Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuroendocrine equivalent of the systemic hypothalamic–pituitary–adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used corticotropin‐releasing hormone (CRH), which triggers the HPA axis, to induce a stress response in human ex vivo male AGA HFs. Caffeine is known to reverse testosterone‐mediated hair growth inhibition in the same hair organ culture model.

BACKGROUND:Recent studies provide evidence for significant and previously underestimated barrier damaging effects of repeated exposure to 60% n-propanol in healthy skin in vivo.OBJECTIVES:To investigate further the cumulative effects of a range of n-propanol concentrations relevant at the workplace in healthy and atopic dermatitis (AD) individuals, and study the modulation of the outcomes by co-exposure and host-related factors.METHODS:Healthy adult and AD volunteers were exposed to n-propanol concentrations from 30% to 75% in occlusion-modified tandem repeated irritation test with measurements of erythema, transepidermal water loss, capacitance, and the natural moisturizing factor (NMF) levels at baseline and after 96 hours.RESULTS:n-Propanol exerted significant barrier damaging effects even at the lowest concentration in both groups. Exposure to all n-propanol concentrations significantly reduced the NMF levels. Preceding low-grade trauma by occlusion/water exposure reduced the skin irritation threshold in both groups. The differences in the severity of the barrier function impairment after exposure to the same concentrations under the same conditions between the AD and control groups were significant.CONCLUSIONS:The negative effects of cumulative exposure to n-propanol in healthy and atopic skin shown in the study suggest the need for critical re-evaluation of its irritant properties in vivo.

Background: Recently, natural moisturizing factors (NMFs) and corneocyte surface topography were suggested as biomarkers for irritant dermatitis. Objectives: To investigate how exposure to different irritants influences corneocyte surface topography, NMF levels and the barrier function of human skin in vivo. Methods: Eight healthy adult volunteers were exposed to aqueous solutions of 60% n-propanol, 0.5% sodium lauryl sulfate (SLS), 0.15% sodium hydroxide, and 2.0% acetic acid, and distilled water, in a repeated irritation test over a period of 96 hours. Erythema, transepidermal water loss (TEWL), skin hydration, the dermal texture index (DTI) and NMF levels were measured at baseline, and after 24 and 96 hours. Results: SLS and sodium hydroxide had the most pronounced effects on erythema and TEWL. Although n-propanol caused only slight changes in TEWL and erythema, it showed pronounced effects on skin hydration, NMF levels, and the DTI. NMF was the only parameter that was significantly altered by all investigated irritants. The changes in the DTI were inversely associated with NMF levels and skin hydration. Conclusion: Skin barrier impairment and the inflammatory response are irritant-specific, emphasizing the need for a multiparametric approach to the study of skin irritation. NMF levels seem to be the most sensitive parameter in detecting irritant-induced skin barrier alterations.

Prevention of the flares is a main goal in the long-term treatment of atopic dermatitis (AD). Therefore we investigated the efficacy of a water-in-oil emollient, containing licochalcone A, omega-6-fatty acids, ceramide 3 and glycerol, for prevention of the flares in adults with mild to moderately severe AD, treated with topical steroids, that led to clearing of the inflammatory lesions and had been discontinued prior to inclusion. The study was a 12-week, double-blind, randomized, vehicle-controlled, left-right comparison test with the number of relapses, defined as re-occurrence of erythema for at least 3 consecutive days, considered the primary outcome. Compared with the vehicle, the active formulation significantly reduced the number of relapses and maintained the barrier homeostasis of the respective arm. To the best of knowledge, this is the first study to show prevention of the AD flares by the use of stand-alone emollient treatment, based on comparison with the corresponding vehicle while excluding concomitant/rescue medications.

BACKGROUND:Increased skin-surface pH is an important host-related factor for deteriorated barrier function in aged skin.OBJECTIVES:We investigated whether restoration of skin pH through topical application of a water-in-oil emulsion with pH 4 improved the barrier homeostasis in aged skin, and compared the effects with an identical galenic formulation with pH 5·8.METHODS:The effects of the test formulations on barrier recovery were investigated by repeated measurements of transepidermal water loss (TEWL) and skin pH 3 h, 6 h and 24 h after acetone-induced impairment of barrier function in aged skin. The long-term effects of the pH 4 and pH 5·8 emulsions were analysed by investigation of the barrier integrity and cohesion, the skin-surface pH and the skin roughness and scaliness before and after a 4-week, controlled application of the formulations.RESULTS:The application of the pH 4 emulsion accelerated barrier recovery in aged skin: 3 h and 6 h after acetone-induced barrier disruption the differences in the TEWL recovery between the pH 4 treated and acetone control fields were significant. Furthermore, long-term application of the pH 4 formulation resulted in significantly decreased skin pH, enhanced barrier integrity and reduced skin-surface roughness and scaliness. At the same time points, the pH 5·8 formulation exerted only minor effects on the barrier function parameters.CONCLUSIONS:Exogenous acidification through topical application of a water-in-oil emulsion with pH 4 leads to improvement of the skin barrier function and maintenance of the barrier homeostasis in aged skin.

