Cannabinoid system in the skin – a possible target for future therapies in dermatology

Abstract:  Cannabinoids and their derivatives are group of more than 60 biologically active chemical agents, which have been used in natural medicine for centuries. The major agent of exogenous cannabinoids is Δ⁹-tetrahydrocannabinol (Δ⁹-THC), natural psychoactive ingredient of marijuana. However, psychoactive properties of these substances limited their use as approved medicines. Recent discoveries of endogenous cannabinoids (e.g. arachidonoylethanolamide, 2-arachidonoylglycerol or palmithyloethanolamide) and their receptors initiated discussion on the role of cannabinoid system in physiological conditions as well as in various diseases. Based on the current knowledge, it could be stated that cannabinoids are important mediators in the skin, however their role have not been well elucidated yet. In our review, we summarized the current knowledge about the significant role of the cannabinoid system in the cutaneous physiology and pathology, pointing out possible future therapeutic targets.     

Health services research in dermatology – current update and perspectives

Background: An indepth knowledge of the demands on health care resources and the quality of health care provision is of major importance for the future care of skin and allergy patients. We present a comprehensive summary of all available health care data and research activities in dermatology in Germany. Methods: A standardized electronic literature search was performed using PUBMED as well as a manual search to identify activities in the field of health services research in dermatology. Furthermore, questionnaires were sent to 114 dermatology hospitals and to 52 health service research institutions in Germany. Results: The overall return rate of the survey was 81%.Hints on projects were given by 30 hospitals and 5 institutions. Most of these projects were in the field of epidemiology, quality of life, economy and prevention. Finally, the search identified 101 health services research projects in Germany. In addition, material gathered from internet and secondary citations from scientific journals produced a total of 216 publications. Only few projects were found on the working conditions of physicians and other health care professionals, on the implementation of guidelines, on needs and use of dermatological services and on the quality of care. Conclusions: The findings demonstrate that there are substantial deficiencies in some important areas of health services research in dermatology.To provide efficient and qualified dermatological health care in Germany in the future, more research projects on the needs, demands and quality of health care are needed.     

Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: current update and future perspective

Scleroderma is a fibrotic condition characterized by immunologic abnormalities, vascular injury and increased accumulation of matrix proteins in the skin. Although the aetiology of scleroderma is not fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from complex interactions among endothelial cells, lymphocytes, macrophages and fibroblasts, via a number of mediators. Cytokines, chemokines and growth factors secreted by inflammatory cells and mesenchymal cells (fibroblasts and myofibroblasts) play an important role in the fibrotic process of scleroderma. Recently, we established a murine model of scleroderma by repeated local injections of bleomycin. Dermal sclerosis was induced in various mouse strains, although the intensity of dermal sclerosis varied among various strains. Histopathological and biochemical analysis demonstrated that this experimental murine scleroderma reflected a number of aspects of human scleroderma. Further investigation of the cellular and molecular mechanisms of inflammatory reaction, fibroblast activation and extracellular matrix deposition following dermal injury by bleomycin treatment will lead to the better understanding of the pathophysiology and the exploration of effective treatment against scleroderma. This review summarizes recent progress of the cellular and molecular events in the pathogenesis of bleomycin-induced scleroderma; moreover, further perspective by using this mouse model has been discussed.     

Clinical potential of Melanotan® (NDP-α-MSH) in skin protection – current status and future perspective

