Understanding Mechanisms and Key Factors Influencing Melanogenesis for the Management of Melasma: An Updated Review.

Melanocytes are highly specialized dendritic cells that deliver melanin to keratinocytes in melanosomes, which are subcellular organelles where melanin is produced and stored. Mammal's skin, hair, and eyes all contain the complex pigment melanin, which gives them color and ultraviolet protection. Melanins have the potential to be free radical sinks and are strong cation chelators. Amino acid tyrosine and its metabolite, dopa, are the precursors to complex metabolic processes that end with melanin production. Melanocytes generate different types and amounts of melanin, which is defined genetically and is impacted by several extrinsic and intrinsic factors such as hormone fluctuations, inflammation, age, and ultraviolet radiation exposure, leading to the stimulation of numerous melanogenesis pathways. Melasma, a common skin pigmentation condition, is associated with the overproduction of melanin and is characterized by brown to gray-brown and black spots that mostly affect the face. The present review addresses the regulatory mechanisms and signaling pathways involved in skin pigmentation with an emphasis on the altered melanogenesis that causes melasma and hyperpigmentation. The current study also illustrates the available treatment options with cellular and molecular mechanisms for the management of melasma. Understanding the mechanism of the pigmentation process may help researchers develop new therapeutic strategies and novel drugs for the management of melasma.

Esophageal Melanocytosis.

Esophageal melanocytosis is a rare entity defined by the proliferation of a melanocytic basal layer of the esophageal squamous lining and deposition of melanin in the esophageal mucosa. Esophageal melanocytosis is considered a benign entity of unknown etiology; however, it has been reported as a melanoma precursor. We report a case of esophageal melanocytosis in a diabetic and hypertensive 67-year-old male with recurrent dizziness and syncope for the past 6 months. Given his complaint of dyspepsia, he underwent an upper gastrointestinal endoscopy, in which an esophageal biopsy revealed the diagnosis of esophageal melanocytosis. The definitive diagnosis of esophageal melanocytosis can only be made by histological analysis. The histologic differential diagnoses include melanocytic nevi and malignant melanoma. Therefore, they need to be ruled out.

Esophageal Melanocytosis

ABSTRACT Esophageal melanocytosis is a rare entity defined by the proliferation of a melanocytic basal layer of the esophageal squamous lining and deposition of melanin in the esophageal mucosa. Esophageal melanocytosis is considered a benign entity of unknown etiology; however, it has been reported as a melanoma precursor. We report a case of esophageal melanocytosis in a diabetic and hypertensive 67-year-old male with recurrent dizziness and syncope for the past 6 months. Given his complaint of dyspepsia, he underwent an upper gastrointestinal endoscopy, in which an esophageal biopsy revealed the diagnosis of esophageal melanocytosis. The definitive diagnosis of esophageal melanocytosis can only be made by histological analysis. The histologic differential diagnoses include melanocytic nevi and malignant melanoma. Therefore, they need to be ruled out.

Amyloid Fibers Increase Free Radicals of Synthetic Melanin.

Functional amyloid fibers are crucial in melanogenesis, but their roles are incompletely understood. In particular, their relationship with intrinsic spin characters of melanin remains unexplored. Here, we show that adding an amyloid scaffold greatly augments the spin density in synthetic melanin. It also brings about concurrent alterations in water dispersibility, bandgaps, and radical scavenging properties of the synthetic melanin, which facilitates its applications in solar water remediation and protection of human keratinocytes from UV irradiation. This work provides implications in the unrevealed role of functional amyloid in melanogenesis and in the origin of the superiority of natural melanin toward its synthetic variants in terms of the spin-related properties.

Genetic and Environmental Factors Influencing the Production of Select Fungal Colorants: Challenges and Opportunities in Industrial Applications.

