Journal: Experimental dermatology
Studies on bimatoprost were performed with two objectives: (i) to determine whether bimatoprost possesses hair growth-stimulating properties beyond eyelash hypertrichosis and (ii) to investigate the biodisposition of bimatoprost in skin for the first time. Bimatoprost, at the dose used clinically for eyelash growth (0.03%) and given once daily for 14 days, increased pelage hair growth in C57/black 6 mice. This occurred as a much earlier onset of new hair growth in shaved mice and the time taken to achieve complete hair regrowth, according to photographic documentation and visual assessment. Bimatoprost biodisposition in the skin was determined at three concentrations: 0.01%, 0.03% and 0.06%. Dose-dependent C(max) values were obtained (3.41, 6.74, 12.3 μg/g tissue), and cutaneous bimatoprost was well maintained for 24 h following a single dose. Bimatoprost was recovered from the skin only as the intact molecule, with no detectable levels of metabolites. Thus, bimatoprost produces hypertrichosis as the intact molecule.
Mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation and survival. There is limited evidence that mTOR influences hair follicles (HFs), which undergo cycles of quiescence (telogen), growth (anagen) and regression (catagen). We sought to investigate whether mTOR, in particular mTOR complex 1 (mTORC1), regulates the hair growth cycle by employing biochemical, immunohistochemical and functional approaches in vivo. Here, we demonstrate that quantitative analysis of mTORC1 kinase activity shows phase-dependent changes, and phosphorylated mTOR at S2448 (p-mTOR) was localized in certain sites of HFs in a phase-dependent manner. These results were indicative of mTOR’s role in hair growth initiation. Finally, in a pharmacological challenge in vivo using the specific mTORC1 inhibitor, rapamycin, hair cycle initiation was delayed, suggesting a functional relevance of mTORC1 in anagen entry. Based on our findings, we propose that mTORC1 may participate in hair cycle regulation, namely the timing of anagen initiation.
The aim of this study is to quantify D. folliculorum colonisation in rosacea subtypes and age-matched controls and to determine the relationship between D. folliculorum load, rosacea subtype and skin innate immune system activation markers. We set up a multicentre, cross-sectional, prospective study in which 98 adults were included: 50 with facial rosacea, including 18 with erythematotelangiectatic rosacea (ETR), and 32 with papulopustular rosacea (PPR) and 48 age- and sex-matched healthy volunteers. Non-invasive facial samples were taken to quantify D. folliculorum infestation by quantitative PCR and evaluate inflammatory and immune markers. Analysis of the skin samples show that D. folliculorum was detected more frequently in rosacea patients than age-matched controls (96% vs 74%, P < 0.01). D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers. Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR. Overexpression of LL-37 and VEGF, as well as CD45RO, MPO and CD163, was observed, indicating broad immune system activation in patients with rosacea. In conclusion, D. folliculorum density is highly increased in patients with rosacea, irrespective of rosacea subtype. There appears to be an inverse relationship between D. folliculorum density and inflammation markers in the skin of rosacea patients, with clear differences between rosacea subtypes.
Sweating is an important physiological process to regulate body temperature in humans and various disorders are associated with dysregulated sweat formation. Primary sweat secretion in human eccrine sweat glands involves Ca(2+) -activated Cl(-) channels (CaCC). Recently, members of the TMEM16 family were identified as CaCCs in various secretory epithelia, however, their molecular identity in sweat glands remained elusive. Here we investigated the function of TMEM16A in sweat glands. Gene expression analysis revealed that TMEM16A is expressed in human NCL-SG3 sweat gland cells as well as in isolated human eccrine sweat gland biopsy samples. Sweat gland cells express several previously described TMEM16A splice variants, as well as one novel splice variant, TMEM16A(acΔe3) lacking the TMEM16A-dimerization domain. Chloride-flux assays using halide-sensitive YFP revealed that TMEM16A is functionally involved in Ca(2+) -dependent Cl(-) secretion in NCL-SG3 cells. Recombinant expression in NCL-SG3 cells showed that TMEM16A(acΔe3) is forming a functional CaCC, with basal and Ca(2+) -activated Cl(-) permeability distinct from canonical TMEM16A(ac). Our results suggest that various TMEM16A isoforms contribute to sweat gland-specific Cl(-) secretion providing opportunities to develop sweat gland-specific therapeutics for treatment of sweating disorders. This article is protected by copyright. All rights reserved.