Non-histaminergic pruritus of any origin is difficult to treat and requires evaluation of new therapeutic strategies which were offered by recent neurophysiologic findings. For example, the discovery of opioid receptors on mast cells and nerve fibers enables the effective administration of opioid receptor antagonists. Up to now, 130 patients with pruritus of different origin were successfully treated with the oral opioidantagonist naltrexone. A significant therapeutic response was achieved under 50–150 mg daily in 66% of patients. In prurigo nodularis, naltrexone also contributed to healing of the skin lesions. Tachyphylaxis was infrequent, and adverse drug effects, in particular nausea, were of short duration. Only recently, the vanilloid receptor 1 (VR1) was demonstrated on nerve fibers and mast cells what explains the antipruritic efficacy of the topical application of capsaicin. Upon continual therapy with this VR1-ligand, neuropeptides are depleted and the nerve fiber is desensitized. A total of 53 patients with pruritus of different origin (prurigo nodularis, psoriasis, eczema, aquagenic pruritus, PUVA itch, hydroxyethyl starch-induced itch, and lymphoma) were selected to receive capsaicin four to six times daily in gradually increasing concentrations (0.025–0.1%). After cessation of the symptoms of neurogenic inflammation, all of the patients experienced a complete elimination of pruritus within 12 days. In addition, capsaicin largely contributed to healing of the skin lesions in prurigo nodularis.     

Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy.     

A succinct review of botulinum toxin in dermatology; update of cosmetic and noncosmetic use

Botulinum toxin A has a wide variety of clinical applications in medical and dermatologic sciences. Nowadays, researchers introduce some other indications for botulinum toxin in cosmetic and especially noncosmetic aspects of dermatology such as medical rhinoplasty, hypertrophic scar, chemical brow lift, supraciliary wrinkles, pompholix, eccrine angiomatosis, Hailey-Hailey, dermatochalasis, lichen simplex, nosthalgia parestetica, and granulosis rubra nasi. In this general overview of the use of botulinum toxin in dermatology, an extensive literature search was carried out to updates of all dermatology-oriented experiments and clinical trials on the mentioned aspect of botulinum toxin.     

Skin aging and sex hormones in women – clinical perspectives for intervention by hormone replacement therapy

Abstract:  The skin, the largest organ of the body, is the organ in which changes associated with aging are most visible. The skin is a target organ for various hormones, and sex steroids have a profound influence on the aging process. A decrease in sex steroids thus induces a reduction of those skin functions that are under hormonal control. Keratinocytes, Langerhans' cells, melanocytes, sebaceous glands, collagen content and the synthesis of hyaluronic acid, for example, are under hormonal influence. Topical application of estrogens has a positive effect on skin aging parameters, whilst numerous studies have also shown the positive influence of systemic hormone replacement therapy on skin aging. As an alternative treatment, phytohormones may be administered, with the structural similarity to 17β-estradiol explaining their estrogen-like effects. However, isoflavonoids exhibit an inferior biological potency to synthetic estrogens. Although a large number of publications have documented the effects of sex hormones on the aging process, it is obvious that hormone replacement should not be administered as an independent treatment for skin aging.     

JAK抑制剂治疗斑秃的现状、前景及其启示

斑秃是一种慢性、异质性炎症性疾病,确切病因未明,虽治疗方法众多,但无特效药,也无对所有患者有效的疗法,加之部分慢性、重度患者对常规治疗反应差,因此急需新型有效的治疗方法。2014年起国外应用JAK抑制剂治疗斑秃,取得确切疗效。JAK抑制剂治疗斑秃的机制主要是抑制免疫细胞产生炎症因子,还可能直接作用于毛囊上皮细胞,推动毛囊周期进入生长期,有效率可达70%～80%,尤其是对重症和激素治疗无效的患者有很好的应用前景。虽其存在价格高、有潜在感染倾向等副作用,但仍不失为重症斑秃治疗的有效和二线措施。本文主要阐述JAK抑制剂的作用机制和治疗斑秃的现状、前景以及由此引发的对斑秃发病机制的启示。     

Loureirin B inhibits fibroblast proliferation and extracellular matrix deposition in hypertrophic scar via TGF‐β/Smad pathway

