Melanocortin 5 receptor signaling pathway in health and disease.

Melanocortin hormone system plays a key role in maintaining the homeostasis of our body via their neuro-immune-endocrine activities and regulates a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function, and exocrine secretion. The pathobiologic actions of all melanocortins are conveyed by melanocortin receptors. As the last melanocortin receptor to be cloned and characterized, melanocortin receptor 5 (MC5R) is widely expressed in both central nervous system and a number of peripheral organ systems in man. However, the exact effect of the MC5R mediated melanocortinergic signaling remains largely uncertain. Owing to the recent advances in developing highly selective peptidomimetic agonists and antagonists of MC5R and also to studies in MC5R knockout animals, our understanding of MC5R pathobiology has been greatly expanded and strengthened. Evidence suggests that MC5R plays a key role in governing immune reaction and inflammatory response, and is pivotal for the regulation of sexual behavior, thermoregulation, and exocrine secretion, like sebogenesis, lacrimal secretion and release of sex pheromones. As such, recent translational efforts have focused on developing novel sebum-suppressive therapies for seborrhoea and acne vulgaris based on antagonizing MC5R. Conversely, selective MC5R agonists have demonstrated promising beneficial effects in immune-mediated diseases, metabolic endocrinopathies and other disease conditions, such as glomerular diseases and dry eyes, skin and mouth. Thus, MC5R-mediated signaling is essential for health. Therapeutic targeting of MC5R represents a promising and pragmatic therapeutic strategy for diverse diseases. This review article delineates the biophysiology of MC5R-mediated biophysiology of the melanocortin hormone system, discusses the existing data on MC5R-targeted therapy in experimental disease models, and envisages the translational potential for treating human diseases.

Topical application of nanoparticles integrated supramolecular hydrogels for the potential treatment of seborrhoeic dermatitis.

The current application was aimed to evaluate the therapeutic potential of selenium and ketoconazole nanoparticles loaded hyaluronic acid gel against seborrhoeic dermatitis (SD). Amalgamation of ketoconazole (antifungal medication) and selenium (pro-oxidant) in an optimized formulation setting may help in the treatment of SD. In this study, selenium and ketoconazole nanoparticles loaded hyaluronic acid (HA) hydrogel was prepared by mechanical mixing followed by sonication. Results of the optimized batch showed a mean particle size of 121 ± 12 nm for ketoconazole and 51 ± 7 nm for selenium. SEM and TEM study revealed the prepared nanoparticles are of nanoscale dimension, with smooth spherical outline. Finally, the optimized nanoparticles were incorporated into HA hydrogel. Hydrogel exhibits desirable physical, mechanical and rheological characteristics appropriate for topical application. Optimized gel formulation exhibited an enhanced permeability with better antifungal, and anti-inflammatory activities, compared with the plain drug suspension. The optimized hydrogel with ketoconazole and selenium in nanotemplate could offer a potential strategy for the treatment of SD.

The role of the microbiome in scalp hair follicle biology and disease.

The skin surface microbiome and its role in skin diseases have received increasing attention over the past years. Beyond, there is evidence for a continuous exchange with the cutaneous immune system in healthy skin, where hair follicles (HFs) provide unique anatomical niches. Especially, scalp HFs form large tubular invaginations, which extend deeply into the skin and harbour a variety of microorganisms. The distinct immunology of HFs with enhanced immune cell trafficking in superficial compartments in juxtaposition to immune-privileged sites crucial for hair follicle cycling and regeneration makes this organ a highly susceptible structure. Depending on composition and penetration depth, microbiota may cause typical infections, but may also contribute to pro-inflammatory environment in chronic inflammatory scalp diseases. Involvement in hair cycle regulation and immune cell maturation has been postulated. Herein, we review recent insights in hair follicle microbiome, immunology and penetration research and discuss clinical implications for scalp health and disease.

Unilateral acne after facial palsy.

We describe a case of unilateral acne which appeared after an episode of facial nerve palsy. An 18-year-old female patient presented with papules and pustules predominantly located on the side where the facial paralysis occurred. The patient suffered right facial paralysis, which was treated with prednisone and kinesiotherapy with massages, electrostimulation, and infrared light. Two weeks later, acne lesions appeared in the area affected by the paralysis. As suggested in other cases of paralysis, including cases of Parkinson's disease and spinal cord injury, an increased sebum excretion rate and the immobility of the affected area are most likely what caused the unilateral acne lesions.

