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The major role of sebaceous glands in mammals is to produce sebum, which coats the epidermis and the hair providing waterproofing, thermoregulation and photoprotection. However, as the need for these functions decreased along the evolutionary changes in humans, a relevant question has been raised: are sebaceous glands and sebum the remnants of our mammalian heritage or do they have overtaken a far more complex role in human skin biology? Trying to provide answers to this question, this review introduces the evolving field of sebaceous immunobiology and puts into the focus the pathways that sebum lipids use to influence the immune milieu of the skin. By introducing possible modifiers of sebaceous lipogenesis and discussing the - human-specific - alterations in composition and amount of sebum, the attribute of sebum as a sensitive tool, which is capable of translating multiple signalling pathways into the dermal micro environment is presented. Further their interaction with macrophages and keratinocytes involves sebum lipid fractions into disease pathogenesis, which could lead - on the other side - to the development of novel sebum-based therapeutic strategies.

Objective: RIS-1/psoriasin/S100A7 is an epithelial antimicrobial peptide, whose expression is upregulated in inflammatory skin diseases and is induced by retinoids. Its molecular expression was investigated in skin cell cultures and in skin specimens to better understand its role in inflammatory procedures of the pilosebaceous unit., Methods: rtPCR and northern blotting of RIS-1/psoriasin and the retinoid-metabolizing genes CYP26AI and CRABP-II were performed in cells cultures (keratinocytes, sebocytes, fibroblasts, endothelial cells, melanocytes, lymphocytes and prostate cells; native and treated with retinoids) and in situ hybridization in normal and inflamed skin (acne, psoriasis)., Results: a) RIS-1/psoriasin is expressed in keratinocytes and fibroblasts in vitro and in keratinocytes of the stratum granulosum in vivo . Retinoids in vitro and inflammatory conditions in vivo increase the levels of RIS-1/psoriasin in keratinocytes (both), sebocytes (inflammation only) and fibroblasts (retinoids). Sebocytes and fibroblasts are the metabolically most active skin cells, since they can upregulate the expression of CRABP-II and CYP26AI, genes responsible for retinoid metabolism. Inflammation modifies the compartmentation of RIS-1/psoriasin in sebaceous glands and the follicular root sheaths., Conclusion: The present data indicate that anti-inflammatory treatment targeting the epithelial compartments of the skin, including such with antibacterial peptides, may be promising for inflammatory skin diseases.

Hyper-glycemic food increases insulin-like growth factor 1 (IGF-1) and insulin signaling and regulates endocrine responses and thereby may modulate the course of acne. Inflammation and adaptive immune responses have a pivotal role in all stages of acne. Recent hypothesis suggests that hyperglycemic food reduces nuclear forkhead box-O1 (FoxO1) transcription factor and may eventually induces acne. The aim of our study was to investigate the role of IGF-1 and insulin on the phosphoinositide-3-kinase (PI3K)/Akt/FoxO1 pathway in human primary T cells and on the molecular functions of T cells in vitro . T cells were stimulated with 0.001 μM IGF-1 or 1 μM insulin +/- 20 μM PI3K inhibitor LY294002. T cells were also exposed to SZ95 sebocyte supernatants which were pre-stimulated with IGF-1 or insulin. We found that 0.001 µM IGF-1 and 1 µM insulin activate the PI3K pathway in T cells leading to up-regulation of p-Akt and p-FoxO1 at 15 and 30 minutes. Nuclear FoxO1 was decreased and FoxO transcriptional activity was reduced. 0.001 µM IGF-1 and 1 µM insulin increased T cell proliferation but have no significant effect on Toll-like receptor2/4 (TLR) expression. Interestingly, supernatants from IGF-1- or insulin-stimulated sebocytes activated the PI3K pathway in T cells but reduced T cell proliferation. Taken together, this study helps to support that high glycemic load diet may contribute to induce activation of the PI3K pathway and increase of proliferation in human primary T cells. Factors secreted by IGF-1- and insulin-stimulated sebocytes induce the PI3K pathway in T cells and reduce T cell proliferation, which probably can reflect a protective mechanism of the sebaceous gland basal cells.

