Characterization of adults concerning the use of a hypothetical mHealth application addressing stress-overeating: an online survey.

BACKGROUND: About 40% of people respond to stress by consuming more unhealthy foods. This behavior is associated with increased energy intake and the risk of obesity. As mobile health (mHealth) applications (apps) have been shown to be an easy-to-use intervention tool, the characterization of potential app users is necessary to develop target group-specific apps and to increase adherence rates. METHODS: This cross-sectional online survey was conducted in the spring of 2021 in Germany. Sociodemographic data and data on personality (Big Five Inventory, BFI-10), stress-eating (Salzburg Stress Eating Scale, SSES), and technology behavior (Personal Innovativeness in the Domain of Information Technology, PIIT; Technology Acceptance Model 3, TAM 3) were collected. RESULTS: The analysis included 1228 participants (80.6% female, mean age: 31.4 ± 12.8 years, mean body mass index (BMI): 23.4 ± 4.3 kg/m2). Based on the TAM score, 33.3% (409/1228) of the participants had a high intention to use a hypothetical mHealth app to avoid stress-overeating. These persons are characterized by a higher BMI (24.02 ± 4.47 kg/m2, p < 0.001), by being stress-overeaters (217/409, 53.1%), by the personality trait "neuroticism" (p < 0.001), by having specific eating reasons (all p < 0.01), and by showing a higher willingness to adopt new technologies (p < 0.001). CONCLUSION: This study suggests that individuals who are prone to stress-overeating are highly interested in adopting an mHealth app as support. Participants with a high intention to use an mHealth app seem to have a general affinity towards new technology (PIIT) and appear to be more insecure with conflicting motives regarding their diet. TRIAL REGISTRATION: This survey was registered in the German Clinical Trials Register (Registration number: DRKS00023984).

Reliability and agreement testing of a new automated measurement method to determine facial vitiligo extent using standardized ultraviolet images and a dedicated algorithm.

BACKGROUND: Facial repigmentation is the primary outcome measure for most vitiligo trials. The Facial Vitiligo Area Scoring Index (F-VASI) score is often chosen as the primary outcome measure to assess the efficacy of treatments for facial vitiligo. Although useful, this scoring system remains subjective and has several limitations. OBJECTIVES: To assess the agreement and reliability of an algorithmic method to measure the percentage depigmentation of vitiligo on the face. METHODS: We developed a dedicated algorithm called Vitil-IA® to assess depigmentation on standardized facial ultraviolet (UV) pictures. We then conducted a cross-sectional study using the framework of the ERASE trial (NCT04843059) in 22 consecutive patients attending a tertiary care centre for vitiligo. Depigmentation was analysed before any treatment and, for 7 of them, after 3 and 6 months of narrowband UVB treatment combined with 16 mg methylprednisolone, both used twice weekly. Interoperator and interacquisition repeatability measures were assessed for the algorithm. The results of the algorithmic measurement were then compared with the F-VASI and the percentage of depigmented skin scores assessed by 13 raters, including 7 experts in the grading of vitiligo lesions. RESULTS: Thirty-one sets of pictures were analysed with the algorithmic method. Internal validation showed excellent reproducibility, with a variation of < 3%. The percentage of depigmentation assessed by the system showed high agreement with the percentage of depigmentation assessed by raters [mean error (ME) -11.94 and mean absolute error (MAE) 12.71 for the nonexpert group; ME 0.43 and MAE 5.57 for the expert group]. The intraclass correlation coefficient (ICC) for F-VASI was 0.45 [95% confidence interval (CI) 0.29-0.62] and 0.52 (95% CI 0.37-0.68) for nonexperts and experts, respectively. When the results were analysed separately for homogeneous and heterogeneous depigmentation, the ICC for homogeneous depigmentation was 0.47 (95% CI 0.31-0.77) and 0.85 (95% CI 0.72-0.94) for nonexperts and experts, respectively. When grading heterogeneous depigmentation, the ICC was 0.19 (95% CI 0.05-0.43) and 0.38 (95% CI 0.20-0.62) for nonexperts and experts, respectively. CONCLUSIONS: We demonstrated that the Vitil-IA algorithm provides a reliable assessment of facial involvement in vitiligo. The study underlines the limitations of the F-VASI score when performed by nonexperts for homogeneous vitiligo depigmentation, and in all raters when depigmentation is heterogeneous.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the International Vitiligo Task Force Part 1: towards a new management algorithm.

BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.

Expression of the α7 Nicotinic Acetylcholine Receptor Is Critically Required for the Antifibrotic Effect of PHA-543613 on Skin Fibrosis.

INTRODUCTION: Targeting the α7 nicotinic acetylcholine receptor (α7nAChR) has recently been suggested as a potential new treatment for fibrotic skin diseases. Here, we performed a genetic and pharmacologic approach to clarify the role of this receptor in the bleomycin (BLM) mouse model of skin fibrosis using α7nAChR KO mice. METHODS: We analyzed the expression of extracellular matrix (ECM) components in murine skin using quantitative RT-PCR, pepsin digestion/SDS-PAGE of proteins and performed hydroxyproline assays as well as histological/immunohistochemical staining of skin sections. To identity the target cells of the α7nAChR agonist PHA-543613, we used murine dermal fibroblasts (MDF). We tested their response to the profibrotic cytokine transforming growth factor-ß1 (TGF-ß1) and utilized gene silencing to elucidate the role of the α7nAChR. RESULTS: We confirmed our previous findings on C3H/HeJ mice and detected a suppressive effect of PHA-543613 on BLM-induced skin fibrosis in the mouse strain C57BL/6J. This antifibrotic effect of PHA-543613 was abrogated in α7nAChR-KO mice. Interestingly, α7nAChR-KO animals exhibited a basal profibrotic signature by higher RNA expression of ECM genes and hydroxyproline content than WT mice. In WT MDF, PHA-543613 suppressed ECM gene expression induced by TGF-ß1. Gene silencing of α7nAChR by small interfering RNA neutralized the effects of PHA-543613 on TGF-ß1-mediated ECM gene expression. CONCLUSION: In summary, we have identified the α7nAChR as the essential mediator of the antifibrotic effect of PHA-543613. MDF are directly targeted by PHA-543613 to suppress collagen synthesis. Our findings emphasize therapeutic exploitation of α7nAChR receptor agonists in fibrotic skin diseases.

Stress eating: an online survey of eating behaviours, comfort foods, and healthy food substitutes in German adults.

BACKGROUND: In many people, stress is associated with changes in eating behaviour. Food products consumed during stress (comfort foods) are often unhealthy. It is rather unknown what comfort foods are consumed in Germany and what healthier food products are considered as alternatives to support stress-eaters in making healthier food choices. METHODS: This online survey was conducted in spring 2021 throughout Germany. Participants were digitally recruited by newsletters, homepages, social media, and mailing lists. The survey included a standardized questionnaire with items concerning e.g. sociodemography, stress, and nutrition. Comfort foods were pre-selected through literature search and food substitutes were defined and discussed by experts. Analyses examined comfort food consumption and substitute preferences dependent on sex, age, body mass index (BMI), and being a self-identified stress-eater. The statistical analysis was performed using R. RESULTS: Survey participants were mostly female (80.6%, 994/1234), had a mean age of 31.4 ± 12.8 years and a mean BMI of 23.4 ± 4.3 kg/m2. Participants stated, that the two favourite comfort foods were chocolate (consumed often/very often by 48.3%, 596/1234) and coffee (consumed often/very often by 45.9%, 566/1234). Regarding food substitutes, the most frequently named alternative food for chocolate and cookies was fresh fruits (for chocolate: 74.4%, 815/1096, for cookies: 62.6%, 565/902). Tea without added sugar (64.4%, 541/840) was the preferred substitute for coffee. Almost 50% of participants (48.1%, 594/1234) identified themselves as stress-eaters, of which 68.9% (408/592) stated to eat (very) often more than usual in subjective stress situations. CONCLUSIONS: The results from this work suggest that specific comfort foods and substitutes are preferred by the participants in stressful situations. This knowledge about food choices and substitutes should be investigated in further studies to improve eating behaviour in stressful situations. TRIAL REGISTRATION: The survey was registered in the German Register of Clinical Studies (Registration number: DRKS00023984 ).

