RESUMEN
The visual appearance of humans is derived significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly on the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). The localization of a second 'immature' SOX10 negative melanocyte population, which was c-KIT/MITF double-positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. This study describes an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells ultimately destined to synthesize melanin, or could they contribute to the hair follicle in non-melanogenic ways?
Asunto(s)
Folículo Piloso , Melaninas , Humanos , Cuero Cabelludo , Rayos Ultravioleta , Cabello , MelanocitosRESUMEN
Melanin is synthesised within melanocytes and transferred to keratinocytes in human skin, thereby regulating skin colour and protecting skin cells against UVR-induced damage. We commonly divide human skin into six phototypes (SPT)-I to -VI (Fitzpatrick scale) according to the skin's tanning response to UVR. In this pilot study, we investigated the impact of UVR (maximum 311nm), blue (peak 450nm) and green visible light (peak 530nm) on melanin production and type in healthy human skin histocultures (SPT-I, -II and -III). UVR, blue and green light stimulated a surface tanning response in SPT-II and -III, but not SPT-I. Using the Warthin-Starry stain for sensitive melanin detection, all three light treatments induced melanogenesis in SPT-II and -III skin. Surprisingly, blue and green light (but not UVR) stimulated melanin synthesis in SPT-I skin. Moreover, melanin synthesis induced by blue and green visible light in SPT-I, SPT-II, and SPT-III skin was not associated with a detectable increase in DNA damage or cell apoptosis. By contrast, both responses were detected after UVR. These data suggest that blue and green visible light can stimulate melanin production in fair-skinned individuals without, at least some of, the harmful consequences of UVR-induced pigmentation. We are currently examining the molecular basis of UVR-independent melanogenesis in fair skin.
Asunto(s)
Daño del ADN , Luz , Melaninas/metabolismo , Pigmentación de la Piel , Rayos Ultravioleta , Apoptosis , Voluntarios Sanos , Humanos , Proyectos PilotoRESUMEN
The innate immune system of human skin consists of a multi-layered barrier consisting of cells and soluble effector molecules charged with maintaining homeostasis and responding to insults and infections. It has become increasingly clear that these barrier layers become compromised in skin diseases, especially in disorders of an (auto)inflammatory nature. In the case of hidradenitis suppurativa, great strides have been made in recent years in characterizing the underlying breakdown in homeostatic innate immunity, including an increasing understanding of the central role of the hair follicle in this process. This breakdown appears to occur at multiple levels: the pilosebaceous unit, associated epithelium, the cutaneous microbiome, alteration of immune cell function and local molecular events such as complement activation. This review seeks to summarize, contextualize and analyse critically our current understanding of how these innate immune barriers become dysregulated in the early stage(s) of hidradenitis suppurativa, and to speculate on where potential hidradenitis suppurativa research could be most fruitful.
Asunto(s)
Hidradenitis Supurativa/inmunología , Inmunidad Innata/inmunología , Microbiota/inmunología , Péptidos Antimicrobianos/inmunología , HumanosRESUMEN
Melanin granules cluster within supra-nuclear caps in basal keratinocytes (KCs) of the human epidermis, where they protect KC genomic DNA against ultraviolet radiation (UVR) damage. While much is known about melanogenesis in melanocytes (MCs) and a moderate amount about melanin transfer from MC to KC, we know little about the fate of melanin once inside KCs. We recently reported that melanin fate in progenitor KCs is regulated by rare asymmetric organelle movement during mitosis. Here, we explore the role of actin, microtubules, and centrosome-associated machinery in distributing melanin within KCs. Short-term cultures of human skin explants were treated with cytochalasin-B and nocodazole to target actin filaments and microtubules, respectively. Treatment effects on melanin distribution were assessed by the Warthin-Starry stain, on centrosome-associated proteins by immunofluorescence microscopy, and on co-localisation with melanin granules by brightfield microscopy. Cytochalasin-B treatment disassembled supra-nuclear melanin caps, while nocodazole treatment moved melanin from the apical to basal KC domain. Centrosome and centriolar satellite-associated proteins showed a high degree of co-localisation with melanin. Thus, once melanin granules are transferred to KCs, their preferred apical distribution appears to be facilitated by coordinated movement of centrosomes and centriolar satellites. This mechanism may control melanin's strategic position within UVR-exposed KCs.