Introduction: Despite the impressive increase of knowledge on acne etiology accumulated during the last 20 years, few efforts have been overtaken to introduce new therapeutic regiments targeting the ideal treatment of acne. The increasing emergence of microbial resistance associated with antibiotics, teratogenicity, particularly associated with systemic isotretinoin, and the need for an adverse drug profile, which can be tolerated by the patient, make the need of new pathogenesis relevant anti-acne agents an emerging issue. Areas covered: A search for phase 1 and 2 acne treatment trials in the US National Institutes of Health database of clinical trials and the European Medicines Agency database with the key words 'acne' and 'treatment' was carried out, on 6 January 2017. Expert opinion: The detected trials mostly investigate topical agents that may act via sebosuppressive effects, antimicrobial properties or anti-inflammatory actions. The compounds under investigation include olumacostat glasaretil, cortexolone 17α-propionate, stearoyl-CoA desaturase 1 inhibitors, agents affecting the melanocortin system, omiganan, and minocycline. Systemic studied anti-acne drugs include finasteride, biologics, low dose anti-inflammatory antibiotics, and leukotriene B4 inhibitors.

Introduction: Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 persons-years and a varying prevalence of 0.05-1% have been reported worldwide., Areas Covered: This manuscript summarizes the current evidence on chemistry, pharmacodynamics, pharmacokinetics, as well as clinical efficacy, safety and tolerability of the currently approved biologic drug adalimumab in the treatment of active moderate to severe HS in adults. Active, inflammatory lesions are expected to improve following 12 weeks of adalimumab treatment. The therapeutic response is greater following the registered weekly adalimumab (40 mg sc) administration in all clinical studies compared with the other treatments. Safety results were consistent with the known adalimumab safety profile. Expert commentary: Active, inflammatory lesions of HS are expected to respond to weekly administered adalimumab treatment. However, non-inflammatory, scarring lesions cannot respond to it. In such cases a combination treatment with radical surgery is required.

Sebaceous glands are skin appendages that secrete sebum onto hair follicles to lubricate the hair and maintain skin homeostasis. In this study, we demonstrated that Cidea is expressed at high levels in lipid-laden mature sebocytes and that Cidea deficiency led to dry hair and hair loss in aged mice. In addition, Cidea-deficient mice had markedly reduced levels of skin surface lipids, including triacylglycerides (TAGs) and wax diesters (WDEs), and these mice were defective in water repulsion and thermoregulation. Furthermore, we observed that Cidea-deficient sebocytes accumulated a large number of smaller-sized lipid droplets (LDs), whereas overexpression of Cidea in human SZ95 sebocytes resulted in increased lipid storage and the accumulation of large LDs. Importantly, Cidea was highly expressed in human sebaceous glands, and its expression levels were positively correlated with human sebum secretion. Our data revealed that Cidea is a crucial regulator of sebaceous gland lipid storage and sebum lipid secretion in mammals and humans.

Skin has been reported to reflect the general inner-health status and aging. Nutrition and its reflection on skin has always been an interesting topic for scientists and physicians throughout the centuries worldwide. Vitamins, carotenoids, tocopherols, flavonoids and a variety of plant extracts have been reported to possess potent anti-oxidant properties and have been widely used in the skin care industry either as topically applied agents or oral supplements in an attempt to prolong youthful skin appearance. This review will provide an overview of the current literature "linking" nutrition with skin aging.

Skin aging is a complex biological process influenced by a combination of endogenous or intrinsic and exogenous or extrinsic factors. Because of the fact that skin health and beauty is considered one of the principal factors representing overall "well-being" and the perception of "health" in humans, several anti-aging strategies have been developed during the last years. It is the intention of this article to review the most important anti-aging strategies that dermatologists have nowadays in hand, including including preventive measurements, cosmetological strategies, topical and systemic therapeutic agents and invasive procedures.

Safety concerns have been raised regarding possible association of major adverse cardiovascular events (MACEs) with use of anti-IL-12/23 biologic agents for the treatment of chronic plaque psoriasis (CPP). Ten MACEs have been recorded in actively-treated patients during the placebo-controlled phase of phase II and III studies compared with zero events in placebo-treated patients, along with a total of 53 MACEs (26 ustekinumab, 27 briakinumab) and five cardiovascular deaths (1 ustekinumab, 4 briakinumab) across all phases of these studies. Two industry-independent meta-analyses of randomized, double-blind, placebo-controlled, monotherapy trials calculated risk for MACEs. One detected statistically significant increase in cardiovascular risk using Peto method (p = 0.04), while the other utilized Mantel-Haenszel fixed-effects model with absolute risk differences as effect measure, but did not achieve significance (p = 0.11). Statistical theory reports that Peto method is more suitable for meta-analyses of studies with baseline event rates of 1% or less and randomization ratios ranging from 1:5 to 1:1 as is the case in these meta-analyses. Potential of anti-IL-12/23 biologic agents to further increase cardiovascular morbidity cannot be excluded and a class effect cannot be denied. Clinicians should screen CPP patients for manageable cardiovascular risk factors before initiating anti-IL-12/23 agents along with intensive monitoring of these patients.

