Aging of skin is an intricate biological process consisting of two types. While intrinsic or chronological aging is an inevitable process, photoaging involves the premature aging of skin occurring due to cumulative exposure to ultraviolet radiation. Chronological and photoaging both have clinically differentiable manifestations. Various natural and synthetic retinoids have been explored for the treatment of aging and many of them have shown histological and clinical improvement, but most of the studies have been carried out in patients presenting with photoaged skin. Amongst the retinoids, tretinoin possibly is the most potent and certainly the most widely investigated retinoid for photoaging therapy. Although retinoids show promise in the treatment of skin aging, irritant reactions such as burning, scaling or dermatitis associated with retinoid therapy limit their acceptance by patients. This problem is more prominent with tretinoin and tazarotene whereas other retinoids mainly represented by retinaldehyde and retinol are considerably less irritating. In order to minimize these side effects, various novel drug delivery systems have been developed. In particular, nanoparticles have shown a good potential in improving the stability, tolerability and efficacy of retinoids like tretinoin and retinol. However, more elaborate clinical studies are required to confirm their advantage in the delivery of topical retinoids.

The Toll protein of Drosophila is a transmembrane receptor involved in dorsoventral polarization during embryonic development and recognition of infection. In mammals, Toll-like receptors (TLRs) constitute a novel protein family involved in innate immunity and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Specific agonists for nine of the ten members of the human TLR family have been described to date. TLRs as well as the TLR-associated adaptor molecule MyD88 have been implicated in the recognition of the fungal pathogens Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis carinii. Moreover, several pathogen associated molecular patterns (PAMPs) located in the cell wall or cell surface of fungi have been identified as potential ligands. Yeast zymosan activates TLR2/ TLR6 heterodimers, whereas Saccharomyces cerevisiae- and C. albicans-derived mannan seems to be detected by TLR4. Phospholipomannan, present in the cell surface of C. albicans has been shown to be recognized by TLR2, while TLR4 mainly interacts with glucuronoxylomannan, the major capsular polysaccharide of C. neoformans. MyD88 has been implicated in TLR signalling of linear (1 --> 3)-beta-D-glucan, and of beta-glucan from P. carinii. These data point towards the ability of the innate immune system to utilize TLRs that are specific to different types and components of pathogenic fungi. Recent evidence further suggests that TLRs cooperate with other immune receptors involved in fungal recognition and that the selective induction of adaptor proteins finally leads to distinct signalling events upon fungal challenge.

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We examined the role of Toll-like receptors (TLRs) by using TLR2-deficient (TLR2(-/-)), TLR4-defective (TLR4(d/d)), and double-knockout murine macrophages and human embryonic kidney (HEK) 293 cells transfected with human TLR2 or TLR4 expression plasmids after stimulation with different preparations of the human pathogenic fungus Candida albicans. Compared with wild-type macrophages, TLR2(-/-) and TLR4(d/d) macrophages had impaired recognition of viable C. albicans, whereas antimycotic (AM)-treated C. albicans solely used TLR2 in a TLR4- and interferon- gamma -independent manner. In human HEK293 cells, AM-treated C. albicans elicited mainly TLR2-dependent activation. The differences in responsiveness to viable C. albicans, compared with C. albicans treated with cytoplasmic membrane-interacting AMs, suggest specific recognition of different pathogen-associated patterns by TLRs in innate antifungal responses. Our analyses of signal transduction after stimulation of wild-type macrophages with AM-treated C. albicans demonstrated involvement of the transcription factors nuclear factor- kappa B and c-Jun/activator protein-1 and of the mitogen-activated protein kinases p38, extracellular-related kinase, and c-Jun NH(2)-terminal kinase.

Fluticasone propionate – the first carbothioate corticosteroid – has been classified as a potent anti-inflammatory drug for dermatological use. It is available as 0.05% cream and 0.005% ointment formulations for the acute and maintenance treatment of patients with dermatological disorders such as atopic dermatitis, psoriasis and vitiligo. This glucocorticoid is characterized by high lipophilicity, high glucocorticoid receptor binding and activation, and a rapid metabolic turnover in skin. Although skin blanching following fluticasone propionate exceeds that of corticosteroids of medium strength, several clinical trials demonstrate a low potential for cutaneous and systemic side-effects, even in difficult-to-treat areas like the face, the eyelids and intertriginous areas. Even among paediatric patients with atopic dermatitis, fluticasone propionate proved to be safe and effective. These pharmacological and clinical properties are reflected by the high therapeutic index of this glucocorticoid.