Asunto(s)
Melaninas/metabolismo , Piel/metabolismo , Actinas/metabolismo , Biomarcadores , Polaridad Celular , Células Cultivadas , Centrosoma/metabolismo , Gránulos Citoplasmáticos/metabolismo , Citoesqueleto/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Hibridación in Situ , Queratinocitos/metabolismo , Melanocitos/metabolismo , FenotipoRESUMEN
Tryptophan hydroxylase (TPH) activity was detected in cultured epidermal melanocytes and dermal fibroblasts with respective Km of 5.08 and 2.83 mM and Vmax of 80.5 and 108.0 µmol/min. Low but detectable TPH activity was also seen in cultured epidermal keratinocytes. Serotonin and/or its metabolite and precursor to melatonin, N-acetylserotonin (NAS), were identified by LC/MS in human epidermis and serum. Endogenous epidermal levels were 113.18 ± 13.34 and 43.41 ± 12.45 ng/mg protein for serotonin (n = 8/8) and NAS (n = 10/13), respectively. Their production was independent of race, gender, and age. NAS was also detected in human serum (n = 13/13) at a concentration 2.44 ± 0.45 ng/mL, while corresponding serotonin levels were 295.33 ± 17.17 ng/mL (n = 13/13). While there were no differences in serum serotonin levels, serum NAS levels were slightly higher in females. Immunocytochemistry studies showed localization of serotonin to epidermal and follicular keratinocytes, eccrine glands, mast cells, and dermal fibrocytes. Endogenous production of serotonin in cultured melanocytes, keratinocytes, and dermal fibroblasts was modulated by UVB. In conclusion, serotonin and NAS are produced endogenously in the epidermal, dermal, and adnexal compartments of human skin and in cultured skin cells. NAS is also detectable in human serum. Both serotonin and NAS inhibited melanogenesis in human melanotic melanoma at concentrations of 10-4 -10-3 M. They also inhibited growth of melanocytes. Melanoma cells were resistant to NAS inhibition, while serotonin inhibited cell growth only at 10-3 M. In summary, we characterized a serotonin-NAS system in human skin that is a part of local neuroendocrine system regulating skin homeostasis.
Asunto(s)
Epidermis/metabolismo , Fibroblastos/metabolismo , Queratinocitos/metabolismo , Melatonina/metabolismo , Serotonina/análogos & derivados , Envejecimiento de la Piel , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Serotonina/metabolismoRESUMEN
Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs ( e.g., beard). Follicle response is epigenetically varied: some remain unaffected ( e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.
Asunto(s)
Andrógenos/farmacología , Epigénesis Genética/efectos de los fármacos , Folículo Piloso/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto , Andrógenos/metabolismo , Femenino , Folículo Piloso/citología , Humanos , Técnicas de Cultivo de ÓrganosRESUMEN
Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20- to 60-fold) between white and black populations are largely attributable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color-based differences in KC incidence. Along with melanin quantity, solar-simulated radiation-induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0-fold in the overall epidermis and by 59.0-, 16.5-, and 5.0-fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer of black skin. These results may explain, at least in part, the considerable skin color differences in KC incidence. These data suggest that a DNA protection factor of at least 60 is necessary in sunscreens to reduce white skin KC incidence to a level that is comparable with that of black skin.-Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., Young, A. R. Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes.
