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Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.

Photoreactivity of melanin has become a major focus of research due to the postulated involvement of the pigment in UVA-induced melanoma. However, most of the hitherto studies were carried out using synthetic melanin models. Thus, photoreactivity of natural melanins is yet to be systematically analyzed. Here, we examined the photoreactive properties of natural melanins isolated from hair samples obtained from donors of different skin phototypes (I, II, III, and V). X-band and W-band electron paramagnetic resonance (EPR) spectroscopy was used to examine the paramagnetic properties of the pigments. Alkaline hydrogen peroxide degradation and hydroiodic acid hydrolysis were used to determine the chemical composition of the melanins. EPR oximetry and spin trapping were used to examine the oxygen photoconsumption and photo-induced formation of superoxide anion, and time-resolved near infrared phosphorescence was employed to determine the singlet oxygen photogeneration by the melanins. The efficiency of superoxide and singlet oxygen photogeneration was related to the chemical composition of the studied melanins. Melanins from blond and chestnut hair (phototypes II and III) exhibited highest photoreactivity of all examined pigments. Moreover, melanins of these phototypes showed highest quantum efficiency of singlet oxygen photogeneration at 332 nm and 365 nm supporting the postulate of the pigment contribution in UVA-induced melanoma.

Melanin is a unique pigment with myriad functions that is found in all biological kingdoms. It is multifunctional, providing defense against environmental stresses such as ultraviolet (UV) light, oxidizing agents and ionizing radiation. Melanin contributes to the ability of fungi to survive in harsh environments. In addition, it plays a role in fungal pathogenesis. Melanin is an amorphous polymer that is produced by one of two synthetic pathways. Fungi may synthesize melanin from endogenous substrate via a 1,8-dihydroxynaphthalene (DHN) intermediate. Alternatively, some fungi produce melanin from l-3,4-dihydroxyphenylalanine (l-dopa). The detailed chemical structure of melanin is not known. However, microscopic studies show that it has an overall granular structure. In fungi, melanin granules are localized to the cell wall where they are likely cross-linked to polysaccharides. Recent studies suggest the fungal melanin may be synthesized in internal vesicles akin to mammalian melanosomes and transported to the cell wall. Potential applications of melanin take advantage of melanin's radioprotective properties and propensity to bind to a variety of substances. [PUBLICATION ABSTRACT]

The neural mechanisms underlying memory regulation during sleep are not yet fully understood.We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs.Wake- and REM sleep–active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

Direct sun exposure is one of the most aggressive factors for human skin. Sun radiation contains a range of the electromagnetic spectrum including UV light. In addition to the stratospheric ozone layer filtering the most harmful UVC, human skin contains a photoprotective pigment called melanin to protect from UVB, UVA, and blue visible light. This pigment is a redox UV-absorbing agent and functions as a shield to prevent direct UV action on the DNA of epidermal cells. In addition, melanin indirectly scavenges reactive oxygenated species (ROS) formed during the UV-inducing oxidative stress on the skin. The amounts of melanin in the skin depend on the phototype. In most phenotypes, endogenous melanin is not enough for full protection, especially in the summertime. Thus, photoprotective molecules should be added to commercial sunscreens. These molecules should show UV-absorbing capacity to complement the intrinsic photoprotection of the cutaneous natural pigment. This review deals with (a) the use of exogenous melanin or melanin-related compounds to mimic endogenous melanin and (b) the use of a number of natural compounds from plants and marine organisms that can act as UV filters and ROS scavengers. These agents have antioxidant properties, but this feature usually is associated to skin-lightening action. In contrast, good photoprotectors would be able to enhance natural cutaneous pigmentation. This review examines flavonoids, one of the main groups of these agents, as well as new promising compounds with other chemical structures recently obtained from marine organisms.

Melanized fungi are known for their remarkable resilience to environmental stress, largely attributed to the protective properties of melanin. In this study, we establish the black yeast Exophiala viscosa as a non-pathogenic, genetically tractable model for the scalable production and functional analysis of DHN-melanin (allomelanin). Cultivation in flasks and bioreactors yielded up to 8.6 g/L of melanin, with the majority tightly incorporated into the cell wall as “melanin ghosts”. Chemical analyses including FTIR, XPS, ssNMR, and EPR confirmed the identity of the pigment as allomelanin and revealed a structural association with chitin. Gene deletions of Pks1, Arp2, and Abr2 validated the DHN-melanin biosynthetic pathway and enabled the generation of pigment-deficient mutants. Functional assays demonstrated that melanin contributes significantly to UV and cold tolerance, while offering limited protection against γ-radiation, suggesting that other pigments,such as carotenoids, may also play a protective role. The unique redox properties, structural integrity, and scalability of melanin production in E. viscosa highlight its potential for bio-derived materials used in radiation shielding, environmental remediation, and thermal regulation. This work establishes E. viscosa as a promising chassis for melanin biomanufacturing and a valuable model for studying fungal melanins in the context of materials science and environmental resilience. Key points • Cultivation of E. viscosa in rich medium yielded up to 8.6 g/L of melanin. • Chemical and genetic analyses identified the pigment as allomelanin. • Melanin enhanced the tolerance of fungal cells to UV radiation and low temperatures.

