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Concept: Human skin color

415

The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.

Concepts: DNA, Gene expression, Ultraviolet, Regulation of gene expression, Skin, Melanin, Human skin color, Melanocyte

263

Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways-HERC2, SLC45A2, and TYR-using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2-10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y.

Concepts: Gene, Genetics, Natural selection, Genotype, Evolution, Copper, Human skin color, Eye color

237

Humans in all societies form and participate in cooperative alliances. To successfully navigate an alliance-laced world, the human mind needs to detect new coalitions and alliances as they emerge, and predict which of many potential alliance categories are currently organizing an interaction. We propose that evolution has equipped the mind with cognitive machinery that is specialized for performing these functions: an alliance detection system. In this view, racial categories do not exist because skin color is perceptually salient; they are constructed and regulated by the alliance system in environments where race predicts social alliances and divisions. Early tests using adversarial alliances showed that the mind spontaneously detects which individuals are cooperating against a common enemy, implicitly assigning people to rival alliance categories based on patterns of cooperation and competition. But is social antagonism necessary to trigger the categorization of people by alliance-that is, do we cognitively link A and B into an alliance category only because they are jointly in conflict with C and D? We report new studies demonstrating that peaceful cooperation can trigger the detection of new coalitional alliances and make race fade in relevance. Alliances did not need to be marked by team colors or other perceptually salient cues. When race did not predict the ongoing alliance structure, behavioral cues about cooperative activities up-regulated categorization by coalition and down-regulated categorization by race, sometimes eliminating it. Alliance cues that sensitively regulated categorization by coalition and race had no effect on categorization by sex, eliminating many alternative explanations for the results. The results support the hypothesis that categorizing people by their race is a reversible product of a cognitive system specialized for detecting alliance categories and regulating their use. Common enemies are not necessary to erase important social boundaries; peaceful cooperation can have the same effect.

Concepts: Psychology, Cognition, Cognitive science, Philosophy of mind, Mind, Thought, Race, Human skin color

170

Human skin color is predominantly determined by melanin produced in melanosomes within melanocytes and subsequently distributed to keratinocytes. There are many studies that have proposed mechanisms underlying ethnic skin color variations, whereas the processes involved from melanin synthesis in melanocytes to the transfer of melanosomes to keratinocytes are common among humans. Apart from the activities in the melanogenic rate-limiting enzyme, tyrosinase, in melanocytes and the amounts and distribution patterns of melanosomes in keratinocytes, the abilities of the actin-associated factors in charge of melanosome transport within melanocytes also regulate pigmentation. Mutations in genes encoding melanosome transport-related molecules, such as MYO5A, RAB27A and SLAC-2A, have been reported to cause a human pigmentary disease known as Griscelli syndrome, which is associated with diluted skin and hair color. Thus we hypothesized that process might play a role in modulating skin color variations. To address that hypothesis, the correlations of expression of RAB27A and its specific effector, SLAC2-A, to melanogenic ability were evaluated in comparison with tyrosinase, using human melanocytes derived from 19 individuals of varying skin types. Following the finding of the highest correlation in RAB27A expression to the melanogenic ability, darkly-pigmented melanocytes with significantly higher RAB27A expression were found to transfer significantly more melanosomes to keratinocytes than lightly-pigmented melanocytes in co-culture and in human skin substitutes (HSSs) in vivo, resulting in darker skin color in concert with the difference observed in African-descent and Caucasian skins. Additionally, RAB27A knockdown by a lentivirus-derived shRNA in melanocytes concomitantly demonstrated a significantly reduced number of transferred melanosomes to keratinocytes in co-culture and a significantly diminished epidermal melanin content skin color intensity (ΔL* = 4.4) in the HSSs. These data reveal the intrinsically essential role of RAB27A in human ethnic skin color determination and provide new insights for the fundamental understanding of regulatory mechanisms underlying skin pigmentation.

Concepts: Ultraviolet, Skin, Melanin, Race, Human skin color, Melanocyte, Eye color, Human skin

155

The aim of the present study was to evaluate the efficacy and safety of lignin peroxidase (LIP) as a skin-lightening agent in patients with melasma. A self-controlled clinical study was performed in 31 women who had melasma on both sides of the face. This study involved 8 weeks of a full-face product treatment. The skin color was measured at days 0, 7, 28 and 56 using a chromameter on the forehead and cheeks. Standardized digital photographic images of each side of the face of all subjects were captured by a complexion analysis system. Clinical scores of the pigmentation were determined by two dermatologists. After using the LIP whitening lotion for 7 days, the luminance (L*) values of the melasma and the normal skin were significantly increased from baseline. The L* values continued to increase at days 28 and 56. The melasma area severity index (MASI) score was statistically decreased after 28 days of treatment. No treatment-related adverse events were observed. LIP whitening lotion was able to eliminate the skin pigmentation after 7 days of treatment, and provides a completely innovative approach to rapid skin lightening. The LIP whitening lotion exhibited good compatibility and was well tolerated.