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung, or even the brain. We have shown that JunB(Δep) mice develop a SLE phenotype linked to increased epidermal Interleukin (IL) -6 secretion. Blocking of IL-6 receptor alpha (IL-6Rα) is considered as therapeutic strategy for treatment of SLE. JunB(Δep) and wild type mice were treated for short (5 weeks) or long term (21 weeks) with the IL-6Rα blocking antibody MR16-1. Skin and kidney of mice were investigated by histology and immunofluorescence and in addition kidneys were analyzed by electron microscopy. Furthermore, soluble IL-6R (sIL-6R), anti-histone and anti-nucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16-1 resulted in significant improvement of SLE-like skin lesions in JunB(Δep) mice, compared to untreated mice. The sIL-6R amount upon long-term treatment with MR16-1 was significantly higher in JunB(Δep) versus untreated JunB(Δep) (p=0.034) or wild type mice (p=0.034). MR16-1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher anti-histone (p=0.028) and anti-nucleosome antibody levels (p=0.028) were measured in MR16-1 treated JunB(Δep) mice after treatment compared to levels before therapy. In conclusion, blockade of IL-6Rα improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune-mediated kidney pathology. Inhibition of IL-6R signaling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies. This article is protected by copyright. All rights reserved.
Type 1 interferons (IFNs) including IFN-β, are widely used in adjuvant therapy for patients who undergo surgery for malignant melanoma to inhibit recurrence and in-transit metastasis. The precise mechanisms underlying the tumor-suppressive effects of IFN-β on melanoma are not yet completely understood.
The 3rd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on October 12-14, 2018 at the Women’s College Hospital in Toronto, Ontario, Canada. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This cross-disciplinary meeting with experts from around the world was an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa pathogenesis, epidemiology, classification, scoring systems, radiologic diagnosis, treatment approaches, and psychologic assessment. Two special sessions this year were HS as a systemic disease and HS management guidelines. There were focused workshops on wound healing and ultrasound. There were two sessions primarily for patients and their families in the HS School program: one workshop focused on mindfulness, and the second involved discussion among clinicians and patients about various disease aspects and the latest management. To facilitate networking between clinical and research experts and those early in their career, a mentoring breakfast was held. This article is protected by copyright. All rights reserved.
Hair follicle formation in developing embryonic skin requires stepwise signaling between the epithelial epidermis and mesenchymal dermis, and their specialized derivatives, the placode/germ/peg and dermal condensate/papilla, respectively. Classically, distinct stages of hair follicle morphogenesis have been defined, in the mouse model, based on 1) changes in cell morphology and aggregation, 2) expression of few known molecular markers, 3) the extent of follicle downgrowth, and 4) the presence of differentiating cell types. Refined genetic strategies and recent emerging technologies, such as live imaging and transcriptome analyses of isolated cell populations or single cells, have enabled a closer dissection of the signaling requirements at different stages of hair follicle formation, particularly early on. They have also led to the discovery of precursor cells for placode, dermal condensate and future bulge stem cells that, combined with molecular insights into their fate specification and subsequent formation, serve as novel landmarks for early hair follicle morphogenetic events and studies of the signaling networks mediating these processes. In this review, we integrate the emergence of hair follicle precursor cell states and novel molecular markers of fate and formation to update the widely used 20-year old seminal classification guide of hair follicle morphogenetic stages by Paus and colleagues. We then temporally describe the latest insights into the early cellular and molecular events and signaling requirements for hair follicle morphogenesis in relation to one another in a holistic manner. This article is protected by copyright. All rights reserved.
Malignant melanoma is an aggressive skin cancer, which can lead to metastasis development. Vascularization enhancement is fundamental for tumor growth, worsening the prognosis. Dynamic Optical Coherence Tomography (D-OCT) enables the in vivo evaluation of vascular patterns in skin lesions.
We developed an automated approach for generating quantitative image analysis metrics (imaging biomarkers) that are then analyzed with a set of thirteen machine-learning algorithms to generate an overall risk score that is called a Q-score. These methods were applied to a set of 120 “difficult” dermoscopy images of dysplastic nevi and melanomas that were subsequently excised/classified. This approach yielded 98% sensitivity and 36% specificity for melanoma detection, approaching sensitivity/specificity of expert lesion evaluation. Importantly, we found strong spectral dependence of many imaging biomarkers in blue or red color channels, suggesting the need to optimize spectral evaluation of pigmented lesions. This article is protected by copyright. All rights reserved.