is the sexual selection hypothesis, which claims that phenotypic diversity arises and/or is maintained owing to variations in preference for mating partners. In this paper, we explore the plausibility of the sexual selection hypothesis by means of computer simulations, in which the inter-population diversity of a quantitative trait is evaluated against the expectation from random drift, using the QST-FST comparison. As possible driving factors of sexual selection, we consider two types of mate-choice preference: preference for the population average and preference for a culturally-transmitted arbitrary trend. Our simulations suggest that sexual selection can, under certain circumstances, maintain and/or generate a detectable amount of inter-population phenotypic diversity, even when populations are ecologically identical and loosely connected to each other by mutual migration. Since mating decisions in humans are considerably affected by social learning, human mate-choice preference may be more readily diversified between populations than in other animals. We suggest, therefore, that some of the observed human phenotypic variations may be better understood as a product of cultural, rather than ecological, diversification.

Decoupling Ionic and Electronic Currents in Melanin

AbstractMelanin, the human skin pigment, has emerged as a model material for bioelectronic interfaces due to its biocompatibility, ability to be processed into electronic‐device‐grade thin films, and transducing charge transport properties. These charge transport properties have been suggested to be of a mixed protonic/electronic nature, regulated by a redox reaction that can be manipulated by changing the material's hydration state. However, to date, there are no detailed reports which clarify, quantify, or disentangle the protonic and electronic contributions to long‐range current conduction in melanin. Described herein, is a systematic hydration controlled electrical study on synthetic melanin thin films utilizing impedance/dielectric spectroscopy, which rationally investigates the protonic and electronic contributions. Through modeling and inspecting the frequency dependent behavior, it is shown that the hydration dependent charge transport is due to proton currents. Results show a real dielectric constant for hydrated melanin of order ≈1 × 103. Surprisingly, this very high value is maintained over a wide frequency range of ≈20–104 Hz. The electronic component appears to have little influence on melanin's hydration dependent conductivity: thus the material should be considered a protonic conductor, and not as previously suggested, a mixed protonic/electronic hybrid.

An explanation for the mysterious distribution of melanin in human skin: a rare example of asymmetric (melanin) organelle distribution during mitosis of basal layer progenitor keratinocytes.

Melanin is synthesized by melanocytes in the basal layer of the epidermis. When transferred to surrounding keratinocytes melanin is the key ultraviolet radiation-protective biopolymer responsible for skin pigmentation. Most melanin is observable in the proliferative basal layer of the epidermis and only sparsely distributed in the stratifying/differentiating epidermis. The latter has been explained as 'melanin degradation' in suprabasal layers. To re-evaluate the currently accepted basis for melanin distribution in human epidermis and to discover whether this pattern is altered after a regenerative stimulus. Normal epidermis of adult human skin, at rest and after tape-stripping, was analysed by a range of (immuno)histochemical and high-resolution microscopy techniques. In vitro models of melanin granule uptake by human keratinocytes were attempted. We propose a different fate for melanin in the human epidermis. Our evidence indicates that the bulk of melanin is inherited only by the nondifferentiating daughter cell postmitosis in progenitor keratinocytes via asymmetric organelle inheritance. Moreover, this preferred pattern of melanin distribution can switch to a symmetric or equal daughter cell inheritance mode under conditions of stress, including regeneration. In this preliminary report, we provide a plausible and histologically supported explanation for how human skin pigmentation is efficiently organized in the epidermis. Steady-state epidermis pigmentation may involve much less redox-sensitive melanogenesis than previously thought, and at least some premade melanin may be available for reuse. The epidermal melanin unit may be an excellent example with which to study organelle distribution via asymmetric or symmetric inheritance in response to microenvironment and tissue demands.

Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation.