Asunto(s)
Daño del ADN , Epidermis/efectos de la radiación , Melaninas/metabolismo , Dímeros de Pirimidina/efectos de la radiación , Neoplasias Cutáneas/epidemiología , Pigmentación de la Piel , Adulto , Población Negra , Epidermis/metabolismo , Humanos , Melaninas/genética , Neoplasias Cutáneas/etnología , Neoplasias Cutáneas/genética , Luz Solar/efectos adversos , Población BlancaRESUMEN
BACKGROUND OBJECTIVES: The past decade has witnessed a rapid expansion of photobiomodulation (PBM), demonstrating encouraging results for the treatment of cutaneous disorders. Confidence in this approach, however, is impaired not only by a lack of understanding of the light-triggered molecular cascades but also by the significant inconsistency in published experimental outcomes, design of the studies and applied optical parameters. This study aimed at characterizing the response of human dermal fibroblast subpopulations to visible and near-infrared (NIR) light in an attempt to identify the optical treatment parameters with high potential to address deficits in aging skin and non-healing chronic wounds. MATERIALS AND METHODS: Primary human reticular and papillary dermal fibroblasts (DF) were isolated from the surplus of post-surgery human facial skin. An in-house developed LED-based device was used to irradiate cell cultures using six discrete wavelengths (450, 490, 550, 590, 650, and 850 nm). Light dose-response at a standard oxygen concentration (20%) at all six wavelengths was evaluated in terms of cell metabolic activity. This was followed by an analysis of the transcriptome and procollagen I production at a protein level, where cells were cultured in conditions closer to in vivo at 2% environmental oxygen and 2% serum. Furthermore, the production of reactive oxygen species (ROS) was accessed using real-time fluorescence confocal microscopy imaging. Here, production of ROS in the presence or absence of antioxidants, as well as the cellular localization of ROS, was evaluated. RESULTS: In terms of metabolic activity, consecutive irradiation with short-wavelength light (â530 nm) exerted an inhibitory effect on DF, while longer wavelengths (>=590 nm) had essentially a neutral effect. Cell behavior following treatment with 450 nm was biphasic with two distinct states: inhibitory at low- to mid- dose levels (<=30 J/cm2 ), and cytotoxic at higher dose levels (>30 J/cm2 ). Cell response to blue light was accompanied by a dose-dependent release of ROS that was localized in the perinuclear area close to mitochondria, which was attenuated by an antioxidant. Overall, reticular DFs exhibited a greater sensitivity to light treatment at the level of gene expression than did papillary DFs, with more genes significantly up- or down- regulated. At the intra-cellular signaling pathway level, the up- or down- regulation of vital pathways was observed only for reticular DF, after treatment with 30 J/cm2 of blue light. At the cellular level, short visible wavelengths exerted a greater inhibitory effect on reticular DF. Several genes involved in the TGF-ß signaling pathway were also affected. In addition, procollagen I production was inhibited. By contrast, 850 nm near-infrared (NIR) light (20 J/cm2 ) exerted a stimulatory metabolic effect in these cells, with no detectable intracellular ROS formation. Here too, reticular DF were more responsive than papillary DF. This stimulatory effect was only observed under in vivo-like low oxygen conditions, corresponding to normal dermal tissue oxygen levels (approximately 2%). CONCLUSION: This study highlights a differential impact of light on human skin cells with upregulation of metabolic activity with NIR light, and inhibition of pro-collagen production and proliferation in response to blue light. These findings open-up new avenues for developing therapies for different cutaneous conditions (e.g., treatment of keloids and fibrosis) or differential therapy at distinct stages of wound healing. Lasers Surg. Med. 50:859-882, 2018. © 2018 Wiley Periodicals, Inc.
Asunto(s)
Fibroblastos/efectos de la radiación , Rayos Infrarrojos , Terapia por Luz de Baja Intensidad , Enfermedades de la Piel/radioterapia , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de la radiación , Fibroblastos/fisiología , Humanos , Dosis de RadiaciónRESUMEN
Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.