Unilateral acne after facial palsy

Abstract: We describe a case of unilateral acne which appeared after an episode of facial nerve palsy. An 18-year-old female patient presented with papules and pustules predominantly located on the side where the facial paralysis occurred. The patient suffered right facial paralysis, which was treated with prednisone and kinesiotherapy with massages, electrostimulation, and infrared light. Two weeks later, acne lesions appeared in the area affected by the paralysis. As suggested in other cases of paralysis, including cases of Parkinson's disease and spinal cord injury, an increased sebum excretion rate and the immobility of the affected area are most likely what caused the unilateral acne lesions.

Low-dose oral isotretinoin for moderate to severe seborrhea and seborrheic dermatitis: a randomized comparative trial.

BACKGROUND: The efficacy of low-dose oral isotretinoin in the treatment of seborrhea and seborrheic dermatitis has been poorly investigated in randomized studies. OBJECTIVES: This study was designed to determine the efficacy and safety of low-dose oral isotretinoin in the treatment of moderate to severe seborrhea and seborrheic dermatitis on the scalp and/or face. METHODS: A randomized, comparative clinical trial, using two groups, was conducted over 6 months. Patients in Group ISO were treated with isotretinoin 10 mg every other day. In Group X, patients received antiseborrheic topical treatment. Patient opinion, investigator assessment, scalp pruritus, sebum production, and quality of life (QoL) comprised the efficacy outcomes. RESULTS: The intention-to-treat population comprised a total of 45 patients with mean ± standard deviation ages of 28.7 ± 5.8 years in Group ISO and 29.8 ± 6.5 years in Group X. The rate of sebum production significantly decreased in Group ISO. Patient opinion, investigator, and QoL assessments improved in both groups. CONCLUSIONS: Low-dose oral isotretinoin can be a therapeutic modality for moderate to severe seborrhea and seborrheic dermatitis.

iTRAQ-based quantitative proteomics of stratum corneum of dandruff scalp reveals new insights into its aetiology and similarities with atopic dermatitis.

The study aimed at detecting differentially expressed proteins in the stratum corneum of dandruff versus non-dandruff scalps to better understand dandruff aetiology. iTRAQ-based quantitative proteomic analysis revealed a total of 68 differentially expressed biomarkers. A detailed analysis of their known physiological functions provided new insights into the affected metabolic pathways of a dandruff scalp. Dandruff scalp showed (1) profound changes in the expression and maturation of structural and epidermal differentiation related proteins, that are responsible for the integrity of the skin, (2) altered relevant factors that regulate skin hydration, and (3) an imbalanced physiological protease-protease inhibitor ratio. Stratum corneum proteins with antimicrobial activity, mainly those derived from sweat and sebaceous glands were also found modified. Comparing our data with those reported for atopic dermatitis revealed that about 50 % of the differentially expressed proteins in the superficial layers of the stratum corneum from dandruff and atopic dermatitis are identical.

Physiological and microbiological verification of the benefit of hair washing in patients with skin conditions of the scalp.

BACKGROUND: It is unclear whether hair washing is effective against scalp eruption and pruritus caused by seborrheic dermatitis or psoriasis vulgaris. AIMS: To assess whether a proper hair-washing regimen, including the use of antibacterial shampoo, can ameliorate scalp eruption symptoms and alter the composition of the scalp microflora. METHODS: Eighteen patients with seborrheic dermatitis or psoriasis vulgaris scalp eruptions were instructed in proper techniques of daily hair washing, rinsing, and shampooing, which they underwent for 12 weeks. They used control shampoo in weeks 1-4 and 9-12, and an antibacterial shampoo during weeks 5-8. At the start of the test period and at weeks 4, 8, and 12, we assessed scalp symptoms (erythema, scaling/desquamation, dryness, itchiness, and scratching scars); microbial DNA levels from lesion and nonlesion areas; and levels of interleukin (IL)-1α, IL-1ra, and total protein in the scalp's horny layer. RESULTS: Compared to baseline values, scaling/desquamation and itchiness improved significantly at weeks 8 and 12. Other observed skin symptoms also improved over time. Malassezia colonization levels in lesion and nonlesion areas decreased gradually; the decrease was significant at week 8 in lesion areas and at weeks 4 and 8 in nonlesion areas. Bacterial colonization levels also decreased gradually, achieving significance in lesion areas at week 4. Gradual decreases in IL-1ra/IL-1α level showed statistical significance at weeks 4 and 12, while the protein quantity significantly decreased at week 12. CONCLUSION: Proper hair washing improved scalp condition symptoms, and possibly the underlying etiology.