Skin aging is a complex process and underlies multiple influences with the probable involvement of heritable and various environmental factors. Several theories have been conducted regarding the pathomechanisms of aged skin, however fundamental mechanisms still remain poorly understood. This article addresses the influence of genetics on skin aging and in particular deals with the differences observed in ethnic populations and between both genders. Recent studies indicate that male and female aged skin differs as far as the type, the consistency and the sensitivity to external factors is concerned. The same has been also documented between elderly people of different origin. Consequently, the aging process taking place in both genders and in diverse ethnic groups should be examined separately and products specialized to each population should be developed in order to satisfy the special needs.

Comorbidities of hidradenitis suppurativa (acne inversa) were reviewed by extracting original and review publications included in MEDLINE, EMBASE and COCHRANE libraries using the terms "hidradenitis," "Verneuil" and "acne inversa." Follicular occlusion disorders, inflammatory bowel diseases, especially Crohn disease, spondylarthropathy, other hyperergic diseases, genetic keratin disorders associated with follicular occlusion and squamous cell carcinoma were the most common hidradenitis suppurativa comorbid diseases. A first classification of these major comorbidities and their possible genetic background reveals a list of chromosome loci and genes, which could be hidradenitis suppurativa candidates. Most of these diseases belong to the group of autoinflammatory disorders, where th17 cell cytokines seem to play a central role.

Background: Although the exact etiology of alopecia areata is still unknown, systemic prednisolone treatment seem to be effective in early stages but significant side effects may occur leading to discontinuation of treatment., Objective: Evaluation of efficacy and saftety of a short-term medium-dose pulse prednisolone treatment in alopecia areata., Results: 84% of the patients with multifocal alopecia areata markedly improved after the completion of the three courses. A patient with the ophiasis type only responded after the third course, but relapsed 7 months later. The patients with alopecia areata totalis and universalis did not respond to the treatment. No major side effects were observed., Methods: Monocenter prospective study of intravenous 100 mg intravenous prednisolone pulse therapy on 3 consecutive days at 1-month-intervals for three courses in 23 patients with active alopecia areata rapidly evolving and/or resistant to topical therapies and no contraindication for systemic steroids., Conclusion: A series of three monthly courses of medium-dose prednisolone pulse therapy is effective and well tolerated in most patients with active, multifocal alopecia areata. The results are rather disappointing in patients with alopecia areara totalis/universalis.

Through the definition of novel biological activities of hormones and their diversity on different skin cell types, it has become apparent that the skin itself possesses the capacity to generate several hormones and substances with hormone-like activity. These substances appear to act through paracrine, autocrine, intracrine and endocrine mechanisms to fulfill their pleiotropic effects. Also new is the knowledge that the skin can metabolize hormones and produce derivatives with potentially systemic activity. These findings point towards novel concepts in our understanding of the role of skin and of its hormones as important players in homeostasis and disorders of the entire human organism. Finally, the scientists active in the field of dermato-endocrinology expect that their activities will exploit the pharmacological and therapeutic function of hormone mediators, their receptors and antagonists. The latter idea has already been realized for corticosteroids, androgens, estrogens, topical vitamin D analogues and retinoids which have today an established place in clinical dermatology.

Environmental pollutants can result in a variant of acne called 'chloracne'. Chloracne is caused by systemic exposure to certain halogenated aromatic hydrocarbons 'chloracnegens', and is considered to be one of the most sensitive indicators of systemic poisoning by these compounds. Dioxin is the most potent environmental chloracnegen. Most cases of chloracne have resulted from occupational and non-occupational exposures, non-occupational chloracne mainly resulted from contaminated industrial wastes and contaminated food products. Non-inflammatory comedones and straw-colored cysts are the primary clinical manifestation of chloracne. Increasing of cysts in number is a signal of aggravation of chloracne. Generalized lesions can appear on the face, neck, trunk, exterimities, genitalia, axillary and other areas. Course of chloracne is chronic. Severity of chloracne is related to dosage of exposed chloracnegens, chloracnegenic potency and individual susceptibility. Histopathology of chloracne is characterized mainly by hyperplasia of epidermal cell, while follicular and sebaceous gland are taken placed by keratinized epidermal cell. The pathogenesis of chloracne maybe related to the imbalance of epidermal stem cell. Chloracne appears to be resistant to all tested forms of treatment. The only way to control chloracne is to prevent exposure to chloracnegens.