Concepts: Clinical trial, Skin, Melanin, Normal distribution, Adverse event, Human skin color, Sun tanning, Skin whitening

150

Skin hyperpigmentation is characterized by increased melanin synthesis and deposition that can cause significant psychosocial and psychological distress. Although several cytokine-receptor signaling cascades contribute to the formation of ultraviolet B-induced cutaneous hyperpigmentation, their possible involvement in other types of skin hyperpigmentation has never been clearly addressed. Since our continuous studies using skin specimens from more than 30 subjects with ethnic skin diversity emphasized a consistent augmentation in the expression of endothelin-1 (ET-1) and its receptor (Endothelin B receptor, ET-B) in hyperpigmented lesions, including senile lentigos (SLs), the precise function of ET-1 signaling was investigated in the present study. In line with previous studies, ET-1 significantly induced melanogenesis followed by increases in melanosome transport in melanocytes and in its transfer to keratinocytes while inhibition of ET-B function substantially depressed melanogenic ability in tissue-cultured SLs. Additionally, in agreement with a previous report that the formation of autophagosomes rather than melanosomes is stimulated according to starvation or defective melanosome production, ET-1 was found to remarkably augment the expression of components necessary for early melanosome formation, indicating its counteraction against autophagy-targeting melanosome degradation in melanocytes. Despite the lack of substantial impact of ET-1 on keratinocyte melanogenic functions, the expression of ET-1 was enhanced following melanosome uptake by keratinocytes. Taken together, our data suggest that ET-1 plays a substantial role in the development and/or maintenance of skin hyperpigmentation in reciprocal cooperation with increased melanosome incorporation.

Concepts: Melanoma, Skin, Melanin, Epidermis, Human skin color, Skin anatomy, Melanocyte, Melanosome

140

Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target to inhibit hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, while kojic acid showed a weak efficacy (IC50 > 400 μM). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified thiamidol (isobutylamido thiazolyl resorcinol), which had an IC50 of 1.1 μM. In contrast, thiamidol only weakly inhibited mushroom tyrosinase (IC50: 108 μM). In melanocyte cultures, thiamidol strongly but reversibly inhibited melanin production (IC50: 0.9 μM) while hydroquinone irreversibly inhibited melanogenesis (IC50: 16.3 μM). Clinically, thiamidol visibly reduced the appearance of age spots within 4 weeks and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies.

Concepts: Skin, Enzyme inhibitor, Inhibitor, Xanthine oxidase inhibitor, Human skin color, Melanocyte, Tyrosinase, Skin whitening

124

UVC light generated by conventional germicidal lamps is a well-established anti-microbial modality, effective against both bacteria and viruses. However, it is a human health hazard, being both carcinogenic and cataractogenic. Earlier studies showed that single-wavelength far-UVC light (207 nm) generated by excimer lamps kills bacteria without apparent harm to human skin tissue in vitro. The biophysical explanation is that, due to its extremely short range in biological material, 207 nm UV light cannot penetrate the human stratum corneum (the outer dead-cell skin layer, thickness 5-20 μm) nor even the cytoplasm of individual human cells. By contrast, 207 nm UV light can penetrate bacteria and viruses because these cells are physically much smaller.

Concepts: DNA, Medicine, Genetics, Human, Ultraviolet, Bacteria, Skin, Human skin color

103

We report on ultraviolet (UV) light induced increases in the UV optical density of thin and optically transparent crystalline DNA films formed through self assembly. The films are comprised of closely packed, multi-faceted and sub micron sized crystals. UV-Vis spectrophotometry reveals that DNA films with surface densities up to 0.031 mg/mm(2) can reduce the transmittance of incident UVC and UVB light by up to 90%, and UVA transmittance by up to 20%. Subsequent and independent film irradiation with either UVA or UVB dosages upwards of 80 J/cm(2) both reduce UV transmittance, with reductions scaling monotonically with UV dosage. To date the induction of a hyperchromic effect has been demonstrated using heat, pH, high salt mediums, and high energy ionising radiation. Both hyperchromicity and increased light scattering could account for the increased film optical density after UV irradiation. Additional characterisation of the films reveal they are highly absorbent and hygroscopic. When coated on human skin, they are capable of slowing water evaporation and keeping the tissue hydrated for extended periods of time.

Concepts: Ionizing radiation, Ultraviolet, Optics, Electromagnetic radiation, Optical fiber, Electromagnetic spectrum, Sunlight, Human skin color

84

Sunlight exposure, with resulting cutaneous synthesis, is a major source of vitamin D for many, while dietary intake is low in modern diets. The constitutive pigment in skin determines skin type, observed as white, brown, or black skin. The melanin pigment absorbs ultraviolet radiation (UVR) and protects underlying skin from damage caused by UVR. It also reduces the UVR available for vitamin D synthesis in the skin. It has been shown that the white-skinned population of the UK are able to meet their vitamin D needs with short, daily lunchtime exposures to sunlight. We have followed the same methodology, based on a 10-year UK all-weather UVR climatology, observation (sun exposure, diet, vitamin D status), and UVR intervention studies with Fitzpatrick skin type V (brown) adults, to determine whether sunlight at UK latitudes could provide an adequate source of vitamin D for this section of the population. Results show that to meet vitamin D requirements, skin type V individuals in the UK need ~25 min daily sunlight at lunchtime, from March to September. This makes several assumptions, including that forearms and lower legs are exposed June-August; only exposing hands and face at this time is inadequate. For practical and cultural reasons, enhanced oral intake of vitamin D should be considered for this population.

Concepts: Vitamin D, Ultraviolet, Sun, Sunlight, Skin, Melanin, Human skin color, Sunscreen