Stress-induced hyperphagia: empirical characterization of stress-overeaters.

BACKGROUND: Stressful situations can have an impact on an individual's eating behavior. People vulnerable to the influence of stress tend to change the quantity and quality of their food intake. Variables such as sex and body mass index (BMI) seem to be related to this stress-eating behavior, but it is rather unclear what factors account to the parameters associated with stress-eating behavior. The aim of this survey was to identify further characteristics of adults in Germany related to stress-overeating, focusing on stress perception, coping, eating motives and comfort foods as well as personality types. METHODS: This online survey was performed throughout Germany and comprised a 38-item pre-tested questionnaire. Stress-induced overeating was classified based on the Salzburg Stress Eating Scale (SSES). Moreover, validated questionnaires were used to identify additional characteristics of stress eaters. Participants were recruited using a convenience sampling approach, and data were collected between January and April 2021. RESULTS: The overall sample consisted of 1222 participants (female 80.8%, aged 31.5±12.8). 42.1% of participants were identified as stress-overeaters. Among the remaining group, 78.9% stated to eat less, 21.1% to eat equally when stressed. Female participants had a higher mean SSES score compared to male participants. The BMI was positively correlated to SSES, r(1220)=0.28, p>0.005. 'Agreeableness' (BigFive) was found to be a negative predictor of stress-overeating. The most pronounced difference in eating motives (The Eating Motivation Survey, TEMS) was found for 'Affect Regulation' and 'Weight Control'. CONCLUSIONS: The results indicate that stress-overeating affects a large proportion of the surveyed population. BMI, personality and eating motives additionally characterize stress-overeaters and may contribute to develop new approaches to address unhealthy stress-related eating patterns.

Value of normative belief in intention to use workplace health promotion apps.

BACKGROUND: Mobile applications (apps) have started to be used for workplace health promotion (WHP). However, the factors that lead to the usage of apps in the workplace from the end-user perspective remain unclear. METHODS: To investigate the research gap, the study evaluates a model for the adoption of WHP apps by combining the theory of planned behavior, the health belief model, and the technology acceptance model. A self-administered questionnaire with validated scales among 354 participants was used to evaluate the proposed model for WHP. RESULTS: Although the study indicated a limited overall model fit, interesting aspects were derived. In particular, the study demonstrated that normative belief (especially), perceived usefulness, and attitudinal belief play important roles in the intention to use WHP apps. CONCLUSION: The study is among the first to validate the theoretical models of mHealth adoption for WHP. Moreover, it shows that not only normative belief but also adjustment to several target groups is a necessary factor to be considered in the development and implementation of an app for WHP.

Protective Role of Melatonin and Its Metabolites in Skin Aging.

The skin, being the largest organ in the human body, is exposed to the environment and suffers from both intrinsic and extrinsic aging factors. The skin aging process is characterized by several clinical features such as wrinkling, loss of elasticity, and rough-textured appearance. This complex process is accompanied with phenotypic and functional changes in cutaneous and immune cells, as well as structural and functional disturbances in extracellular matrix components such as collagens and elastin. Because skin health is considered one of the principal factors representing overall "well-being" and the perception of "health" in humans, several anti-aging strategies have recently been developed. Thus, while the fundamental mechanisms regarding skin aging are known, new substances should be considered for introduction into dermatological treatments. Herein, we describe melatonin and its metabolites as potential "aging neutralizers". Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. It regulates circadian rhythmicity and also exerts anti-oxidative, anti-inflammatory, immunomodulatory, and anti-tumor capacities. The intention of this review is to summarize changes within skin aging, research advances on the molecular mechanisms leading to these changes, and the impact of the melatoninergic anti-oxidative system controlled by melatonin and its metabolites, targeting the prevention or reversal of skin aging.