Background: Central or peripheral stress may induce the development of clinical inflammation in the pilosebaceous unit (PSU) leading to the development or to exacerbation of preexisting acne. The presence of a complete corticotropin-releasing hormone (CRH) system has been confirmed in human sebocytes in vitro. CRH is capable to induce lipid synthesis, steroidogenesis and interact with testosterone and growth hormone. alpha-Melanocyte-stimulating hormone (alpha-MSH) and its receptors can regulate melanogenesis as well as affect inflammation, apoptosis and sebogenesis., Objectives: The purpose of the study was to investigate by immunohistochemistry if changes of CRH/CRH-binding protein (CRHBP)/CRH receptors (CRHR) as well as melanocortin-1 receptor (MC-1R) expression are detectable in acne lesions vs. normal skin, especially in the sebaceous gland (SG)., Results: Very strong expression of CRH was observed in acne-involved skin in SG cells comparing with weaker expression in non-involved and normal skin SG. The strongest reaction for CRHBP in acne-involved SG was in differentiating sebocytes. CRHR-1 and -2 exhibited the strongest expression in sweat glands and SG, respectively. Sebocytes and cells of the ductus seboglandularis (DSG) of acne-involved and non-involved skin showed very intense MC-1R expression in contrast to less intense scattered immunoreactivity in normal skin samples., Methods: 33 patients with acne vulgaris and 8 age-matched volunteers without acne participated in the study. Skin biopsies were taken from acne-involved face, the non-involved thigh skin of the same patients and from normal human skin., Conclusions: These data suggest that NP, such as the complete CRH system and MC-1R, are involved in the pathogenesis of acne.

Tissue inflammation is a major component of the acne process. Leukotriene B(4) (LTB(4)) is considered to be a major player in the development of tissue inflammation. Synthesis of LTB(4) is controlled by the enzyme 5-lipoxygenase. Since Zileuton blocks the activity of 5-lipoxygenase, experimental and clinical studies have been conducted to test mode of function, as well as efficacy and safety of this compound in the treatment of acne vulgaris. Human SZ95 sebocytes and inflammatory cells in vitro express the enzymes of the leukotriene pathway at mRNA and protein levels and enzymes involved in the biosynthesis of LTB(4) are activated in sebaceous glands of acne lesions. Pre-treatment of SZ95 sebocytes with Zileuton partially prevented short-term arachidonic acid-induced effects, such as induction of LTB(4), increase of neutral lipid content and stimulation of interlekin-6 release. Long-term treatment with Zileuton directly reduced the content of neutral lipids and interleukin-6 release from SZ95 seb ocytes. PPAR mRNA levels were not regulated by Zileuton. In a first pilot clinical study with 10 patients with papulopustular acne Zileuton 4 x 600 mg/d p.o. for 3 months decreased the acne severity index in a time-dependent manner being 41% of the initial score at week 12 (p < 0.05). This was mostly due to a decrease of the number of inflammatory lesions of 29% (p < 0.01). In addition, total sebum lipids significantly decreased (35%, p < 0.05) and the pro-inflammatory free fatty acids (22%) and lipoperoxides (26%) were markedly diminished in patients' sebum under treatment. The magnitude of clinical improvement strongly correlated with the reduction of total sebum lipids (p = 0.0009, r(2) = 0.81) and free fatty acids (p = 0.0003, r(2) = 0.82). In a further study, a 40-year-old female with mild disseminated sebaceous gland hyperplasia and seborrhea, responded with normalization of the casual skin surface lipids and similar reduction of facial sebum synthesis under treatment with Zileuton over 2weeks and-after a wash-out phase-low-dose isotretinoin (10 mg/2nd d) over 5 weeks. These data are in agreement with a phase II multicenter, clinical study in 101 patients with mild to moderate inflammatory facial acne conducted in the US, which showed a significant efficacy of Zileuton in a subset of patients with moderate acne, whereas those patients treated with Zileuton showed a significant mean decrease in inflammatory lesions compared to the placebo group. In all clinical studies, Zileuton was found to be safe and well tolerated.