Asunto(s)
Citosina/metabolismo , Metilación de ADN , Genoma Humano , Inuk/genética , Nucleosomas/genética , Animales , Mapeo Cromosómico , Epigénesis Genética , Epigenómica , Evolución Molecular , Expresión Génica , Regulación de la Expresión Génica , Humanos , Filogenia , Regiones Promotoras Genéticas , Análisis de Secuencia de ADNRESUMEN
Skin pigmentation is directed by epidermal melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously, we reported that MC:KC contact is required for melanosome transfer that can be enhanced by filopodi, and by UVR/UVA irradiation, which can upregulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca2+ -dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca2+ , while ultraviolet radiation (UVR) raises intra-MC Ca2+ via calcium-selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear. Here we evaluated the role of E-cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-cadherin, Cdc42, VASP and ß-catenin, all of which were upregulated by UVR in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased ß-catenin, Cdc42, Myosin X and E-cadherin expression in these skin cells. Together, these data suggest that filopodial proteins and E-cadherin, which are upregulated by intracellular (UVR-stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation.
Asunto(s)
Cadherinas/metabolismo , Calcio/farmacología , Melaninas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/efectos de la radiación , Rayos Ultravioleta , Adulto , Cadherinas/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Células Epidérmicas , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Uniones Intercelulares , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Sistema de Señalización de MAP Quinasas , Masculino , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanocitos/efectos de la radiación , Melanosomas/metabolismo , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Miosinas/metabolismo , Fosfoproteínas/metabolismo , Seudópodos/efectos de los fármacos , Seudópodos/metabolismo , Seudópodos/efectos de la radiación , ARN Interferente Pequeño , Regulación hacia Arriba/efectos de la radiación , beta Catenina/metabolismo , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Cutaneous science has seen considerable development in the last 25 years, in part due to the Omics revolution, and the appreciation that this organ is hardwired into the body's key neuro-immuno-endocrine axes. Moreover, there is greater appreciation of how stratification of skin disorders will permit more targeted and more effective treatments. Against this has been how the remarkable extension in the average human life-span, though in the West at least, this parallels worrying increases in lifestyle-associated conditions like diabetes, skin cancer etc. These demographic trends bring greater urgency to finding clinical solutions for numerous age-related deficits in skin function caused by extrinsic and intrinsic factors. Mechanisms for aging skin include the actions of reactive oxygen species (ROS), mtDNA mutations, and telomere shortening, as well as hormonal changes. We have also significantly improved our understanding of how to harness the skin's considerable regenerative capacity e.g., via its remarkable investment of stem cell subpopulations. In this way we hope to develop new strategies to selectively target the skin's capacity to undergo optimal wound repair and regeneration. Here, the unsung hero of the skin regenerative power may be the humble hair follicle, replete with its compliment of epithelial, mesenchymal, neural and other stem cells. This review introduces the topic of human skin aging, with a focus on how maintenance of function in this complex multi-cell type organ is key for retaining quality of life into old age.
Asunto(s)
Envejecimiento de la Piel , Cabello , Humanos , Uñas , Piel , Fenómenos Fisiológicos de la Piel , Luz Solar/efectos adversosAsunto(s)
Liebres , Trastornos de la Pigmentación , Tortugas , Animales , Humanos , Piel , Pigmentación de la PielRESUMEN
Photobiomodulation is reported to positively influence hair regrowth, wound healing, skin rejuvenation and psoriasis. Despite rapid translation of this science to commercial therapeutic solutions, significant gaps in our understanding of the underlying processes remain. The aim of this review was to seek greater clarity and rationality specifically for the selection of optical parameters for studies on hair regrowth and wound healing. Our investigation of 90 reports published between 1985 and 2015 revealed major inconsistencies in optical parameters selected for clinical applications. Moreover, poorly understood photoreceptors expressed in skin such as cytochrome c oxidase, cryptochromes, opsins etc. may trigger different molecular mechanisms. All this could explain the plethora of reported physiological effects of light. To derive parameters for optimal clinical efficacy of photobiomodulation, we recommend a more rational approach to underpin clinical studies, with research on molecular targets and pathways using well-defined biological model systems to enable translation of optical parameters from in vitro to in vivo. Furthermore, special attention needs to be paid when conducting studies for hair regrowth, aiming for double-blind, placebo-controlled randomized clinical trials as the gold standard for quantifying hair growth.