Natural colorants, mostly of plant and fungal origins, offer advantages over chemically synthetic colorants in terms of alleviating environmental pollution and promoting human health. The market value of natural colorants has been increasing significantly across the globe. Due to the ease of artificially culturing most fungi in the laboratory and in industrial settings, fungi have emerged as the organisms of choice for producing many natural colorants. Indeed, there is a wide variety of colorful fungi and a diversity in the structure and bioactivity of fungal colorants. Such broad diversities have spurred significant research efforts in fungi to search for natural alternatives to synthetic colorants. Here, we review recent research on the genetic and environmental factors influencing the production of three major types of natural fungal colorants: carotenoids, melanins, and polyketide-derived colorants. We highlight how molecular genetic studies and environmental condition manipulations are helping to overcome some of the challenges associated with value-added and large-scale productions of these colorants. We finish by discussing potential future trends, including synthetic biology approaches, in the commercial production of fungal colorants.

Multiphoton FLIM Analyses of Native and UVA-Modified Synthetic Melanins.

To better understand the impact of solar light exposure on human skin, the chemical characterization of native melanins and their structural photo-modifications is of central interest. As the methods used today are invasive, we investigated the possibility of using multiphoton fluorescence lifetime (FLIM) imaging, along with phasor and bi-exponential fitting analyses, as a non-invasive alternative method for the chemical analysis of native and UVA-exposed melanins. We demonstrated that multiphoton FLIM allows the discrimination between native DHI, DHICA, Dopa eumelanins, pheomelanin, and mixed eu-/pheo-melanin polymers. We exposed melanin samples to high UVA doses to maximize their structural modifications. The UVA-induced oxidative, photo-degradation, and crosslinking changes were evidenced via an increase in fluorescence lifetimes along with a decrease in their relative contributions. Moreover, we introduced a new phasor parameter of a relative fraction of a UVA-modified species and provided evidence for its sensitivity in assessing the UVA effects. Globally, the fluorescence lifetime properties were modulated in a melanin-dependent and UVA dose-dependent manner, with the strongest modifications being observed for DHICA eumelanin and the weakest for pheomelanin. Multiphoton FLIM phasor and bi-exponential analyses hold promising perspectives for in vivo human skin mixed melanins characterization under UVA or other sunlight exposure conditions.

A Model Eumelanin from 5,6-Dihydroxyindole-2-Carboxybutanamide Combining Remarkable Antioxidant and Photoprotective Properties with a Favourable Solubility Profile for Dermo-Cosmetic Applications.

The search for new synthetic melanin-related pigments that maintain the antioxidant and photoprotective properties of naturally occurring dark eumelanins, while overcoming their unfavorable solubility, and molecular heterogeneity is presently a very active issue for dermo-cosmetic purposes. In this work, we explored the potential of a melanin obtained from the carboxybutanamide of a major eumelanin biosynthetic precursor, 5,6-dihydroxyindole-2-carboxylic acid (DHICA), by aerobic oxidation under slightly alkaline conditions. Analysis of the pigment by EPR, ATR-FTIR and MALDI MS indicated a substantial structural similarity to DHICA melanin, while investigation of the early intermediates confirmed unchanged regiochemistry of the oxidative coupling. The pigment exhibited a UVA-visible absorption even more intense than that of DHICA melanin, and a noticeable solubility in polar solvents of dermo-cosmetic relevance. The hydrogen- and/or electron-donor ability, and the iron (III) reducing power as determined by conventional assays provided evidence for marked antioxidant properties not merely ascribable to the more favorable solubility profile, while the inhibitory action of the radical- or photosensitized solar light-induced lipid peroxidation was more marked compared to that of DHICA melanin. Overall, these results hint at this melanin, which remarkable properties are, in part, due to the electronic effects of the carboxyamide functionality as a promising functional ingredient for dermo-cosmetic formulations.

A Comprehensive Review of Mammalian Pigmentation: Paving the Way for Innovative Hair Colour-Changing Cosmetics.

The natural colour of hair shafts is formed at the bulb of hair follicles, and it is coupled to the hair growth cycle. Three critical processes must happen for efficient pigmentation: (1) melanosome biogenesis in neural crest-derived melanocytes, (2) the biochemical synthesis of melanins (melanogenesis) inside melanosomes, and (3) the transfer of melanin granules to surrounding pre-cortical keratinocytes for their incorporation into nascent hair fibres. All these steps are under complex genetic control. The array of natural hair colour shades are ascribed to polymorphisms in several pigmentary genes. A myriad of factors acting via autocrine, paracrine, and endocrine mechanisms also contributes for hair colour diversity. Given the enormous social and cosmetic importance attributed to hair colour, hair dyeing is today a common practice. Nonetheless, the adverse effects of the long-term usage of such cosmetic procedures demand the development of new methods for colour change. In this context, case reports of hair lightening, darkening and repigmentation as a side-effect of the therapeutic usage of many drugs substantiate the possibility to tune hair colour by interfering with the biology of follicular pigmentary units. By scrutinizing mammalian pigmentation, this review pinpoints key targetable processes for the development of innovative cosmetics that can safely change the hair colour from the inside out.

