Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers.

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.

Concentration-dependent stimulation of melanin production as well as melanocyte and keratinocyte proliferation by melatonin in human eyelid epidermis.

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.

Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging.

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.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective.

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.

Biomaterials in Craniomaxillofacial Reconstruction: Past, Present, and Future.

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.

The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity.

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.

The mechanism of chronic nicotine exposure and nicotine withdrawal on pain perception in an animal model.

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.