Remo Campiche

Profiling mRNA of the Graying Human Hair Follicle Constitutes a Promising State-of-the-Art Tool to Assess Its Aging: An Exemplary Report

Determining hitherto uninvestigated and safe targets to halt the aging process is important in our aging society. Graying is a hallmark of the aging process and may be used to identify aging tissue for comparative analysis. Here we analyzed differential gene expressions between pigmented, gray, and white human scalp skin hair follicles (HFs) from identical donors. Forming intersections between five donors identified 194/192 downregulated and 186/177 upregulated genes in gray/white HFs. These included melanogenesis (tyrosinase; tyrosinase-related protein 1)- and melanosome structure (Melan-A; Pmel17)-associated genes and regulation of melanocyte relevant tyrosine kinases. Alongside these expected changes, regulated genes included nonmelanocyte-related genes associated with aging as well as nonaging-related genes associated with melanocytes. Intriguingly, among them, genes associated with energy metabolism (i.e., glutaminase) and axon guidance (plexin C1) were altered. These results were reflected by pathway analysis and exemplarily confirmed by PCR and immunohistochemical studies. Supplementing cultured HFs with glutamine or plexin C1 revealed biological relevance and pharmacointerventional potential of these microarray results in altering the HF aging process. Together, we present intriguing data obtained from intra-individual sample comparison that suggest the graying HF to be a valid aging model and a promising target for testing therapeutic interventions.

Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Protective effects of an extract of the freshwater microalga Scenedesmus rubescens on UV‐irradiated skin cells

Skin ageing results from intrinsic but also extrinsic factors of which UV irradiation is a main cause. It is hence of interest to have means to protect skin from UV irradiation‐induced damage. We selected an extract of the freshwater microalga Scenedesmus rubescens and assessed its potential to protect skin from photoageing caused by UV irradiation.

Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1

The enzyme 11β-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11β-HSD1 is an attractive intervention strategy and the discovery of novel selective 11β-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11β-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11β-HSD2, 17β-HSD1 and 17β-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.

The effects of benzylsulfonyl-D-Ser-homoPhe-(4-amidino-benzylamide), a dual plasmin and urokinase inhibitor, on facial skin barrier function in subjects with sensitive skin

The aim of this study was to optimize the synthesis of the plasmin and urokinase (uPA) inhibitor benzylsulfonyl‐D‐Ser‐homoPhe‐(4‐amidino‐benzylamide) (BSFAB), to characterize its activity and mechanism of action and to assess its use to improve stratum corneum (SC) barrier function.

Analyzing the microarray mRNA profile of graying human hair follicles: a promising approach in stress and aging research

Regenerative medicine needs new but safe treatment approaches to balance the reported increase in stress and aging related diseases. Graying is one hallmark of aging and is associated with excessive oxidative as well as psycho-emotional stress. In graying individuals fully pigmented hair follicles are found next to white and intermediary hair follicles. Thus, young and old hair follicles are observed in parallel that share the identical genetic background. Here, we discuss data obtained by microarray analysis of 15 tissue samples, and we studied the functional relevance in the ex vivo hair follicle organ culture model. We found the expected regulation of genes responsible for pigment-production by melanocytes, the cells that generate the pigment and are gradually lost from graying hair follicles. Among the around 200 regulated gens, we also found genes associated with cellular energy metabolism (e.g. glutaminase) and with nerve fiber growth (e.g. plexin C1). These results could be confirmed on mRNA and protein level as well as by pathway-analysis. Ex vivo treatment of cultured hair follicles with l -glutamine or plexin C1 revealed biological relevance and pharmaco-interventional potential of these selected microarray-results in that these compounds were able to halt the culture-induced premature aging process and cellular stress responses (pigment production, cell proliferation, -differentiation, -apoptosis, senescence). We therefore consider the graying hair follicle a useful model to study aging and stress associated responses and report here energy metabolism and cellular plasticity as important areas for future research.