RESUMEN
KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well-studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.
Asunto(s)
Mastocitos , Mastocitosis , Melanocitos , Proteínas Proto-Oncogénicas c-kit , Factor de Células Madre , Humanos , Factor de Células Madre/metabolismo , Melanocitos/metabolismo , Mastocitos/metabolismo , Mastocitosis/tratamiento farmacológico , Mastocitosis/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Melanoma/metabolismo , Melanoma/tratamiento farmacológico , Vitíligo/metabolismo , Vitíligo/tratamiento farmacológico , Vitíligo/terapia , Trastornos de la Pigmentación/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , AnimalesRESUMEN
Hair graying holds psychosocial importance and serves as an excellent model for studying human pigmentation and aging in an accessible miniorgan. Current evidence suggests that graying results from an interindividually varying mixture of cumulative oxidative and DNA damage, excessive mTORC1 activity, melanocyte senescence, and inadequate production of pigmentation-promoting factors in the hair matrix. Various regulators modulate this process, including genetic factors (DNA repair defects and IRF4 sequence variation, peripheral clock genes, P-cadherin signaling, neuromediators, HGF, KIT ligand secretion, and autophagic flux. This leads to reduced MITF- and tyrosinase-controlled melanogenesis, defective melanosome transfer to precortical matrix keratinocytes, and eventual depletion of hair follicle (HF) pigmentary unit (HFPU) melanocytes and their local progenitors. Graying becomes irreversible only when bulge melanocyte stem cells are also depleted, occurring later in this process. Distinct pigmentary microenvironments are created as the HF cycles: early anagen is the most conducive phase for melanocytic reintegration and activation, and only during anagen can the phenotype of hair graying and repigmentation manifest, whereas the HFPU disassembles during catagen. The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. We advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.
Asunto(s)
Folículo Piloso , Melanocitos , Ratones , Animales , Humanos , Melanocitos/metabolismo , Pigmentación/fisiología , Envejecimiento/fisiología , Células Madre , Color del CabelloAsunto(s)
Lentigo , Trastornos por Fotosensibilidad , Humanos , Lentigo/diagnóstico , Lentigo/etiología , Mano , PielRESUMEN
It remains unclear how the multifunctional indoleamine neurohormone, melatonin, alters melanin production and melanocytes within intact human epidermis under physiologically relevant conditions. In the current pilot study, we aimed to clarify this in long-term organ-cultured, full-thickness human eyelid skin, selected for its clinically recognized sensitivity to pigmentation-modulatory hormones. Warthin-Starry histochemistry showed that 100 µM melatonin significantly increased epidermal melanin content and melanocyte dendricity after 6 days of organ culture, even though tyrosinase activity in situ was inhibited, as assessed by quantitative immunohistomorphometry. While the higher melatonin dose tested here (200 µM) did not change epidermal melanization, but again inhibited tyrosinase activity, it increased the number and proliferation of both gp100+ epidermal melanocytes and keratinocytes as well as protein expression of the premelanosomal marker, gp100, ex vivo. Contrary to most previous studies, these eyelid skin organ culture results suggest that long-term melatonin application exerts overall stimulatory, dose-dependent effects on the epidermal pigmentary unit within intact human skin, which appear surprisingly tyrosinase-independent. While these provocative preliminary findings require further work-up and independent confirmation, they encourage one to systematically explore whether prolonged melatonin therapy can (re-)stimulate melanogenesis and increase the pool/activity of epidermal melanocytes in hypopigmented skin lesions.
Asunto(s)
Melaninas , Melatonina , Humanos , Melaninas/metabolismo , Melatonina/metabolismo , Monofenol Monooxigenasa/metabolismo , Proyectos Piloto , Melanocitos/metabolismo , Epidermis/metabolismo , Queratinocitos/metabolismo , Proliferación Celular , Células CultivadasRESUMEN
INTRODUCTION: The analysis of the role of the mitochondria in oxidative damage and skin aging has been a significant aspect of dermatological research. Mitochondria generate most reactive oxygen species (ROS) which, in excess, are cytotoxic and DNA-damaging and promote (photo-)aging. However, ROS also possesses key physiological and regulatory functions and mitochondrial dysfunction is prominent in several not primarily senescence-associated skin diseases and skin cancers. Although many standard dermatotherapeutics modulate mitochondrial function, dermatological therapy rarely targets the mitochondria. Accordingly, there is a rationale for 'mitochondrial dermatology'-based approaches to be applied to therapeutic research, as we advocate here. AREAS COVERED: This paper examines the functions of mitochondria in cutaneous physiology beyond energy (ATP) and ROS production. Keratinocyte differentiation and epidermal barrier maintenance, appendage morphogenesis and homeostasis, photoaging and skin cancer are considered. Based on related PubMed search results, the paper evaluates thyroid hormones, glucocorticoids, Vitamin D3 derivatives, retinoids, cannabinoid receptor agonists, PPARγ agonists, thyrotropin, and thyrotropin-releasing hormone as instructive lead compounds. Moreover, the mitochondrial protein MPZL3 as a promising new drug target for future 'mitochondrial dermatology' is highlighted. EXPERT OPINION: Future dermatological therapeutic research should have a mitochondrial medicine emphasis. Focusing on selected lead agents, protein targets, in silico drug design, and model diseases will fertilize a mito-centric approach.