S1 Guideline: Diagnosis and therapy of vitiligo.

Vitiligo is a common skin disorder characterized by immune-mediated destruction of melanocytes. Non-segmental vitiligo, the most common clinical subtype, has usually a chronic course and often results in significant psychosocial consequences for the affected patient. Early recognition, awareness of comorbidity, precise assessment of disease extent and activity, evaluation of impairment of quality of life as well as rapid initiation of treatment based on currently available evidence-based therapies are crucial cornerstones in the management of vitiligo. This S1 guideline helps German dermatologists to better diagnose and treat vitiligo.

Does autoimmune vitiligo protect against COVID-19 disease?

The SARS-CoV-2 pandemic has evolved to a global health problem with a dramatic morbidity and mortality rate impacting our daily life and those of many patients. While there is evidence that some diseases are associated with an increased risk for development of a more severe course of COVID-19, little is known on protective conditions. Importantly, clearance of viral infection and protection against disease manifestation crucially depends on functional innate and adaptive immunity and the interferon signalling axis. Here, we hypothesize that patients with non-segmental vitiligo (NSV), an autoimmune skin (and mucosal) disorder, may clear SARS-CoV-2 infection more efficiently and have a lower risk of COVID-19 development. Conversely, in case of COVID-19 development, vitiligo autoimmunity may influence the cytokine storm-related disease burden. In addition, immune activation during SARS-CoV-2 infection or COVID-19 disease might increase vitiligo disease activity. Our hypothesis is based on the shift of the immune system in NSV towards adaptive type 1 (IFNγ and CD8 T cells) and innate immune responses. Identified susceptibility genes of NSV patients may further confer increased antiviral activity. To validate our hypothesis, we suggest an international consortium to perform a retrospective data registry and patient-reported study on a large number of NSV patients worldwide during the COVID-19 pandemic.

[Successful treatment of generalized pustular psoriasis with certolizumab]. / Erfolgreiche Behandlung einer generalisierten pustulösen Psoriasis mit Certolizumab.

Generalized pustular psoriasis is a rare, often relapsing and usually severe inflammatory skin disease with concomitant systemic symptoms in many cases. The disease is in part due to mutations in the gene of the interleukin-36 receptor antagonist (IL36RN) explaining the autoinflammatory nature of this condition. Here, we report on a 39-year-old pregnant woman who stopped her medication with secukinumab due to her pregnancy. Subsequently, she suffered from severe exacerbation of her disease and was admitted to our hospital. The patient had a known mutation in the IL36RN (Ser113Leu) gene. At the 33rd week of her pregnancy therapy with certolizumab was initiated and resulted in a rapid remission within a few weeks. After the patient gave birth, remission could be maintained under the given therapy with this biologic.

Alemtuzumab-induced Alopecia areata - a case report and systematic literature review of adverse events associated with Alemtuzumab.

Alemtuzumab is currently approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Despite the efficacy of this therapy several side effects in the skin have been noted during or after infusion including vitiligo, alopecia areata, malignant skin tumors and infections. Awareness of these effects and their treatment is of essential interdisciplinary importance. This minireview provides an overview of the dermatological side effects described in the current literature. We also suggest pathomechanisms underlying these phenomena. To introduce this review, we present the case of a woman with RRMS who developed severe alopecia areata for the first time on alemtuzumab.

Targeting the α7 nicotinic acetylcholine receptor-A novel road towards the future treatment of skin diseases.