[Anatomical and functional differences of the skin in various ethnic groups]. / Anatomische und funktionelle Unterschiede der Haut verschiedener Ethnien.

Besides the differences in skin and hair color among different ethnic groups, morphological and functional differences in skin and hair have also been demonstrated. The color of skin and hair is determined by two types of melanin, eumelanin (brown to black pigment) and phaeomelanin (red to yellow pigment). In addition to the individual mixture of these pigment types, there are also differences in the melanosome arrangement of Caucasian, Asian, and African skin. Although the epidermis thickness is the same in all people, darker skin has a higher number of stratum corneum layers and a thicker dermis with a higher number of fibroblasts. The hairs of different ethnic groups also vary regarding shape and thickness: they are round in Asians, elliptical in Blacks and intermediate in Whites. Hair diameter is the greatest in Asians, followed by Blacks and is the smallest in Whites, whereas the number of hairs is highest in Whites, followed by that in Asians and Blacks.

Neuromelanins in brain aging and Parkinson's disease: synthesis, structure, neuroinflammatory, and neurodegenerative role.

Neuromelanins are compounds accumulating in neurons of human and animal brain during aging, with neurons of substantia nigra and locus coeruleus having the highest levels of neuromelanins. These compounds have melanic, lipid, peptide, and inorganic components and are contained inside special autolysosomes. Neuromelanins can participate in neuroprotective or toxic processes occurring in Parkinson's disease according to cellular environment. Their synthesis depends on the concentration of cytosolic catechols and is a protective process since it prevents the toxic accumulation of catechols-derived reactive compounds. Neuromelanins can be neuroprotective also by binding reactive/toxic metals to produce stable and non-toxic complexes. Extraneuronal neuromelanin released by dying dopamine neurons in Parkinson's disease activates microglia which generate reactive oxygen species, reactive nitrogen species, and proinflammatory molecules, thus producing still neuroinflammation and neuronal death. Synthetic neuromelanins have been prepared with melanic, protein structure, and metal content closely mimicking the natural brain pigment, and these models are also able to activate microglia. Neuromelanins have different structure, synthesis, cellular/subcellular distribution, and role than melanins of hair, skin, and other tissues. The main common aspect between brain neuromelanin and peripheral melanin is the presence of eumelanin and/or pheomelanin moieties in their structure.

Highlighting nuances of blue light phototherapy: Mechanisms and safety considerations.

The efficacy of blue light therapy in dermatology relies on numerous clinical studies. The safety remains a topic of controversy, where potentially deleterious effects were derived from in vitro rather than in vivo experiments. The objectives of this work were (1) to highlight the nuances behind "colors" of blue light, light propagation in tissue and the plurality of modes of action; and (2) to rigorously analyze studies on humans reporting both clinical and histological data from skin biopsies with focus on DNA damage, proliferation, apoptosis, oxidative stress, impact on collagen, elastin, immune cells, and pigmentation. We conclude that blue light therapy is safe for human skin. It induces intriguing skin pigmentation, in part mediated by photoreceptor Opsin-3, which might have a photoprotective effect against ultraviolet irradiation. Future research needs to unravel photochemical reactions and the most effective and safe parameters of blue light in dermatology.