Receptors are proteins, embedded in a cell or cytoplasmic membrane, to which a mobile signaling molecule may attach. Receptor ligands may be peptides (such as neurotransmitters), hormones, pharmaceutical drugs and/or a toxins, whereas "binding" ordinarily initiates a cellular response. Human sebocytes are biologically and metabolically very active cells and consequently express numerous receptors. Three of four groups of peptide/neurotransmitter receptors, the so-called serpentine receptor group are present (corticotropin-releasing hormone receptors 1 and 2, melanocortin-1 and 5 receptors, mu-opiate receptors, VPAC receptors, cannabinoid receptors 1 and 2, vascular endothelial growth factor receptor and histamine 1 receptor). The single-transmembrane domain receptors are represented by the insulin-like growth factor-I receptor and the third group, which does not possess intrinsic tyrosine kinase activity, by the growth factor receptor. Nuclear receptors expressed in sebocytes are grouped into two major subtypes. From the steroid receptor family, the androgen receptor and the progesterone receptor are expressed. The thyroid receptor family includes the estrogen receptors (alpha and beta isotypes), the retinoic acid receptors (isotypes alpha and gamma) and retinoid X receptors (isotypes alpha, beta, gamma), the vitamin D receptor, the peroxisome proliferator-activated receptors (isotypes alpha, delta and gamma) and the liver X receptors (alpha and beta isotypes). The vanilloid receptor belongs to the transient ion channels and is expressed in differentiating human sebocytes. Further sebocyte receptors, which may influence their function are fibroblast growth factor receptor 2, epidermal growth factor receptor, c-MET, CD14, Toll-like receptor 2, Toll-like receptor 4 and Toll-like receptor 6. Receptor-ligand interactions control sebocyte proliferation, differentiation and lipid synthesis. However, not every ligand that binds to a sebocyte receptor also activates it, such ligands are receptor antagonists and inverse agonists.

Hormones can exert their actions through endocrine, paracrine, juxtacrine, autocrine and intracrine pathways. The skin, especially the pilosebaceous unit, can be regarded as an endocrine organ meanwhile a target of hormones, because it synthesizes miscellaneous hormones and expresses diverse hormone receptors. Over the past decade, steroid hormones, phospholipid hormones, retinoids and nuclear receptor ligands as well as the so-called stress hormones have been demonstrated to play pivotal roles in controlling the development of pilosebaceous units, lipogenesis of sebaceous glands and hair cycling. Among them, androgen is most extensively studied and of highest clinical significance. Androgen-mediated dermatoses such as acne, androgenetic alopecia and seborrhea are among the most common skin disorders, with most patients exhibiting normal circulating androgen levels. The "cutaneous hyperandrogenism" is caused by in stiu overexpression of the androgenic enzymes and hyperresponsiveness of androgen receptors. Regulation of cutaneous steroidogenesis is analogous to that in gonads and adrenals. More work is needed to explain the regional difference within and between the androgn-mediated dermatoses. The pilosebaceous unit can act as an ideal model for studies in dermato-endocrinology.

Acne and seborrhoea are sebaceous gland-related diseases that are also exclusively human diseases. Therefore, fundamental research on human sebaceous cell function and control requires human models in vitro. The human sebocyte culture model was first introduced in 1989. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. Over the years, modifications of the technique have improved the culture of human sebocytes in vitro, but the primary cultured sebocytes can still be maintained for no more than six passages in vitro. The immortalized human sebaceous gland cell lines SZ95, SEB-1 and Seb-E6E7 have been developed in recent years, which make it possible to get a large number of sebocytes from the same donor culture. Cultured human sebocytes in vitro has become a useful tool in studying sebaceous gland activity and regulation, and understanding the pathophysiological mechanisms and treatment of acne and other sebaceous gland related diseases.

Dermato-Endocrinology, is a new platform for clinicians and scientists interested in the role of the skin as an endocrine, autocrine or paracrine organ.

Aging in men is associated with a progressive decline in the production of several hormones, including androgens. The extent to which an age-dependent decline in androgen levels lead to health problems or can affect quality of life remains under debate. Clinical results on replacement therapy do not yet provide a definitive clue on the benefit/risk balance. A sexual dimorphism of the immune system is well established, and the differences between female and male immune responses under normal, as well as pathological, conditions are generally attributed to the influence of estrogens, progestins, and androgens. The suppressive effects of male sex hormones on immune functions have been observed in a wide variety of disease processes and appear to be testosterone-mediated. Endogenous testosterone inhibits skin wound healing response in males and is associated with an enhanced inflammatory response. Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerates--whereas testosterone retards--barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates.