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.     

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.     

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.     

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.     

Interleukin (IL)‐6 modulates transforming growth factor‐β receptor I and II (TGF‐βRI and II) function in epidermal keratinocytes

It been shown that IL‐6 modulates TGF‐β1 expression in fibroblasts, however, what role IL‐6 plays concerning TGF‐βR expression and function in skin is unknown. Therefore, the aim of this study was to investigate the mechanism by which IL‐6 might modulates TGF‐β receptors in skin. Skin from WT, IL‐6 over‐expressing mice and IL‐6 treated keratinocyte cultures was analysed for TGF‐βRI and TGF‐βRII expression via histology, PCR and flow cytometry. Receptor function was assessed by cell migration, bromodeoxyuridine (BrdU) proliferation assays, and Smad7 expression and Smad2/3 phosphorylation. Receptor localization within the membrane was determined by co‐immunoprecipitation. IL‐6 overexpression and treatment increased TGF‐βRII expression in the epidermis. IL‐6 treatment of keratinocytes induced TGF‐βRI and II expression and augmented TGF‐β1‐induced function as demonstrated through increased migration and decreased proliferation. Additionally, IL‐6 treatment of keratinocytes altered receptor activity as indicated by altered Smad2/3 phosphorylation and increased Smad7 and membrane localization. These results suggest that IL‐6 regulates keratinocyte function by modulating TGF‐βRI and II expression and signal transduction via trafficking of the receptor to lipid raft pools.     

Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)‐related overgrowth spectrum: A brief report

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA‐mutation is described. This case is an example of the clinical diversity of the PIK3CA‐Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly‐Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.     

Expression of α‐methylacyl‐CoA racemase (P504S) in sebaceous neoplasms

Background: α‐Methylacyl‐CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal β‐oxidation of branched‐chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. Methods: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi‐objective grading schema. Results: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. Conclusions: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC. Halsey MA, Calder KB, Mathew R, Schlauder S, Morgan MB. Expression of α‐methylacyl‐CoA racemase (P504S) in sebaceous neoplasms.     

Studies on serum 8‐hydroxy guanosine (8‐OHdG) as reliable biomarker for psoriasis

Background Oxidative stress was implicated in the psoriasis disease development and may damage DNA leading to keratinocytes cell death. No serum biomarker was available for the oxidative DNA damage. Objectives To evaluate the 8‐OHdG (8‐Hydroxy guanosine) as reliable biomarker for the oxidative stress in psoriatic patients with severity. Methods A total of 30 patients were considered for the study and graded according to the Psoriasis Area Severity Index (PASI) and 10 healthy controls. Blood was collected under aseptic condition, and serum was separated. Serum 8‐OHdG and total antioxidant capacity was measured by competitive enzyme linked immunosorbent assay using `8‐OHdG Check’ and PAO kit (JaICA, Fukuroi City, Japan). Results The average serum 8‐OHdG level in the control, mild, moderate and severe groups were 1.18 ± 0.93 ng/mL, 3.46 ± 0.82 ng/mL, 3.68 ± 0.67 ng/mL and 4.86 ± 1.7 ng/mL respectively. There was no significant difference in the average level of total antioxidant capacity of control, mild, moderate and severe groups, and the values presented were 295.88 ± 206 μmol/L, 1392.20 ± 225 μmol/L, 1199.57 ± 257 μmol/L and 1184.24 ± 207 μmol/L respectively. Conclusion Serum 8‐OHdG levels could be used as good biomarker for the early diagnosis of psoriasis and its management.     

Multicenter study „Medical‐Occupational Rehabilitation Procedure Skin – optimizing and quality assurance of inpatient‐management (ROQ)”

Scientifically based prevention and patient management concepts in occupational dermatology have substantially improved during recent years. Currently the public statutory employers' liability insurance bodies fund a multi‐step intervention approach designed to provide quick preventive help for all levels of severity of occupational dermatoses. An administrative guideline (hierarchical multi‐step intervention procedure for occupational skin diseases –“Stufenverfahren Haut”) insures professional support and optimal patient orientation by the statutory insurers' representatives. For secondary prevention, the so‐called dermatologist's procedure (“Hautarztverfahren”) was recently updated in order to provide more rapid dermatologic consultations which are covered for by the public statutory employers' liability insurance bodies. Additionally, combined outpatient dermatologic and health‐educational intervention seminars (“secondary individual prevention”[SIP]) are offered to affected employees in a nationwide scheme. For those cases of occupational dermatoses in which these outpatient prevention measures are not successful, interdisciplinary inpatient rehabilitation measures have been developed (“tertiary individual prevention”[TIP]). TIP requires 3 weeks inpatient treatment including intensive health care instruction and psychological counseling, followed by outpatient treatment by the local dermatologist. In 2005, a German prospective cohort multicenter study (“Medical‐Occupational Rehabilitation Procedure Skin – optimizing and quality assurance of inpatient‐management”–“Medizinisch‐Berufliches Rehabilitationsverfahren Haut – Optimierung und Qualitätssicherung des Heilverfahrens”[ROQ]) started which will further standardize TIP and evaluate scientific sustainability in depth (3‐year dermatological follow‐up of 1,000 patients). The study is being funded by the German Statutory Accident Insurance (Deutsche Gesetzliche Unfallversicherung [DGUV]).