Possible intermediary role of ghrelin in seborrhea.

Seborrhea, or oily skin, is a very common condition, especially among young people, caused by the increased secretion of sebum by sebaceous glands in the skin. Based on today's knowledge, a regulatory role of various hormones especially androgens is considered for sebaceous gland secretion; but despite significant evidences emphasis on the effects of the gastrointestinal disorders on coetaneous manifestations, the role of gastrointestinal problems in sebum secretion has not been emphasized yet. This study aimed to explain hormonal changes occurring in gastroesophageal reflux disease which may cause changes in sebaceous gland secretion so that, by explaining these communication mechanisms, common investigations between gastroenterology and dermatology can be performed to evaluate the accuracy of this hypothesis.

Role of sebaceous glands in inflammatory dermatoses.

Skin is an important interface between the host and its environment. Inflammatory dermatoses often have disrupted skin barrier function, rendering patients more susceptible to allergenic triggers leading to an exaggerated immune response. The skin surface lipid film, an important component of the skin barrier, comprises a mixture of keratinocyte and sebaceous gland-derived lipids. Recent evidence demonstrated that defective keratinocyte lipid synthesis predisposes for the development of atopic dermatitis. However, the important role of sebaceous gland-derived lipids in skin inflammatory diseases may be underrecognized. This overview focuses on the importance of the contribution of sebaceous glands to barrier function. Sebaceous gland alteration may play a role in the pathogenesis of common skin diseases including acne vulgaris, atopic dermatitis, psoriasis, rosacea, and seborrheic dermatitis.

Cathepsin S, a new pruritus biomarker in clinical dandruff/seborrhoeic dermatitis evaluation.

Dandruff/seborrhoeic dermatitis (D/SD) is characterized by Malassezia colonization, impaired barrier function with subsequent inflammation, resulting in dandruff and itching. Histamine is one of the biomarkers of pruritus now widely used in treatment efficacy trials. The exact mechanism leading to histamine release and pruritus is not yet clear. However, it could involve cathepsin S, an activator of proteinase-activated receptor 2 (PAR2). The purpose of this study was to evaluate the levels of cathepsin S, PAR2 and histamine in patients with D/SD compared with healthy subjects through non-invasive sampling of the scalp and to correlate those markers with D/SD clinical parameters. A significant increase in the three biological markers was observed in the D/SD group versus healthy subjects, and those markers were correlated with clinical parameters. In conclusion, cathepsin S could be a potential marker of pruritus in D/SD and could help assessing the effect of treatments.

Ovarian SAHA syndrome is associated with a more insulin-resistant profile and represents an independent risk factor for glucose abnormalities in women with polycystic ovary syndrome: a prospective controlled study.

BACKGROUND: SAHA syndrome is characterized by the tetrad: seborrhea, acne, hirsutism, and androgenetic alopecia. No previous study has examined the prevalence of glucose abnormalities in ovarian SAHA and explored whether it may be an independent risk factor for glucose abnormalities. OBJECTIVE: In a prospective controlled study, we investigated the spectrum of glucose abnormalities in ovarian SAHA and explored whether it is associated with a more insulin-resistant profile. METHODS: In all, 316 patients with a diagnosis of polycystic ovary syndrome (PCOS) (56 with SAHA) and 102 age-matched healthy women were examined and underwent a 2-hour oral glucose tolerance test. Serum glucose homeostasis parameters, hormones, and adipokines were determined. RESULTS: SAHA prevalence was 17.7% in patients with PCOS and predominance of the severe PCOS phenotype. Ovarian SAHA was independently associated with a more insulin-resistant profile (higher homeostatic model assessment of insulin resistance score, lower quantitative insulin sensitivity check index [QUICKI] and MATSUDA indices, and relative hypoadiponectinemia), and represented an independent risk factor for glucose abnormalities regardless of anthropometric features, age, and PCOS phenotype. LIMITATION: There was no performance of skin biopsies. CONCLUSION: The prompt recognition of SAHA syndrome in women with PCOS permits an earlier diagnosis and surveillance of metabolic abnormalities, especially in Mediterranean PCOS population exhibiting a lower prevalence of glucose abnormalities.