Asunto(s)
Envejecimiento de la Piel , Enfermedades de la Piel , Envejecimiento , Humanos , Mitocondrias/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Enfermedades de la Piel/tratamiento farmacológicoRESUMEN
The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin-lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation-related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from nonhuman species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responses to melatonin are best interrogated in a physiological tissue context. Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis-inhibitory effects of melatonin may occur via activation of Nrf2-mediated PI3K/AKT signaling, estrogen receptor-mediated and/or melanocortin-1 receptor- and cAMP-dependent signaling, and/or via melatonin-regulated changes in peripheral clock genes that regulate human melanogenesis, namely Bmal1 and Per1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto- and senescence-protective as well as antioxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function. We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture-based observations translate into melatonin-induced pigmentary changes in a physiological tissue context, that is, in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models.
Asunto(s)
Melatonina , Folículo Piloso/metabolismo , Humanos , Melaninas , Melanocitos/metabolismo , Melatonina/metabolismo , Melatonina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
ABSTRACT: Deformity and tissue loss involving the craniomaxillofacial region occurs frequently as a result of trauma, oncologic resection, or a congenital malformation. In order to maximize the patient's quality of life, reconstruction of the craniomaxillofacial skeleton must seek to restore aesthetics as well as function. Advances in diagnostic technology, surgical technique, instrumentation, and innovative biomaterials used have transformed the way reconstructive surgeons approach their patients' needs. From the advent of alloplastic reconstruction, surgeons have sought the ideal material for use in craniomaxillofacial surgery. Substances such as metals, ceramics, glasses, and more recently resorbable polymers and bioactive materials have all been utilized.While autologous bone has remained widely-favored and the gold standard, synthetic alternatives remain a necessity when autologous reconstruction is not readily available. Today, alloplastic material, autografting via microvascular tissue transfer, hormone and growth factor-induced bone formation, and computer-aided design and manufacturing of biocompatible implants represent only a fraction of a wide range of options used in the reconstruction of the craniomaxillofacial skeleton. We present a brief review of the materials used in the repair of deformities of the craniomaxillofacial skeleton as well as a look into the potential future direction of the field.
Asunto(s)
Implantes Dentales , Procedimientos de Cirugía Plástica , Materiales Biocompatibles , Estética Dental , Humanos , Calidad de VidaRESUMEN
Smokers have a higher incidence of chronic pain than non-smokers, but the neural mechanism is not yet fully understood. Nicotine is the main component of tobacco and acts as an agonist for nicotinic cholinergic receptors (nAChRs) in the nervous system. This study was approved by the IACUC of UM. The effects of chronic nicotine administration on mechanical sensitivity were studied using a rat model. The changes in the expression levels of the α7 isoform of nAChR (α7-nAChR), inflammatory cytokines TNFα and COX-2, as well as the density of neuro-immune cells (astrocytes and microglia) were measured concurrently. The results indicate that long-term nicotine administration induces hypersensitivity to mechanical stimuli, as demonstrated by a significant reduction in the pain perception threshold. In response to nicotine, the expression levels of α7-nAChR increased in the periaqueductal gray matter (PAG) and decreased in the spinal cord. Acute administration of the selective α7-nAChR agonist CDP-Choline reversed this hypersensitivity. Chronic nicotine administration led to an increase of microglial cells in the dorsal horn of the spinal cord and increased expression levels of the cytokines TNFα and COX-2. This study suggests that decreased α7-nAChR expression in the spinal cord, as a result of long-term exposure to nicotine, may be causatively linked to chronic pain. Simultaneously, the increase of neuro-immune factors in the spinal cord is also a potential factor leading to chronic pain.
Asunto(s)
Modelos Animales de Enfermedad , Hiperalgesia/metabolismo , Nicotina/toxicidad , Médula Espinal/metabolismo , Tacto/fisiología , Receptor Nicotínico de Acetilcolina alfa 7/biosíntesis , Animales , Dolor Crónico/inducido químicamente , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Citidina Difosfato Colina/farmacología , Citidina Difosfato Colina/uso terapéutico , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Masculino , Nicotina/administración & dosificación , Nicotina/agonistas , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
It has been demonstrated that smoking is associated with an increase in postoperative and chronic pain. The changes in the pain-related neural pathways responsible for these effects are unknown. Additionally, the effects of nicotine withdrawal, resulting from smoking abstinence preoperatively, has not been evaluated in terms of its impact on pain sensation. In this study, an animal model has been used to assess these effects. A rat model of long-term nicotine exposure was used. Von Frey mechanical sensory tests were performed. Western Blot and immunohistological analysis were conducted on spinal cord samples. Mechanical sensory thresholds increased in the initial period (1-3 weeks), indicating hyposensitivity. Long-term (410 weeks) and under nicotine withdrawal, the mechanical sensory thresholds decreased, indicating hyperalgesia. During short-term nicotine exposure, glutamate decarboxylase 67 (GAD67), GAD65, and µ-opioid receptors (MOR) up-regulated. Beta-endorphins down-regulated. Increased γ -aminobutyric acid (GABA) and MOR appear responsible for the hyposensitivity since the GABA receptor antagonist, bicuculline and opioid receptor antagonist, naloxone decreased the mechanical thresholds of nicotine-induced hyposensitivity. In long-term nicotine exposure, the expression of GAD67, MOR, and GABA decreased. Baclofen, a derivative of GABA, reversed the hyperalgesia seen with nicotine withdrawal. Therefore, nicotine acts as an analgesic when used acutely or short-term. Long-term exposure or nicotine withdrawal (similar to smoking cessation) results in hyperalgesia. Nicotine appears to alter pain sensitivity by affecting the expression of GAD65, GAD67, MOR, endorphins, and GABA. This may partially explain the increased pain and opioid use seen in chronic smokers in the postoperative period.