Evgenia Makrantonaki

A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria.

ABSTRACT flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2) (K. Takeda and S. Akira, Cell. Microbiol. 5:143-153, 2003). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C16:1) and oleate (C18:1), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1—a gene with numerous NF-κB elements in its promoter—is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.

Molecular Mechanisms of Skin Aging : State of the Art

Abstract:  The process of skin aging in humans is complex and is induced by multiple factors, including genetic and various environmental ones . In particular, the superposition of environmental factors, such as UV irradiation on skin, results in massive wound‐like morphological alterations mainly of the dermis. In sun‐protected areas the most pronounced changes occur within the epidermis and affect mostly the basal cell layer. As a result, while sun‐protected aged skin appears thin, finely wrinkled, and dry, photoaged skin is characterized by deep wrinkles, laxity, and roughness. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways in the generation of aged skin. Recent data obtained by expression‐profiling studies and studies of progeroid syndromes (e.g., Hutchinson‐Gilford progeria, Werner syndrome, Rothmund‐Thomson syndrome, Cockayne syndrome, ataxia teleangiectasia, and Down syndrome) illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, ubiquitin‐induced proteolysis, and cellular metabolism. One of the major factors that has been proposed to play an exquisite role in the initiation of aging is the physiological hormone decline occurring with age. However, hormones at age‐specific levels may not only regulate age‐associated mechanisms but also regulate tumor‐suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies in dealing with the various diseases accompanying aging, including cancer.

Clinical aspects and molecular diagnostics of skin aging.

This contribution will address the effect of aging on skin functions, with a particular focus on skin permeability, wound healing, angiogenesis, lipogenesis, sweat production, immune function, and vitamin D synthesis. With accelerating age, skin functions deteriorate due to structural and morphologic changes. Skin is prone to the development of several diseases, varying from benign to malignant. Because the number of persons aged 80 and older is expected to rise in the next decades, disease prevention will become an important issue. Screening examinations and prevention through public education starting at an early age regarding sun avoidance, the use of sunscreens and the importance of a balanced nutrition are the first steps for successful healthy aging. Although the fundamental mechanisms in the pathogenesis of aged skin are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways. Recent data obtained by expression profiling studies and studies of progeroid syndromes illustrate that among the most important biologic processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, extracellular matrix, lipid synthesis, ubiquitin-induced proteolysis and cellular metabolism. Among others, a major factor that has been implicated in the initiation of aging is the physiologic decline of hormones occurring with age. However, hormones at age-specific levels may regulate not only age-associated mechanisms but also tumor suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies to deal with the various diseases accompanying high age, including cancer.

Skin anti-aging strategies

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.

Characteristics and Pathomechanisms of Endogenously Aged Skin

The skin, being in direct contact with several environmental factors (e.g. UV irradiation), does not only undergo endogenous aging, which has to do with the ‘biological clock’ of the skin cells per se, but also exogenous aging. While exogenous skin aging has been extensively studied, the pathomechanisms of endogenous skin aging remain far less clear. Endogenous skin aging reflects reduction processes, which are common in internal organs. These processes include cellular senescence and decreased proliferative capacity, decrease in cellular DNA repair capacity and chromosomal abnormalities, loss of telomeres, point mutations of extranuclear mtDNA, oxidative stress and gene mutations. As a consequence, aged skin in nonexposed areas shows typical characteristics including fine wrinkles, dryness, sallowness and loss of elasticity. Recent data have illustrated that lack of hormones occurring with age may also contribute to the aging phenotype. Improvement of epidermal skin moisture, elasticity and skin thickness, enhanced production of surface lipids, reduction of wrinkle depth, restoration of collagen fibers and increase of the collagen III/I ratio have been reported after hormone replacement therapy or local estrogen treatment in postmenopausal women. Furthermore, an in vitro model of endogenous skin aging consisting of human SZ95 sebocytes which were incubated under a hormone-substituted environment illustrated that hormones at age- and sex-specific levels were able to alter the development of cells by regulating their transcriptome. In conclusion, among other factors the hormone environment plays a distinct role in the generation of aged skin.

An update on the role of the sebaceous gland in the pathogenesis of acne

The pathogenesis of acne, a disease of the pilosebaceous follicle and one of the most common chronic skin disorders, is attributed to multiple factors such as increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratinisation and the proliferation of Propionibacterium acnes within the follicle. In particular, the sebaceous gland plays an exquisite role in the initiation of the disease as it possesses all the enzyme machinery for the production of hormones and cytokines. In addition, in response to the altered tissue environment in the pilosebaceous follicle as well as in answer to emotional fret, stress response system mechanisms with induction of central and local expression of neuropeptides, are also initiated. This review summarises the latest advances in understanding the role of sebaceous gland cells in the pathomechanism of acne.

Testosterone metabolism to 5α‐dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator‐activated receptor ligand linoleic acid in human sebocytes

Background  Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator‐activated receptor (PPAR) ligands were suggested to be adequate candidates.

Age-specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro.

The importance of hormones in endogenous aging has been displayed by recent studies performed on animal models and humans. To decipher the molecular mechanisms involved in aging we maintained human sebocytes at defined hormone‐substituted conditions that corresponded to average serum levels of females from 20 (f20) to 60 (f60) years of age. The corresponding hormone receptor expression was demonstrated by reverse transcription–polymerase chain reaction (RT–PCR), Western blotting and immunocytochemistry. Cells at f60 produced significantly lower lipids than at f20. Increased mRNA and protein levels of c‐Myc and increased protein levels of FN1, which have been associated with aging, were detected in SZ95 sebocytes at f60 compared to those detected at f20 after 5 days of treatment. Expression profiling employing a cDNA microarray composed of 15 529 cDNAs identified 899 genes with altered expression levels at f20 vs. f60. Confirmation of gene regulation was performed by real‐time RT–PCR. The functional annotation of these genes according to the Gene Ontology identified pathways related to mitochondrial function, oxidative stress, ubiquitin‐mediated proteolysis, cell cycle, immune responses, steroid biosynthesis and phospholipid degradation – all hallmarks of aging. Twenty‐five genes in common with those identified in aging kidneys and several genes involved in neurodegenerative diseases were also detected. This is the first report describing the transcriptome of human sebocytes and its modification by a cocktail of hormones administered in age‐specific levels and provides an in vitro model system, which approximates some of the hormone‐dependent changes in gene transcription that occur during aging in humans.

Skin and brain age together: The role of hormones in the ageing process.

The importance of the endocrine environment in the initiation of the ageing process has been elucidated in several in vivo and in vitro studies. Changes in endocrine pathways accompany healthy ageing, these include the growth hormone/insulin-like growth factor-I axis (somatopause) and that of sexual hormones, namely estradiol (menopause), testosterone (andropause), and dehydroepiandrosterone and its sulphate (adrenopause). The clinical significance of these changes is variable and results in morphological and functional alterations of all organ systems including the skin and the central nervous system. Moreover, the pathogenesis of age-associated diseases such as epithelial skin cancer and neurodegenerative diseases has been partly attributed to the lack of hormones. Several studies have been conducted in an attempt to reverse the ageing process and clinical signs by substitution of the serum hormone levels in older individuals, however the benefits of hormone replacement therapy, if any, are still controversial. On the other hand, recent data suggest that skin is a window to the human organism and represents an adequate model for ageing research, also implying the use of skin samples for evaluating the ageing status of the central nervous system.

Interplay of IGF-I and 17β-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro

In order to obtain greater insights into the molecular mechanisms accompanying hormonal aging the effects of growth hormone (GH), insulin-like growth factor-I (IGF-I), 17beta-estradiol, progesterone and dehydroepiandrosterone were tested as single agents in concentrations corresponding to 20- and 60-year-old females on human SZ95 sebocytes and fibroblasts. Cell proliferation and viability were measured by 4-methylumbelliferyl heptanoate and lactate dehydrogenase microassays, respectively, whereas lipid accumulation was documented via nile red microassay and fluorescence microscopy. mRNA and protein expression were evaluated via real-time RT-PCR and Western blotting or ELISA, accordingly. Our results depict the importance of IGF-I for lipid synthesis in SZ95 sebocyte and demonstrate the lack of 17beta-estradiol, dehydroepiandrosterone and progesterone activity on lipid synthesis and SZ95 sebocyte proliferation suggesting that the action of these hormones in vivo may be implemented through indirect pathways. Fibroblast showed to be more susceptible to 17beta-estradiol treatment, while IGF-I could significantly stimulate fibroblast proliferation in a dose-dependent manner. Furthermore, an interplay between the 17beta-estradiol and IGF-I signaling pathway was documented in both cell types. In conclusion, IGF-I is a key regulator of human skin aging and declining IGF-I levels with age may play a significant role in the reduction of skin surface lipids and thickness.