Oxidative stress in patients with scalp seborrheic dermatitis.

Seborrheic dermatitis (SD) is a common, chronic inflammatory skin disease that mainly affects the scalp. The objective of this study was to evaluate the activities of superoxide dismutase (SOD) and catalase (CAT) and the levels of malondialdehyde (MDA) in scraping samples of patients with scalp SD. Thirty consecutive patients with a diagnosis of scalp SD and thirty-one healthy volunteers were enrolled. The samples were obtained by scraping the skin surface of the scalp. SOD and CAT activities and MDA levels were measured in scraping samples by spectrophotometric method. SOD and CAT activities and MDA levels were significantly higher in patients than in controls (p<0.001 all). There was a positive correlation between the severity of the disease and itching scores (contingency coefficient = 0.671, p<0.001). Except for this correlation, there was no significant correlation among age, sex, duration and severity of the disease, itching scores, antioxidant enzymes and MDA levels in the patient group (p>0.05). Cutaneous oxidative stress in patients with SD may play an important role in the pathogenesis of the disease. Further clinical and laboratory evaluation of the oxidant/antioxidant system in patients with SD is warranted.

Skin lipid profiling in normal and seborrhoeic shih tzu dogs.

BACKGROUND: Seborrhoea is a clinical condition resulting in excessive lipid and/or scale on the skin and is a common and important skin disease of dogs. However, there is little information on the skin surface lipid composition of dogs with seborrhoea. HYPOTHESIS/OBJECTIVES: To compare skin surface lipid profiles in normal and seborrhoeic shih tzu dogs. METHODS: Fourteen client-owned dogs (seven seborrhoeic and seven normal) were investigated. Lipids in sebaceous glands (SGs) were extracted from homogenized tissues of SG hyperplasia. Surface lipid was collected by tape stripping [stratum corneum (SC)-enriched fraction] and acetone-wetted cotton swab (acetone-extracted fraction). Lipids in SGs, SC-enriched fractions and acetone-extracted fractions were evaluated by high-performance thin-layer chromatography. RESULTS: Lipids in SGs mainly consisted of cholesterol esters, wax esters and triglycerides, whereas lipids in the SC-enriched fraction mainly consisted of ceramides. The acetone-extracted fraction contained a mixture of lipid classes recognized in SG- and SC-enriched fractions. In seborrhoeic dogs, concentrations of wax esters and triglycerides in the acetone-extracted fraction were significantly higher than in control dogs (P = 0.0285). Amounts of total ceramides (in micrograms) per milligram of SC were not significantly different between the two groups (P = 0.5204). Interestingly, two unknown ceramide fractions, which accounted for 20% of the total ceramides, were recognized exclusively in seborrhoeic dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: These results provide evidence that the skin surface lipid profiles are altered in shih tzu dogs with seborrhoea.

A comprehensive pathophysiology of dandruff and seborrheic dermatitis - towards a more precise definition of scalp health.

Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.

Investigations of seborrheic dermatitis. Part II. Influence of itraconazole on the clinical condition and the level of selected cytokines in seborrheic dermatitis.