BACKGROUND:Androgenetic alopecia (AGA) is the most common cause of hair loss in men. Topical minoxidil solutions can help to treat AGA but have to be applied continuously to be effective. OBJECTIVES:A new minoxidil formulation with improved cosmetic characteristics (DC0120, Pierre-Fabre Dermatologie) was tested for noninferiority vs a comparator minoxidil product (ALOSTIL® , Johnson & Johnson) in stimulating hair growth in men with AGA. METHODS:Two 10 cm2 areas on the scalp of each subject were randomized to receive DC0120, the comparator, or one of their corresponding vehicles, applied twice per day for 16 weeks. Nonvellus target area hair count (TAHC) was measured within treatment areas at baseline (day 1) and after 8 and 16 weeks by digital phototrichogram. RESULTS:Two hundred and twenty subjects were included and randomized, of which 210 completed the study. The mean change in nonvellus TAHC between baseline and week 16 was +22.0 hairs/cm2 (95% CI: 18.1; 25.9) in the DC0120 group and +20.5 hairs/cm2 (95% CI: 16.6; 24.4) in the comparator group. The adjusted mean difference in TAHC changes between the two treatments was +1.5 hairs/cm2 (95% CI -2.3; 5.2), with the lower 95% confidence interval above the noninferiority threshold of -7 hairs/cm2 . This indicated that DC0120 was noninferior to the comparator. Both minoxidil treatments also increased nonvellus TAHC compared to vehicle groups at 8 and 16 weeks. No new safety signals were observed. CONCLUSIONS:DC0120 was as safe and effective as a similar marketed minoxidil product for stimulating hair growth in men with AGA.

Irritant damage to the permeability barrier elicits a cascade of responses that could be investigated by minimally invasive in vivo methods providing different information on biochemical and functional levels. Recent studies have shown that parallel to impairment of the barrier function and reduction of the natural moisturising factor (NMF), irritants such as the anionic detergent sodium lauryl sulfate (SLS) influence the corneocyte surface topography, investigated by atomic force microscopy and expressed by the Dermal Texture Index (DTI). To extend these findings, we investigated the early and late effects of different water soluble irritants on the barrier function, DTI, NMF and primary cytokine levels in healthy volunteers exposed to 60% N-propanol, 0.5% SLS, 0.15% sodium hydroxide, 2.0% acetic acid and occlusion with water in a controlled tandem repeated irritation test (TRIT) over 96 h. The irritant response was assessed by measuring erythema, transepidermal water loss (TEWL) and capacitance at baseline, 24 h and 96 h later; the cytokine levels, NMF and DTI were assessed in tape strips, collected at the same time points from the irritant-exposed and non-exposed sites. The magnitude of effects exerted by the irritants on the barrier integrity and properties, primary cytokine levels and DTI, found in the study, differed significantly, based on the chemical characteristics. The changes in DTI correlated with the NMF levels while being less influenced by inflammation. Though the observed differences may be influenced by the applied irritant concentration, our results confirm the need for a multi-parametric approach in the characterization of the irritant-specific barrier response and identification of sensitive outcome parameters for studying skin irritation in vivo.

Melatonin is produced in almost all living taxa and is probably 2-3 billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non-enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O-demethylation or non-enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor-dependent and receptor-independent mechanisms, receptors for melatonin metabolites remain to be identified, while their receptor-independent activities are well documented. The human skin with its main cellular components including malignant cells can both produce and rapidly metabolize melatonin in cell-type and context-dependent fashion. The predominant metabolism in human skin occurs through indolic, CYP-mediated and kynuric pathways with main metabolites represented by 6-hydroxymelatonin, N-1-acetyl-N-2-formyl-5-methoxykynuramine (AFMK), N-1-acetyl-5--methoxykynuramine (AMK), 5-methoxytryptamine, 5-methoxytryptophol and 2-hydroxymelatonin. AFMK, 6-hydroxymelatonin, 2-hydroxymelatonin and probably 4-hydroxymelatonin can potentially be produced in epidermis through UVB-induced non-enzymatic melatonin transformation. The skin metabolites are also the same as those produced in lower organisms and plants indicating phylogenetic conservation across diverse species and adaptation by skin of the primordial defense mechanism. As melatonin and its metabolites counteract or buffer environmental stresses to maintain its homeostasis through broad-spectrum activities, both melatoninergic and degradative pathways must be precisely regulated, because the nature of phenotypic regulations will depend on local concentration of melatonin and its metabolites. These can be receptor-mediated or represent non-receptor regulatory mechanisms.