Comparative Evaluation of Clinical Efficacy of Diode LASER and Cryosurgery for Gingival Pigmentation: A Split-Mouth Randomized Clinical Study

ABSTRACT Objective: To compare and evaluate the clinical efficacy of diode laser and cryosurgery for treating melanin pigmentation of gingiva. Material and Methods: A total of twenty-five subjects with physiological gingival pigmentation on the facial aspect of both maxillary and mandibular anterior arches (50 sites), both male and female, with an average age ranging from 18-35 years, participated in the study. The sites were randomly divided into Group I: depigmentation by Laser and Group II: depigmentation by Cryosurgery. The following parameters were assessed for the evaluation of treatment results: Melanin Oral Pigmentation Index (PI), Visual Analogue Scale (VAS) for pain evaluation and Healing index (HI). The data collected was statistically evaluated. Results: On intergroup comparison, there was no statistical difference in the score from baseline (p>0.05); however, a statistically significant difference was seen at the end of 1 year (p<0.05). Moreover, 57-60% of arches showed recurrence of pigmentation in the laser group whereas; only 12.7-17% recurrence was seen in the cryosurgery group at the end of the first year. Conclusion: Treatment of gingival hyperpigmentation with laser and cryosurgery shows a marked improvement of gingival pigmentation in both groups, but the cryosurgery depigmentation sites showed more sustainability.

Hyperpigmentation Inhibits Early Skeletal Muscle Development in Tengchong Snow Chicken Breed.

Tengchong snow, which has white feathers and black meat, is one of the most important black-bone chicken breeds and a genetic treasure of black food in China. Although the black meat traits are dominant, there are some chickens with white meat traits born in the process of folk selection and breeding. The purpose of this study was to compare the differences in skeletal muscle development between Tengchong snow black meat chickens (BS) and white meat chickens (WS), as well as whether excessive melanin deposition has an effect on skeletal muscle development. The BS and WS groups were selected to determine their muscle development difference at stages of 1, 7, 14, 21, and 42 days, using histological stain methods to analyze the development and composing type of breast and leg muscle fibers, as well as the count of melanin in BS muscle fibers. Finally, we were validated key candidate genes associated with muscle development and melanin synthesis. The results showed that BS breast muscle development was inhibited at 7, 14, and 21 days, while the leg muscle was inhibited at 7, 14, 21, and 42 days, compared to WS. Melanin deposition was present in a temporal migration pattern and was greater in the leg muscles than in the breast muscles, and it focused around blood vessels, as well as the epithelium, perimysium, endomysium, and connective tissue. Additionally, melanin produced an inhibitory effect similar to MSTN during skeletal muscle fiber development, and the inhibition was strongest at the stage of melanin entry between muscle fibers, but the precise mechanisms need to be confirmed. This study revealed that melanin has an inhibitory effect on the early development of skeletal muscle, which will provide new insights into the role of melanin in the black-boned chicken and theoretical references for the future conservation and utilization of black-boned chicken.

The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal Dystrophy

RPE65, an abundant membrane-associated protein present in the retinal pigment epithelium (RPE), is a vital retinoid isomerase necessary for regenerating 11-cis-retinaldehyde from all-trans retinol in the visual cycle. In patients with inherited retinal dystrophy (IRD), precise genetic diagnosis is an indispensable approach as it is required to establish eligibility for the genetic treatment of RPE65-associated IRDs. This case report aims to report the specific phenotype−genotype correlation of the first patient with a homozygous missense variant RPE65 c.499G>T, p. (Asp167Tyr). We report a case of a 66-year-old male who demonstrated a unique phenotype manifesting less severe functional vision deterioration in childhood and adolescence, and extensive nummular pigment clusters. The underlying causes of the differences in the typical bone spicule and atypical nummular pigment clumping are unknown, but suggest that the variant itself influenced the rate of photoreceptor death. Functional studies are needed to define whether the substitution of aspartate impairs the folding of the tertiary RPE65 structure only and does not lead to the complete abolishment of chromophore production, thus explaining the less severe phenotype in adolescence.

Melanins from the Lichens Lobaria pulmonaria and Lobaria retigera as Eco-Friendly Adsorbents of Synthetic Dyes.