INTRODUCTION: The pathogenesis of seborrheic dermatitis has not been fully elucidated. A number of anascogenic yeasts of Malassezia spp. appear to be involved in the intensity of the symptoms. The purpose of the study is to evaluate the levels of selected inflammatory cytokines, IL-2, IL-4, IFN-γ and TNF-α, in the serum after treatment with itraconazole. MATERIAL/METHODS: Sixty-six subjects were enrolled in the study. The control group consisted of 30 participants (23 females and 7 males) without any clinical disorders, aged 24-65 (37.41±6.08 years). Thirty-six patients with seborrheic dermatitis (16 females and 20 males), aged 19-76 (38.61±13.77), constituted the study group. The measurement of IL-2, IL-4, IFN-γ and TNF-α levels was performed by ELISA using a Human High Sensitivity kit (Diaclone, France). RESULTS: After six-week treatment with itraconazole administered daily at a dose of 200 mg using pulse therapy, there was remission of the disease or at least substantial clinical improvement in the patients with seborrheic dermatitis. The levels of IL-2 and IFN-γ cytokines in the study group were higher than in the control group. After the treatment the level of IFN-γ secretion in the male patients with seborrheic dermatitis significantly increased. The levels of the other studied cytokines did not significantly differ. CONCLUSIONS: The treatment with itraconazole had a beneficial effect on the clinical condition of the skin of the patients. IFN-γ is a cytokine whose secretion might affect the condition of the skin in seborrheic dermatitis.

The utility of ATF3 in distinguishing cutaneous squamous cell carcinoma among other cutaneous epithelial neoplasms.

The histopathologic distinction between benign and malignant cutaneous keratinocytic proliferations can pose a difficult diagnostic challenge - often with important clinical implications. Activating transcription factor 3 (ATF3) has emerged as a potential biomarker which may aid in the segregation of these lesions, and we hypothesize that ATF3 expression may be a specific marker of cutaneous squamous cell carcinoma (SCC). Using immunohistochemistry, we characterized ATF3 expression in a series of 126 cutaneous epithelial proliferations, including SCC (n = 27), basal cell carcinomas (BCC, n = 59), seborrheic keratoses with atypia (SK, n = 16), hyperplastic actinic keratoses (AK, n = 12) and prurigo nodularis cases (PN, n = 12). We showed strong, nuclear and/or nucleolar expression of ATF3 in a statistically significant number of cases of SCC compared to BCC, SK and PN. We conclude that ATF3 expression is a surrogate of malignancy (or pre-malignancy) in keratinocytic epithelial proliferations and thus helps distinguish SCC from other cutaneous epithelial neoplasms.

Seborrheic dermatitis: an update.

Seborrheic dermatitis is a chronic relapsing inflammatory skin disorder clinically characterized by scaling and poorly defined erythematous patches. The prevalence of adult seborrheic dermatitis is estimated at 5%. Although the exact cause of seborrheic dermatitis has yet to be understood, Malassezia yeasts, hormones (androgens), sebum levels and immune response are known to play important roles in its development. Additional factors including drugs, winter temperatures and stress may exacerbate seborrheic dermatitis. A variety of treatment modalities are available, including antifungal agents, topical low-potency steroids and calcineurin inhibitors (immunomodulators). This review summarizes current knowledge on the etiopathogenesis and therapy of adult seborrheic dermatitis.

Stratum corneum dysfunction in dandruff.

Dandruff is characterized by a flaky, pruritic scalp and affects up to half the world's population post-puberty. The aetiology of dandruff is multifactorial, influenced by Malassezia, sebum production and individual susceptibility. The commensal yeast Malassezia is a strong contributory factor to dandruff formation, but the presence of Malassezia on healthy scalps indicates that Malassezia alone is not a sufficient cause. A healthy stratum corneum (SC) forms a protective barrier to prevent water loss and maintain hydration of the scalp. It also protects against external insults such as microorganisms, including Malassezia, and toxic materials. Severe or chronic barrier damage can impair proper hydration, leading to atypical epidermal proliferation, keratinocyte differentiation and SC maturation, which may underlie some dandruff symptoms. The depleted and disorganized structural lipids of the dandruff SC are consistent with the weakened barrier indicated by elevated transepidermal water loss. Further evidence of a weakened barrier in dandruff includes subclinical inflammation and higher susceptibility to topical irritants. We are proposing that disruption of the SC of the scalp may facilitate dandruff generation, in part by affecting susceptibility to metabolites from Malassezia. Treatment of dandruff with cosmetic products to directly improve SC integrity while providing effective antifungal activity may thus be beneficial.