Fungal melanins have remarkable bioactivities, but their practical applications are limited, partly due to their hydrophobic nature. Melanin modification with amino acids was reported to improve their water solubility. This research aimed to extract, and modify the melanins from Calvatia craniiformis and Xylaria plebeja with arginine, and to evaluate their neuroprotective effects against Parkinsonian toxins. MTT assay showed that all melanins and melanin derivatives could protect SH-SY5Y neuroblastoma cells from 1 mM H2O2. Xylaria plebeja melanin and melanin derivative at 100 µg/mL increased the cell viability about 16.0% compared to the negative control, whereas C. craniiformis melanin and its modified form enhanced the cell viability by 18.4% and 8.3%, respectively and that of the positive control (20 µM resveratrol) was 35.5%. Regarding neuroprotective effects against MPTP, the positive control, C. craniiformis melanin, and modified melanin increased the cell viability with approximately 5.0%, but that of X. plebeja melanin and modified melanin were 13.0%. Both melanins and melanin derivatives from C. craniiformis and X. plebeja showed significant neuroprotective effects against H2O2. However, only X. plebeja melanin and modified melanin displayed significant neuroprotective effects against MPTP and therefore they would be potential materials for follow-up research in Parkinson’s disease prevention.

Skin color varies among human populations and is thought to be under selection, with light skin maximizing vitamin D production at higher latitudes and dark skin providing UV protection in equatorial zones. To identify the genes that give rise to the palette of human skin tones, Crawford et al. applied genome-wide analyses across diverse African populations (see the Perspective by Tang and Barsh). Genetic variants were identified with likely function in skin phenotypes. Comparison to model organisms verified a conserved function of MFSD12 in pigmentation. A global genetic panel was used to trace how alleles associated with skin color likely moved across the globe as humans migrated, both within and out of Africa. Science , this issue p. eaan8433 ; see also p. 867 Genome-wide analysis of 2000 Africans identifies and functionally characterizes pigmentation loci. Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5 , MFSD12 , DDB1 , TMEM138 , OCA2 , and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians.

Melanin is a dark colored pigment produced by various living organisms. In this study, the melanin-producing fungus was isolated from a washing machine and identified as Scolecobasidium musae by 18 S rDNA analysis. Melanin production by S. musae was reported for the first time. Melanin was obtained from the dark-colored biomass produced by S. musae in submerged culture. The pigment was then purified, characterized, and identified. It was determined that purified melanin was dissolved easily in alkaline solutions but insoluble in organic solvents. Devices such as UV-Vis spectroscopy, XRD, FTIR, NMR, EPR, and elemental analysis were used to determine the chemical content and structure of the produced melanin. The melanin synthesis pathway was investigated using melanin inhibitors and by performing LC-MS analysis of the fermentation medium in which S. musae grew. It was found that the newly produced melanin from S. musae possesses antioxidant and photoprotective properties (sun protection and UV protection for Staphylococcus aureus ). These results provide new possibilities for the biotechnological applications of this naturally producing melanin pigment. Graphical Abstract

Slow-wave sleep and rapid eye movement (or paradoxical) sleep have been found in mammals, birds and lizards, but it is unclear whether these neuronal signatures are found in non-amniotic vertebrates. Here we develop non-invasive fluorescence-based polysomnography for zebrafish, and show—using unbiased, brain-wide activity recording coupled with assessment of eye movement, muscle dynamics and heart rate—that there are at least two major sleep signatures in zebrafish. These signatures, which we term slow bursting sleep and propagating wave sleep, share commonalities with those of slow-wave sleep and paradoxical or rapid eye movement sleep, respectively. Further, we find that melanin-concentrating hormone signalling (which is involved in mammalian sleep) also regulates propagating wave sleep signatures and the overall amount of sleep in zebrafish, probably via activation of ependymal cells. These observations suggest that common neural signatures of sleep may have emerged in the vertebrate brain over 450 million years ago. Fluorescence-based polysomnography in zebrafish reveals two major sleep signatures that share features with those of amniotes, which suggests that common neural sleep signatures emerged in the vertebrate brain over 450 million years ago.