The ethanolic extract of Resina Draconis (RDEE) has been reported beneficial to normal wound healing yielding more regularly arranged collagen fibres. Loureirin B, a major component in RDEE, has been supposed to be effective on the prevention and treatment of pathological scars. To investigate the therapeutic effects of loureirin B on hypertrophic scar (HS), fibroblasts from human HS and normal skin (NS) were isolated. Results showed that loureirin B dose‐dependently downregulated both mRNA and protein levels of type I collagen (ColI), type III collagen (ColIII) and α ‐ smooth muscle actin (α ‐ SMA) in HS fibroblasts. Loureirin B also suppressed fibroblast proliferative activity and redistributed cell cycle, but did not affect cell apoptosis. In vivo rabbit ear scar model, loureirin B significantly improved the arrangement and deposition of collagen fibres, decreased protein levels of ColI, ColIII and α ‐ SMA and suppressed myofibroblast differentiation and scar proliferative activity. In NS fibroblasts, loureirin B effectively inhibited TGF‐β1‐induced upregulation of ColI, ColIII and α‐SMA levels, myofibroblast differentiation and the activation of Smad2 and Smad3. Loureirin B also affected mRNA levels of major MMPs and TIMPs in TGF‐β1‐stimulated fibroblasts. Taken together, this study demonstrates that loureirin B could downregulate the expression of fibrosis‐related molecules by regulating MMPs and TIMPs levels, inhibit scar fibroblast proliferation and suppress TGF‐β1‐induced fibrosis, during which TGF‐β1/Smad2/3 pathway is likely involved. These findings suggest that loureirin B is a potential therapeutic compound for HS treatment.     

Doctor–patient relations in dermatology: obligations and rights for a mutual satisfaction

The author examines different aspects of patient–doctor relationship in dermatological consultations. At first, a definition of patients satisfaction is given, based on available literature. It has been shown that satisfaction depends on diagnosis, but also on the doctor's ability to provide explanations on the probable cause of the illness, information on how long the symptom will probably last, and if she/he demonstrates empathy. Satisfaction also increases if the illness is serious, but decreases if quality of life linked to the symptom is underestimated by the doctor. After providing a philosophical definition of ethics, which emphasizes the importance of mutual satisfaction of patient and doctor, the concepts of empathy and compassion in patient-doctor relations are defined. Their importance in consultations is underlined, reporting, for example, that doctors with good communication skills experience fewer difficult consultations (8% vs. 23%). Afterwards, the dermatological consultation is analysed in its practical aspects, trying to define a good-quality consultation. First of all, the pitfalls that can affect good time management are analysed, suggesting to structure the consultation using the Soap method. Particular situations are analysed, such as announcing bad news and dealing with borderline patients. Finally, the concept of transference is defined, remembering that doctor–patient relationships can replay some difficult relationship coming from the past, and thus doctors need to be aware of this possibility and learn how to manage it.     

Non‐invasive bioengineering methods in an intervention study in 1020 male metal workers: results and implications for occupational dermatology

Background: Measurements of transepidermal water loss (TEWL) as an indicator of skin barrier function and colorimetry for quantifying erythema have been recommended for monitoring persons at risk of occupational hand dermatitis. Objective: This study examines the practicability and usefulness of biophysical measurements at the workplace. Patients/Material/Methods: A sample of 1020 male metal workers was enrolled; 800 participants were followed up for 1 year. TEWL results and colorimetry (a* value), respectively, were used as effectiveness outcomes, comparing the findings in the four study arms (skin care, skin protection, both combined, and control group). Results: At 1 year follow‐up, the TEWL was slightly but significantly lower in the group of participants randomized for application of barrier cream alone, indicating a protective effect. However, addressing both the individual absolute change of a* value and the differences of TEWL (delta‐TEWL) of the dominant hand over the study period, no significant difference was found between the four groups. Conclusions: Dermatological examinations at the workplace cannot be replaced by bioengineering techniques. The supplementary benefit is apparently low, possibly because of difficulties in achieving standardized measurement conditions and other technical reasons.     