Nicotinic acetylcholine receptors (nAChRs) are members of the superfamily of neurotransmitter-gated ion channels. The natural ligand for nAChRs is the endogenous neurotransmitter acetylcholine. Among the nAChRs is the α7nAChR. It is not only expressed by neural tissues but also in the skin. A number of different resident cutaneous cell types including epidermal keratinocytes, sebocytes and dermal fibroblasts express functional α7nAChR. Moreover, cells of the immune system such as lymphocytes, macrophages and monocytes, playing an important role in skin homeostasis, also express α7nAChR. Translational research focusing on the exploitation of the α7nAChR in dermatology has revealed that this neuroendocrine receptor could be promising target for the treatment of inflammatory skin diseases. For example, α7nAChR agonists can counteract transforming growth factor-ß1-mediated responses in dermal fibroblasts, key effector cells in scleroderma. In accordance with this α7nAChR, agonists are effective in both inflammation and non-inflammation-driven models of experimentally induced skin fibrosis. Moreover, α7nAChR agonists can modulate expression of proinflammatory cytokines in epidermal keratinocytes that are crucially involved in the pathogenesis of psoriasis and other inflammatory skin diseases. Finally, the capability of α7nAChR agonists to suppress ultraviolet light A/B-induced responses, for example production of proinflammatory cytokines and oxidative stress, the latter crucially involved in dermal photoageing, points to a potential of such agents in the prevention of extrinsic skin ageing. Therefore, emphasis on translational research targeting the α7nAChR in skin may lead to the development of new treatment and prevention modalities against fibrosclerotic skin diseases, psoriasis vulgaris, atopic dermatitis, acne, photodermatoses and extrinsic skin ageing.

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Despite groundbreaking new treatments such as checkpoint inhibition and targeted therapy, the overall response and survival rates are limited in patients with metastatic melanoma. Here, we hypothesize that melatonin and its metabolites could be promising boosters of the efficacy of BRAF/MEK inhibitors in patients with advanced melanoma. Melatonin, a well-known endogenous synchronizer of the circadian biorhythm has a variety of promising effects for melanoma biology. It regulates proliferation, apoptosis and oxidative phosphorylation via melatonin receptors, and receptor-independent pathways due to its lipophilicity. By means of interfering with the above cellular pathways, melatonin and related compounds may alter the cAMP-PKA-MITF axis, modulate tumor cell metabolism, affect MAPK signalling pathway thereby enhancing the suppressive effect of BRAF/MEK inhibitors on melanoma cell growth, and survival. Such findings could fuel preclinical studies and clinical studies where melatonin or its metabolites are combined with targeted therapy to better treat patients with metastatic melanoma.

Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.

Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness.

[Melanocortin peptides : Fundamentals, translational research, clinical dermatology, and future perspectives]. / Melanokortinpeptide : Grundlagen, translationale Forschung, klinische Dermatologie und Zukunftsperspektiven.

Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic function of the naturally occurring melanocortin peptides in skin. Moreover, the melanocortins are crucially involved in the ultraviolet light-induced tanning response. Under pathophysiologic conditions, melanocortin peptides induce cutaneous hyperpigmentation, likewise via the MC1R axis, e.g. in patients with Addison's disease, ectopic precursor pro-opiomelanocortin (POMC) syndrome and in those with abnormally elevated melanocortin blood levels. Translational research on α­MSH (melanocyte-stimulating hormones) and their antagonists has further revealed a variety of other biological activities beyond pigmentation. They include cytoprotection, antioxidative effects, regulation of collagen metabolism and fibrosis, sebum production, and cutaneous wound healing. These findings have also promoted the development of novel therapies in clinical dermatology including the exploitation of afamelanotide. In 2015, this agent became the first in-class synthetic α­MSH analogue to be approved in dermatology for the treatment of erythropoetic protoporphyria. In addition to afamelanotide, setmelanotide has recently emerged as a highly selective MC4R agonist useful for the treatment of distinct forms of genetically determined obesity, e.g., POMC deficiency. Future perspectives in dermatology reside in treatment of other difficult-to-treat skin diseases with α­MSH analogues, either with topical or systemic formulations. Moreover, synthetic melanocortin peptide derivatives lacking the central pharmacophor but with maintained anti-inflammatory effects could become a promising strategy for the design of new therapies in dermatology.

Are melanocortin peptides future therapeutics for cutaneous wound healing?