Asunto(s)
Terapia por Luz de Baja Intensidad , Enfermedades de la Piel/terapia , Cicatrización de Heridas/efectos de la radiación , Folículo Piloso/efectos de la radiación , Humanos , Células Fotorreceptoras/efectos de la radiación , Investigación Biomédica TraslacionalRESUMEN
Bone morphogenetic proteins (BMPs) are a large family of multi-functional secreted signalling molecules. Previously BMP2/4 were shown to inhibit skin pigmentation by downregulating tyrosinase expression and activity in epidermal melanocytes. However, a possible role for other BMP family members and their antagonists in melanogenesis has not yet been explored. In this study we show that BMP4 and BMP6, from two different BMP subclasses, and their antagonists noggin and sclerostin were variably expressed in melanocytes and keratinocytes in human skin. We further examined their involvement in melanogenesis and melanin transfer using fully matched primary cultures of adult human melanocytes and keratinocytes. BMP6 markedly stimulated melanogenesis by upregulating tyrosinase expression and activity, and also stimulated the formation of filopodia and Myosin-X expression in melanocytes, which was associated with increased melanosome transfer from melanocytes to keratinocytes. BMP4, by contrast, inhibited melanin synthesis and transfer to below baseline levels. These findings were confirmed using siRNA knockdown of BMP receptors BMPR1A/1B or of Myosin-X, as well as by incubating cells with the antagonists noggin and sclerostin. While BMP6 was found to use the p38MAPK pathway to regulate melanogenesis in human melanocytes independently of the Smad pathway, p38MAPK, PI3-K and Smad pathways were all involved in BMP6-mediated melanin transfer. This suggests that pigment formation may be regulated independently of pigment transfer. These data reveal a complex involvement of regulation of different members of the BMP family, their antagonists and inhibitory Smads, in melanocytes behaviour.
Asunto(s)
Proteína Morfogenética Ósea 4/farmacología , Proteína Morfogenética Ósea 6/farmacología , Queratinocitos/metabolismo , Melanocitos/metabolismo , Pigmentación/efectos de los fármacos , Piel/citología , Adulto , Anciano , Proteína Morfogenética Ósea 4/antagonistas & inhibidores , Proteína Morfogenética Ósea 4/metabolismo , Proteína Morfogenética Ósea 6/antagonistas & inhibidores , Proteína Morfogenética Ósea 6/metabolismo , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Técnicas de Cocultivo , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/efectos de la radiación , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/enzimología , Queratinocitos/efectos de la radiación , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Melanocitos/efectos de la radiación , Melanocitos/ultraestructura , Persona de Mediana Edad , Modelos Biológicos , Monofenol Monooxigenasa/metabolismo , Miosinas/metabolismo , Pigmentación/efectos de la radiación , Seudópodos/efectos de los fármacos , Seudópodos/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Proteínas Smad/metabolismo , Rayos Ultravioleta , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/efectos de la radiación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
It has long been appreciated in science that correlation does not imply causation. However, with any logical fallacy, simply spotting that the reasoning behind an argument is faulty does not imply that the resulting conclusion is false. Thus, I begin the tricky business of exploring the basis upon which researchers and clinicians are often tempted to conclude that two medical conditions (here alopecia areata and vitiligo), with some striking resemblances, are in fact related. This is relevant, particularly if assumptions of shared aetiology (and to some extent shared pathomechanism) encourage a common strategy to finding a treatment or cure.