Dietary supplements in dermatology: A review of the evidence for zinc,biotin, vitamin D,nicotinamide, and Polypodium

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Study of three complementary techniques for measuring cutaneous hydration in vivo in human subjects: NMR spectroscopy, transient thermal transfer and corneometry – application to xerotic skin and cosmetics

Background/aims: The aim of this study was to determine the capability and the analytical quality of three different in vivo, non‐invasive, quantitative methods for measuring skin hydration: two innovative methods that have been used for more than eight years – nuclear magnetic resonance spectroscopy (NMR‐S) and transient thermal transfer (TTT) – and the more widely used and conventional corneometry. Methods: The work presented evaluated the capability and precision, as well as cutaneous exploration depths, of the three methods. Experiments were carried out in vivo following the hydration, in kinetic terms, induced by topic application of reference moisturizing products. Spatio‐temporal efficacy of a lipolotion was also studied by the TTT method. Cases of xerotic skin were studied with TTT and corneometry. Results: The results obtained showed better repeatability and reproducibility with the TTT and NMR‐S methods than with corneometry. NMR‐S is one of the only direct hydration measurement methods. It measures skin hydration down to the outer dermis with high precision. It is indicated for products having an action down to the deep cutaneous layers. By changing thermal power parameters, the TTT method can determine hydration to the outer, middle or deep epidermal layers. It is, therefore, possible to track the penetration of products in various layers of the epidermis. The small size of the probe enables the hydration measurement of skin sites (lips, eyelids) that were not, up to now, measurable with the two other methods. Corneometric investigations are restricted to the surface of the horny layer; measurements are easy and rapid but influenced by the composition of products applied to the skin and their phases: aqueous, oily or ionic. The xerotic skin study highlights the importance of exploration in different layers of the epidermis, as dehydration concerns not only the upper layers of the epidermis but also the medial and deep layers. With the TTT method, it has been possible to highlight the penetration dynamics of a lipolotion with, initially, an increase in the hydration in the outer epidermis, followed 3 h later by a transfer from the outer to the middle epidermis. Conclusion: NMR‐S, TTT and corneometry represent three possible ways to assess skin hydration. Because they explore different cutaneous depths, they are more complementary than competitive. Transient thermal transfer, although a semi‐direct method, is a precise, informative, and innovative solution to evaluate skin hydration at different epidermal depths and sites.     

High frequency of the 425A-->G splice-site mutation and novel mutations of the COL7A1 gene in central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa

BACKGROUND: Mutations in the type VII collagen gene (COL7A1) are responsible for dominant and recessive forms of dystrophic epidermolysis bullosa (DEB). These mutations are usually specific for individual families; only a few cases of recurring mutations have been identified. OBJECTIVES: Forty-three unrelated Hungarian and German patients with different DEB phenotypes were screened for novel and recurrent COL7A1 mutations. METHODS: All patients were classified based on clinical and genetic findings, skin immunofluorescent antigen mapping, and electron microscopic studies. Mutation analysis was performed by amplification of genomic DNA with polymerase chain reaction using COL7A1-specific primers, heteroduplex analysis, and direct nucleotide sequencing. Restriction endonuclease digestion was used for family screening and mutation verification. Results In this group of patients, the splice-site mutation 425A-->G was observed frequently, in 11 of 86 alleles (12.8%), once in homozygous form and in nine cases in heterozygous form. One of 100 control alleles from clinically unaffected individuals also carried the mutation. We also identified three novel mutations: the 976-3C-->A splice-site mutation, and the 4929delT and 8441-15del20 deletions. CONCLUSIONS: High recurrence of the splice-site mutation 425A-->G in central European patients with DEB should be taken into account when designing COL7A1 mutation detection strategies. Reporting of three novel COL7A1 mutations in this study further emphasizes the molecular heterogeneity of DEB and provides more information for studies on genotype-phenotype correlations in different DEB subtypes.