Cutaneous wound healing is a complex process divided into different phases, that is an inflammatory, proliferative and remodelling phase. During these phases, a variety of resident skin cell types but also cells of the immune system orchestrate the healing process. In the last year, it has been shown that the majority of cutaneous cell types express the melanocortin 1 receptor (MC1R) that binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and elicits pleiotropic biological effects, for example modulation of inflammation and immune responses, cytoprotection, antioxidative defense and collagen turnover. Truncated α-MSH peptides such as Lys-Pro-Val (KPV) as well as derivatives like Lys-d-Pro-Thr (KdPT), the latter containing the amino acid sequence 193-195 of interleukin-1ß, have been found to possess anti-inflammatory effects but to lack the pigment-inducing activity of α-MSH. We propose here that such peptides are promising future candidates for the treatment of cutaneous wounds and skin ulcers. Experimental approaches in silico, in vitro, ex vivo and in animal models are outlined. This is followed by an unbiased discussion of the pro and contra arguments of such peptides as future candidates for the therapeutic management of cutaneous wounds and a review of the so-far available data on melanocortin peptides and derivatives in wound healing.

Tropisetron via α7 nicotinic acetylcholine receptor suppresses tumor necrosis factor-α-mediated cell responses of human keratinocytes.

Tropisetron is a serotonin receptor (5-HT-R)-modulating agent and approved as an antiemetic for patients undergoing chemotherapy. In the gut, it acts via specific serotonin receptors, 5-HT3 -R, to elicit its beneficial effects against nausea. We investigated whether tropisetron can affect inflammatory cell responses of human primary epidermal keratinocytes (NHK) which are key cells in the regulation of skin homoeostasis. Tropisetron significantly and dose-dependently suppressed tumor necrosis factor (TNF)-α-mediated mRNA expression and protein secretion of interleukin (IL)-6 and IL-8 in these cells. This effect of tropisetron was independent of p65/NF-κB as shown by various NF-κB signal transduction read-outs. Importantly, the anti-inflammatory tropisetron effect on NHK was neither mediated by 5-HT3 -R nor 5-HT4 -R since these receptors were absent in NHK. In contrast, NHK expressed α7 nicotinic acetylcholine receptors (α7nAchR) which previously were found to bind tropisetron. The α7nAchR antagonist α-bungarotoxin neutralized, whereas AR-R17779, a specific α7nAchR agonist, mimicked the suppressive effect of tropisetron on TNF-α-mediated IL-6 and IL-8 expression in NHK. Our findings suggest that tropisetron and probably other α7nAchR-activating agents could be useful for the future therapy of inflammatory skin diseases.

Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT-1 melanoma cells.

Melanogenesis is a key parameter of differentiation in melanocytes and melanoma cells; therefore, search for factors regulating this pathway are strongly desired. Herein, we investigated the effects of melatonin, a ubiquitous physiological mediator that is found throughout animals and plants. In mammals, the pineal gland secretes this indoleamine into the blood circulation to exert an extensive repertoire of biological activities. Our in vitro assessment indicates an oncostatic capacity of melatonin in time-dependent manner (24, 48, 72 hours) in highly pigmented MNT-1 melanoma cells. The similar pattern of regulation regarding cell viability was observed in amelanotic Sk-Mel-28 cells. Subsequently, MNT-1 cells were tested for the first time for evaluation of melanin/melatonin interaction. Thus primary, electron paramagnetic resonance (EPR) spectroscopy demonstrated that melatonin reduced melanin content. Artificially induced disturbances of melanogenesis by selected inhibitors (N-phenylthiourea or kojic acid) were slightly antagonized by melatonin. Additionally, analysis using transmission electron microscopy has shown that melatonin, particularly at higher dose of 10-3  mol/L, triggered the appearance of premelanosomes (stage I-II of melanosome) and MNT-1 cells synthesize de novo endogenous melatonin shown by LC-MS. In conclusion, these studies show a melanogenic-like function of melatonin suggesting it as an advantageous agent for treatment of pigmentary disorders.