Synthetic dyes are widely used in the industry; they are chemically stable, difficult to neutralize, and therefore they are a threat to the environment when released into wastewaters. The dyes have a significant impact on plant performance by impairing photosynthesis, inhibiting growth, and entering the food chain and may finally result in the toxicity, mutagenicity and carcinogenicity of food products. Implementation of the dark piment melanin for the adsorption of the synthetic dyes is a new ecologically friendly approach for bioremediation. The aim of the present work was to study the physico-chemical characteristics of melanins from the lichens Lobaria pulmonaria and Lobaria retigera, analyze their adsorption/desorption capacities towards synthetic dyes, and assess the capacity of melanins to mitigate toxicity of the dyes for a common soil bacterium Bacillus subtilis. Unique chelating properties of melanins determine the perspectives of the use of these high molecular weight polymers for detoxification of xenobiotics.

Melanisation in Boreal Lichens Is Accompanied by Variable Changes in Non-Photochemical Quenching.

Lichens often grow in microhabitats where they absorb more light than they can use for fixing carbon, and this excess energy can cause the formation of harmful reactive oxygen species (ROS). Lichen mycobionts can reduce ROS formation by synthesizing light-screening pigments such as melanins in the upper cortex, while the photobionts can dissipate excess energy radiationlessly using non-photochemical quenching (NPQ). An inherent problem with using fluorimetry techniques to compare NPQ in pale and melanised thalli is that NPQ is normally measured through a variously pigmented upper cortex. Here we used a dissection technique to remove the lower cortices and medullas of Lobaria pulmonaria and Crocodia aurata and then measure NPQ from the underside of the thallus. Results confirmed that NPQ can be satisfactorily assessed with a standard fluorimeter by taking measurement from above using intact thalli. However, photobionts from the bottom of the photobiont layer tend to have slightly lower rates of PSII activity and lower NPQ than those at the top, i.e., display mild "shade" characteristics. Analysis of pale and melanised thalli of other species indicates that NPQ in melanised thalli can be higher, similar or lower than pale thalli, probably depending on the light history of the microhabitat and presence of other tolerance mechanisms.

Effect of Melanization on Thallus Microstructure in the Lichen Lobaria pulmonaria.

Lichens often grow in microhabitats where they experience severe abiotic stresses. Some species respond to high UV radiation by synthesizing dark brown melanic pigments in the upper cortex. However, unlike the melanized structures of non-lichenized fungi, the morphology of the melanic layer in lichens remains unstudied. Here, we analyzed the morphology, ultrastructure, and elemental composition of the melanized layer in UV-exposed thalli of the lichen Lobaria pulmonaria (L.) Hoffm. Using light microscopy, we detected a pigmented layer sensitive to staining with 3,4-L-dihydroxyphenylalanine, a precursor of eumelanin, in the upper cortex of melanized thalli. Analysis of cross-sections of melanized thalli using scanning electron microscopy revealed that melanin-like granules are deposited into the hyphal lumens. Melanized thalli also possessed thicker hyphal cell walls compared to pale thalli. Energy-dispersive X-ray spectroscopy analysis of the elemental composition of the hyphal walls and extracted melanin indicated that the type of melanin synthesized by L. pulmonaria is eumelanin. Transmission electron microscopy was used to show that during melanization melanosome-like dark vesicles are transported to the cell surface and secreted into the cell walls of the fungal hyphae. Results from this study provide new insights into the effects of melanin synthesis on the microstructure of lichen thalli.

A Straightforward Access to New Amides of the Melanin Precursor 5,6-Dihydroxyindole-2-carboxylic Acid and Characterization of the Properties of the Pigments Thereof.

We report herein an optimized procedure for preparation of carboxamides of 5,6-dihydroxyindole-2-carboxylic acid (DHICA), the main biosynthetic precursor of the skin photoprotective agents melanins, to get access to pigments with more favorable solubility properties with respect to the natural ones. The developed procedure was based on the use of a coupling agent (HATU/DIPEA) and required protection of the catechol function by easily removable acetyl groups. The O-acetylated compounds could be safely stored and taken to the reactive o-diphenol form just before use. Satisfactorily high yields (>85%) were obtained for all amides. The oxidative polymerization of the synthesized amides carried out in air in aqueous buffer at pH 9 afforded melanin-like pigmented materials that showed chromophores resembling those of DHICA-derived pigments, with a good covering of the UVA and the visible region, and additionally exhibited a good solubility in alcoholic solvents, a feature of great interest for the exploitation of these materials as ingredients of dermocosmetic formulations.