Melatonin (MEL, N-acetyl-5-methoxytryptamine) and its main kynurenic metabolites AFMK (N1-acetyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine) have been recently shown to significantly enhance epidermal proliferation/differentiation of human skin ex vivo under normal, non-UV-exposed conditions. Here, we investigated the ability of MEL, AFMK and AMK to stabilize skin homeostasis under UVR exposure. Human ex vivo skin was irradiated with the validated UV dose of 300 mJ/cm2 (UVB/A) or sham-irradiated (0 mJ/cm2) (control) and pre-incubated with or without MEL, AFMK and AMK (10–3 M) for 1 h prior to UVR exposure. The skin was then directly removed from the culture (0 h) or further cultivated for 24 or 48 h. Immunofluorescence staining of skin cryosections showed that UVR decreased protein expression of insulin like growth factor-1 (IGF-1), cytokeratin-14 (K14), a marker of non-differentiating (proliferating) basal layer keratinocytes, as well as p63 protein, a multi-isoform p53 family member required for epidermal development by 9% (IGF-I), 22% (K-14; p<0.01) and 8% (p63) after 24 h, as well as 5% (IGF-1), 12% (K-14) and 28% (p63) at 48 h post-UVR, respectively. Pre-incubation with the tested compounds inhibited the negative effects of UVR leading to 78% and 9% increase of IGF-1 24 h after UV exposure by MEL and AMK, respectively, but not by AFMK. K-14 was enhanced by 33% (MEL), 37% (AFMK) and 47% (AMK) and p63 was enhanced by 27% by AMK, but not by MEL or AFMK. At 48 h post UV exposure, protein levels of IGF-1 were increased by 20% by AMK, but not by MEL or AFMK, and by 38% (MEL), 37% (AFMK) and 23% (AMK) for K-14. Protein expression of p63 was enhanced by 39% by AMK, but not by MEL or AFMK. In conclusion, UV showed an inhibition of epidermal proliferation and differentiation in human full skin which was partly reversed by MEL, AFMK and AMK. So, these compounds have the potential to attenuate alterations in skin homeostasis caused by UVR.

BACKGROUND:Hair loss is caused by a variety of hair growth disorders, each with its own pathogenetic mechanism.METHODS:This review is based on pertinent articles retrieved by a selective search in PubMed, on the current German and European guidelines, and on the authors' clinical and scientific experience.RESULTS:Excessive daily hair loss (effluvium) may be physiological, as in the postpartum state, or pathological, due for example to thyroid disturbances, drug effects, iron deficiency, or syphilis. Androgenetic alopecia generally manifests itself in women as diffuse thinning of the hair over the top of the scalp, and in men as receding temporal hairlines and loss of hair in the region of the whorl on the back of the head. Alopecia areata is patchy hair loss arising over a short time and involving the scalp, eyebrows, beard, or entire body. The hair loss of alopecia areata is reversible in principle but hard to treat. Folliculitis decalvans is a form of alopecia with scarring, characterized by inflamed papules, pustules, and crusts at the edges of the lesions. Lichen planopilaris generally presents with small patches of baldness, peripilar erythema, and round areas of skin scaling. Kossard's frontal fibrosing alopecia is characterized by a receding hairline and loss of eyebrows.CONCLUSION:Hair loss is a symptom, not a diagnosis. The pathogenesis of the alopecias involves a range of genetic, endocrine, immune, and inflammatory processes, each of which calls for its own form of treatment.

Cell stress-inducible heat shock protein 90 (Hsp90) has been recognized as key player in mediating inflammatory responses. While its systemic blockade was successfully used to treat autoimmune diseases in preclinical models, efficacy of a topical route of Hsp90 inhibitor administration has so far not been evaluated in chronic inflammatory and autoimmune-mediated dermatoses. Here, effects of the Hsp90 blocker 17-allylamino-demethoxygeldanamycin (17AAG) applied topically to the skin were determined in experimental inflammatory epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Topical 17AAG ameliorated clinical disease severity when given before or during occurrence of skin lesions without causing cutaneous or systemic toxicity in mice with antibody transfer- and immunization-induced EBA. In both EBA models and in the setting of locally induced inflammation, topical 17AAG treatment was associated with (i) reduced neutrophilic infiltrates, (ii) decreased NFκB activation, (iii) lowered expression of matrix metalloproteinases and Flightless I, and (iv) induction of anti-inflammatory Hsp70 in the skin. Our results suggest that topical delivery of Hsp90 antagonists, offering the benefit of a reduced risk of systemic side effects of Hsp90 inhibition, may be useful for the control of EBA and possibly other related inflammatory skin disorders.