In human skin, melanogenesis is a tightly regulated process. Indeed, several extracellular signals are transduced via dedicated signalling pathways and mostly converge to MITF, a transcription factor integrating upstream signalling and regulating downstream genes involved in the various inherent mechanisms modulating melanogenesis. The synthesis of melanin pigments occurs in melanocytes inside melanosomes where melanogenic enzymes (tyrosinase and related proteins) are addressed with the help of specific protein complexes. The melanosomes loaded with melanin are then transferred to keratinocytes. A more elaborate level of melanogenesis regulation comes into play via the action of non-coding RNAs (microRNAs, lncRNAs). Besides this canonical regulation, melanogenesis can also be modulated by other non-specific intrinsic pathways (hormonal environment, inflammation) and by extrinsic factors (solar irradiation such as ultraviolet irradiation, environmental pollution). We developed a bioinformatic interaction network gathering the multiple aspects of melanogenesis and skin pigmentation as a resource to better understand and study skin pigmentation biology.

Innovative Natural Ingredients-Based Multiple Emulsions: The Effect on Human Skin Moisture, Sebum Content, Pore Size and Pigmentation.

The increased interest in natural cosmetics has resulted in a higher market demand for preservative-free products based on herbal ingredients. An innovative W/O/W type emulsions containing herbal extracts were prepared directly; its cation form was induced by an ethanolic rosemary extract and stabilized using weak herbal gels. Due to the wide phytochemical composition of herbal extracts and the presence of alcohol in the emulsion system, which can cause skin irritation, sensitization or dryness when applied topically, the safety of the investigated drug delivery system is necessary. The aim of our study was to estimate the potential of W/O/W emulsions based on natural ingredients for skin irritation and phototoxicity using reconstructed 3D epidermis models in vitro and to evaluate in vivo its effect on human skin moisture, sebum content and pigmentation by biomedical examination using a dermatoscopic camera and corneometer. According to the results obtained after in vitro cell viability test the investigated emulsion was neither irritant nor phototoxic to human skin keratinocytes. W/O/W emulsion did not cause skin dryness in vivo, despite the fact that it contained ethanol. We can conclude that the emulsion is safe for use as a leave-on product due to the positive effect on human skin characteristics or as a semisolid pharmaceutical base where active compounds could be encapsulated.

Melanocyte development in the mouse tail epidermis requires the Adamts9 metalloproteinase.

The mouse tail has an important role in the study of melanogenesis, because mouse tail skin can be used to model human skin pigmentation. To better understand the development of melanocytes in the mouse tail, we cloned two dominant ENU-generated mutations of the Adamts9 gene, Und3 and Und4, which cause an unpigmented ring of epidermis in the middle of the tail, but do not alter pigmentation in the rest of the mouse. Adamts9 encodes a widely expressed zinc metalloprotease with thrombospondin type 1 repeats with few known substrates. Melanocytes are lost in the Adamts9 mutant tail epidermis at a relatively late stage of development, around E18.5. Studies of our Adamts9 conditional allele suggest that there is a melanocyte cell-autonomous requirement for Adamts9. In addition, we used a proteomics approach, TAILS N-terminomics, to identify new Adamts9 candidate substrates in the extracellular matrix of the skin. The tail phenotype of Adamts9 mutants is strikingly similar to the unpigmented trunk belt in Adamts20 mutants, which suggests a particular requirement for Adamts family activity at certain positions along the anterior-posterior axis.

Potential of Medicinal Plants Extractives as Anti-Melanogenesis Ingredients

Melanin is the pigment in the human and animal skin that is synthesized by tyrosinase from L-tyrosine to L-DOPA, following the oxidation of L-DOPA to L-DOPA quinone. Skin whitening agents have been desired as treatment of skin diseases caused by the excess accumulation of melanin on the human skin, because skin darkening is one of the serious aesthetic problems in human beings. Inhibiting the tyrosinase activity and the protein expression are the target to develop the skin whitening agent. A large number of active compounds have been isolated and identified from natural product to develop whitening agents so far. This review reports the potential of traditional medicinal plant extractives and the effective novel ingredients as anti-melanogenesis.