In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)

Tyrosinase is a key enzyme that catalyses the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC₅₀ value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.     

Connexin‐26‐Mutation bei „Keratitis‐Ichthyosis‐Deafness”‐Syndrom (KID‐Syndrom)

Background: Keratitis‐ichthyosis‐deafness syndrome (KID syndrome) is an extremely rare disorder. Inheritance is autosomal dominant but many cases occur sporadically following a spontaneous mutation. The cause of KID syndrome are missense mutations of the gene GJB2, encoding connexin 26. Patients and Methods: We clinically studied two cases of KID syndrome and extracted genomic DNA from peripheral blood. Results: The patients showed different heterozygous mutations of the connexin 26 gene and had quite different clinical courses. Conclusions: Both patients showed heterozygous mutations of the connexin 26 gene; a different Cx26 dominant mutation can cause a very different clinical course.     

5‐Bromo‐2′‐deoxyuridine induced effluvium via p53‐mediated CD326‐positive keratinocyte apoptosis in C57BL/6 mice

Anagen effluvium develops because of disturbances in the hair follicle cycle, leading to acute and severe hair loss in humans. The objective of this study was to establish a mouse model of anagen effluvium by 5‐bromo‐2′‐deoxyuridine (BrdU) treatment, and evaluate the pathological changes and underlying mechanisms. We treated 9–10‐day‐old pups and 3–7‐week‐old C57BL/6 mice with BrdU. After successfully inducing hair loss in the neonatal pups, microscopic, immunohistochemical and flow cytometry analyses were conducted. BrdU induced early onset alopecia in neonates and caused epidermal thickening and hair shaft breakage. BrdU appeared to incorporate the CD326‐positive keratinocyte layer and induced p53‐related apoptosis. Keratinocyte apoptosis caused immune cell infiltration in the dermal region; M2 macrophages and neutrophils were dominant. The BrdU‐induced hair loss was dose‐dependent, and alopecia was visible at a dose range of 25–200 μg/g bodyweight. The BrdU‐induced anagen effluvium mouse model is novel and easily established by administrating four simple BrdU injections to pups; these mice showed synchronized onset of alopecia symptoms with little individual variation. Moreover, this model showed an alopecia phenotype similar to that of human anagen effluvium with acute, severe and widespread hair loss.     

Beneficial effects of the melanocortin analogue Nle4‐D‐Phe7‐α‐MSH in acne vulgaris

Background α‐Melanocyte‐stimulating hormone (α‐MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light‐mediated tanning. As α‐MSH has been shown to possess anti‐inflammatory effects, we assessed the clinical potential of a superpotent α‐MSH analogue, afamelanotide (Nle⁴‐d ‐Phe⁷‐α‐MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. Methods Afamelanotide (16 mg) was given in a phase II open‐label pilot study subcutaneously as a sustained‐release resorbable implant formulation to 3 patients with mild‐to‐moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient‐reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. Results The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short‐term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. Conclusions Afamelanotide appears to have anti‐inflammatory effects in patients with mild‐to‐moderate acne vulgaris. Future trials are needed to confirm the anti‐inflammatory action of this melanocortin analogue in patients with acne vulgaris.     

4‐(4‐Hydroxyphenyl)‐2‐butanol (rhododendrol)‐induced melanocyte cytotoxicity is enhanced by UVB exposure through generation of oxidative stress

4‐(4‐Hydroxyphenyl)‐2‐butanol (rhododendrol, RD), a skin‐whitening agent, was reported to cause skin depigmentation in some users, which is attributed to its cytotoxicity to melanocyte. It was reported that cytotoxicity to melanocyte is possibly mediated by oxidative stress in a tyrosinase activity‐dependent manner. We examined the effect of UV radiation (UVR) on RD‐induced melanocyte cytotoxicity as an additional aggravating factor. UVR enhanced RD‐induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress. Increased generation of intracellular reactive oxygen species (ROS) was detected. Pretreatment with N‐acetyl cysteine (NAC), antioxidant and precursor of glutathione significantly attenuated ER stress‐induced cytotoxicity in NHEMs treated with RD and UVR. Increase in cysteinyl‐RD‐catechol and RD‐pheomelanin in NHEMs treated with RD and UVR suggested that, after UVR excitation, RD or RD metabolites are potent ROS‐generating substances and that the tendency to produce RD‐pheomelanin during melanogenesis amplifies ROS generation in melanocytes. Our results help to elucidate the development mechanisms of RD‐induced leukoderma and provide information for innovation of safe skin‐whitening compounds.     

Anti‐p200‐Pemphigoid – Eine neue blasenbildende Autoimmundermatose

Anti‐p200 pemphigoid is an autoimmune skin disease characterized by tense blisters, subepidermal split formation, and mainly neutrophilic inflammatory infiltration of the dermal‐epidermal junction (DEJ). Direct immunofluorescence microscopy of perilesional skin biopsies demonstrates linear deposits of IgG and C3 along the DEJ, while by indirect immunofluorescence microscopy on NaCl‐split human skin, patients' IgG labels the dermal side. The antigenic target of the autoantibodies is a 200 kD protein (p200) of the lower lamina lucida that can be detected in human dermal extracts by immunoblotting. While p200 is thought to be important for cell‐matrix adhesion, its exact identity is unknown. To date, the p200 autoantigen has been demonstrated to be distinct from bullous pemphigoid antigens 180 und 230, laminin 1, 5, and 6, α6β4 integrin, and type VII collagen. Biochemical characterization of the p200 molecule revealed a noncollagenous N‐glycosylated acidic protein with an isoelectric point of approximately 5.5. We provide an overview on pathogenesis, clinical features, diagnosis, and treatment of this unique autoimmune dermatosis.     

Berufliche Beifuß‐Allergie

Background: Mugwort (Artemisia vulgaris) has traditionally been used as a spice, vegetable and as a herbal medicine. The main representatives of the Artemisia family besides Artemisia vulgaris include Artemisia absinthum and Artemisia dracunculus (estragon). Mugwort pollen allergens are important in triggering late summer and fall pollinosis; in addition cross reactivity occurs between Artemisia vulgaris pollen allergens and celery, carrottes and certain spices belonging to the family of Umbelliferae. Patients: A florist with a pre‐existing sunflower allergy developed a life‐threatening glottal edema after occupational contact with mugwort. She did not suffer from an oral allergy syndrome towards mugwort pollen cross allergens. Results: Skin testing (prick and scratch testing) revealed a strong sensitisation against mugwort and estragon. Specific IgE antibodies against mugwort, sunflower, carrots, celery, fennel and anis were elevated in the peripheral blood. Conclusions: The observation of a severe mugwort allergy with life‐threatening complications in a florist underscores the high allergenic potential of Artemisia vulgaris and documents for the first time the occupational significance of this allergy.