Cell stress-inducible Hsp90 has been recognized as key player in mediating inflammatory responses. Although its systemic blockade was successfully used to treat autoimmune diseases in preclinical models, efficacy of a topical route of Hsp90 inhibitor administration has so far not been evaluated in chronic inflammatory and autoimmune-mediated dermatoses. Here, effects of the Hsp90 blocker 17-allylamino-demethoxygeldanamycin (17AAG) applied topically to the skin were determined in experimental inflammatory epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Topical 17AAG ameliorated clinical disease severity when given before or during the occurrence of skin lesions without causing cutaneous or systemic toxicity in mice with antibody transfer-and immunization-induced EBA. In both EBA models and in the setting of locally induced inflammation, topical 17AAG treatment was associated with (i) reduced neutrophilic infiltrates, (ii) decreased NF-kappa B activation, (iii) lowered expression of matrix metalloproteinases and Flii, and (iv) induction of anti-inflammatory Hsp70 in the skin. Our results suggest that topical delivery of Hsp90 antagonists, offering the benefit of a reduced risk of systemic adverse effects of Hsp90 inhibition, may be useful for the control of EBA and possibly other related inflammatory skin disorders.

Melatonin is an ubiquitous molecule with a variety of functions including potent antioxidative properties. Due to its lipophilic character, it easily crosses cellular and intracellular membranes and reaches all subcellular organelles. Because of its ability to scavenge free radicals, melatonin protects against oxidative stress, for example, induced by ultraviolet radiation (UVR). Here, we investigated, in a dose-dependent (0, 10, 25, and 50 mJ/cm(2) ) and time-dependent (0, 4, 24, 48 hr post-UVR) manner, whether melatonin prevents the UVR-mediated alterations in ATP synthesis and the generation of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEK). Additionally, we evaluated the molecular mechanism of action of melatonin with regard to activation of phase-2 antioxidative enzymes via nuclear erythroid 2-related factor (Nrf2). We found that (i) melatonin counteracted UVR-induced alterations in the ATP synthesis and reduced free radical formation; (ii) melatonin induced the translocation of Nrf2 transcription factor from the cytosol into the nucleus resulting in, (iii) melatonin enhanced gene expression of phase-2 antioxidative enzymes including γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), and NADPH: quinone dehydrogenase-1 (NQO1) representing an elevated antioxidative response of keratinocytes. These results suggest that melatonin not only directly scavenges ROS, but also significantly induces the activation of phase-2 antioxidative enzymes via the Nrf2 pathway uncovering a new action mechanism that supports the ability of keratinocytes to protect themselves from UVR-mediated oxidative stress.

Alcohol-based disinfectants and detergents are common workplace factors for irritant contact dermatitis (ICD). Though occlusion and water are relevant co-exposures, the tandem effects of occlusion and sequential exposure to alcohols and detergents have not been studied. We therefore investigated the combined effects of occlusion with water and repeated exposure to n-propanol and/or sodium lauryl sulphate (SLS) in an occlusion-modified tandem irritation test. The outcomes included visual scoring, measurement of erythema, transepidermal water loss, capacitance and natural moisturizing factor (NMF) levels. Occlusion abrogated the skin barrier function and significantly enhanced the irritant-induced barrier damaging effects. The NMF levels of all irritant-exposed fields decreased significantly compared with the non-exposed fields; occlusion enhanced the decrease in NMF. Although SLS exerted more pronounced effects on the measured parameters, the barrier function impairment and NMF decrease after exposure to n-propanol in workplace-relevant concentrations, found in the study, confirm the significance of short-chain aliphatic alcohols for occupational ICD.

Melatonin, a lipophilic compound synthesized and released from the pineal gland, effectively acts against ultraviolet radiation (UVR), one of the main inducers of epidermal damage, skin cancer, inflammation, and DNA photo damage. One of the common known stress protein induced by UVR is heat shock protein 70 (Hsp70), highly expressed in human keratinocytes, providing cellular resistance to such stressors. Here, using human full‐thickness skin and normal human epidermal keratinocytes (NHEK), we investigated the interaction of melatonin and Hsp70 toward UVR‐induced inflammatory and apoptotic responses. The following observations were made: (i) UVR upregulated Hsp70 gene expression in human epidermis while melatonin significantly inverted this effect, (ii) similar patterns of regulation were observed within Hsp70 protein level, and (iii) mechanistic studies involving silencing of Hsp70 RNA (Hsp70 si RNA) showed prominent decrease of IκB‐ α (an inhibitor of NF‐κB) and enhanced gene expression of pro‐inflammatory cytokines (IL‐1 β , IL‐6, Casp‐1) and pro‐apoptotic protein (Casp‐3) in NHEK. Parallel investigation using melatonin (10 −3 m ) significantly inverted these responses regardless depletion of Hsp70 RNA suggesting a compensatory action of this compound in the defense mechanisms. Our findings combined with data reported so far thus enrich existing knowledge about the potent anti‐apoptotic and anti‐inflammatory action of melatonin.