Asunto(s)
Alopecia Areata/epidemiología , Enfermedades Autoinmunes/epidemiología , Vitíligo/epidemiología , Alopecia Areata/etiología , Enfermedades Autoinmunes/etiología , Comorbilidad , Humanos , Vitíligo/etiologíaRESUMEN
Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal testing and extensive clinical trials. There are several in vitro approaches to mimicking human skin behavior, ranging from simple cell monolayer to complex organotypic and bioengineered 3-dimensional models. Some have been approved for preclinical studies in cosmetics, pharmaceuticals, and chemicals. However, development of physiologically reliable in vitro human skin models remains in its infancy. This review reports on advances in in vitro complex skin models to study skin homeostasis, aging, and skin disease.
RESUMEN
Skin pigmentation is a multistep process of melanin synthesis by melanocytes, its transfer to recipient keratinocytes and its degradation. As dyspigmentation is a prominent marker of skin ageing, novel effective agents that modulate pigmentation safely are being sought for both clinical and cosmetic use. Here, a number of plant extracts were examined for their effect on melanogenesis (by melanin assay and Western blotting) and melanin transfer (by confocal immunomicroscopy of gp100-positive melanin granules in cocultures and by SEM analysis of filopodia), in human melanocytes and in cocultures with phototype-matched normal adult epidermal keratinocytes. Mulberry, Kiwi and Sophora extracts were assessed against isobutylmethylxanthine, hydroquinone, vitamin C and niacinamide. Compared with unstimulated control, all extracts significantly reduced melanogenesis in human melanoma cells and normal adult epidermal melanocytes. These extracts also reduced melanin transfer and reduced filopodia expression on melanocytes, similar to hydroquinone and niacinamide, indicating their effectiveness as multimode pigmentation actives.
Asunto(s)
Actinidia , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Morus , Extractos Vegetales/farmacología , Sophora , 1-Metil-3-Isobutilxantina/farmacología , Ácido Ascórbico/farmacología , Células Cultivadas , Técnicas de Cocultivo , Frutas , Humanos , Hidroquinonas/farmacología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Melaninas/metabolismo , Melanocitos/metabolismo , Microscopía Confocal , Niacinamida/farmacología , Hojas de la Planta , Raíces de PlantasRESUMEN
Hair diversity, its style, colour, shape and growth pattern is one of our most defining characteristics. The natural versus temporary style is influenced by what happens to our hair during our lifetime, such as genetic hair loss, sudden hair shedding, greying and pathological hair loss in the various forms of alopecia because of genetics, illness or medication. Despite the size and global value of the hair care market, our knowledge of what controls the innate and within-lifetime characteristics of hair diversity remains poorly understood. In the last decade, drivers of knowledge have moved into the arena of genetics where hair traits are obvious and measurable and genetic polymorphisms are being found that raise valuable questions about the biology of hair growth. The recent discovery that the gene for trichohyalin contributes to hair shape comes as no surprise to the hair biologists who have believed for 100 years that hair shape is linked to the structure and function of the inner root sheath. Further conundrums awaiting elucidation include the polymorphisms in the androgen receptor (AR) described in male pattern alopecia whose location on the X chromosome places this genetic contributor into the female line. The genetics of female hair loss is less clear with polymorphisms in the AR not associated with female pattern hair loss. Lifestyle choices are also implicated in hair diversity. Greying, which also has a strong genetic component, is often suggested to have a lifestyle (stress) influence and hair follicle melanocytes show declining antioxidant protection with age and lowered resistance to stress. It is likely that hair research will undergo a renaissance on the back of the rising information from genetic studies as well as the latest contributions from the field of epigenetics.
Asunto(s)
Cabello , Genética , Color del Cabello , HumanosRESUMEN
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.
Asunto(s)
Luz , Fototerapia , Humanos , Piel/efectos de la radiación , Rayos Ultravioleta , ApoptosisRESUMEN
Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review.