Jan Batzer

Anti-inflammatory efficacy of licochalcone a : correlation of clinical potency and in vitro effects

Licochalcone A (LicA), a major phenolic constituent of the licorice species Glycyrrhiza inflata, has recently been reported to have anti-inflammatory as well as anti-microbial effects. These anti-inflammatory properties might be exploited for topical applications of LicA. We conducted prospective randomized vehicle-controlled clinical trials to assess the anti-irritative efficacy of cosmetic formulations containing LicA in a post-shaving skin irritation model and on UV-induced erythema formation. The clinical trials were accompanied by a series of in vitro experiments to characterize anti-inflammatory properties of LicA on several dermatologically relevant cell types. Topical LicA causes a highly significant reduction in erythema relative to the vehicle control in both the shave- and UV-induced erythema tests, demonstrating the anti-irritative properties of LicA. Furthermore, LicA is a potent inhibitor of pro-inflammatory in vitro responses, including N-formyl-MET-LEU-PHE (fMLP)- or zymosan-induced oxidative burst of granulocytes, UVB-induced PGE2 release by keratinocytes, lipopolysaccharide (LPS)-induced PGE2 release by adult dermal fibroblasts, fMLP-induced LTB4 release by granulocytes, and LPS-induced IL-6/TNF-α secretion by monocyte-derived dendritic cells. The reported data suggest therapeutic skin care benefits from LicA when applied to sensitive or irritated skin.

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin

Interactions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color.

The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.

The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV‐induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV‐protective effects against DNA damage in UVB‐tanned skin (but not in UVA‐tanned skin) were significantly higher. UVA‐induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up‐regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB‐exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV‐induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis.

4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation

Background  Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern. Therefore, many topical products are available, containing various active ingredients aiming to reduce melanin production and distribution. The most prominent target for inhibitors of hyperpigmentation is tyrosinase, the key regulator of melanin production. Many inhibitors of tyrosinase are described in the literature; however, most of them lack clinical efficacy.

Reconstituted 3-dimensional human skin of various ethnic origins as an in vitro model for studies of pigmentation

Reconstituted 3-dimensional human skin equivalents containing melanocytes and keratinocytes on an artificial dermal substitute are gaining popularity for studies of skin metabolism because they exhibit morphological and growth characteristics similar to human epidermis. In this study, we show that such a pigmented epidermis model can be used to assess the regulation of pigmentation by known melanogenic compounds. In monolayers or in melanocyte-keratinocyte co-cultures, melanocyte-keratinocyte interactions are missing or are spatially limited. The commercial skin equivalents used in this study were derived from epidermal cells obtained from donors of three different ethnic origins (African- American, Asian, and Caucasian), and they reflect those distinct skin phenotypes. We used these pigmented human epidermis models to test compounds for potential effects on pigmentation in a more physiologically relevant context, which allows further characterization and validation of interesting melanogenic factors. We used known melanogenic stimulators (alpha-melanocyte-stimulating hormone and 3,4-dihydroxyphenylalanine) and inhibitors (hydroquinone, arbutin, kojic acid, and niacinamide) and examined their effects on the production of melanin and its distribution in upper layers of the skin. Our studies indicate that commercial skin equivalents provide a convenient and cost-effective alternative to animal testing for evaluating the regulation of mammalian pigmentation by melanogenic factors and for elucidating their mechanisms of action.

Short- and Long-Term Effects of UV Radiation on the Pigmentation of Human Skin

The incidence of skin cancer, including cutaneous melanoma, has risen substantially in recent years, and epidemiological and laboratory studies show that UV radiation is a major causative factor of this increase. UV damage also underlies photoaging of the skin, and these deleterious effects of UV can be, in part, prevented in skin with higher levels of constitutive pigmentation. We review the clinical studies we have made in recent years regarding the rapid and the long-term responses of the pigmentary system in human skin to UV exposure.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 32-35; doi:10.1038/jidsymp.2009.10.

Molecular and histological characterization of age spots

Age spots, also called solar lentigines and lentigo senilis, are light brown to black pigmented lesions of various sizes that typically develop in chronically sun‐exposed skin. It is well known that age spots are strongly related to chronic sun exposure and are associated with photodamage and an increased risk for skin cancer; however, the mechanisms underlying their development remain poorly understood. We used immunohistochemical analysis and microarray analysis to investigate the processes involved in their formation, focusing on specific markers associated with the functions and proliferation of melanocytes and keratinocytes. A total of 193 genes were differentially expressed in age spots, but melanocyte pigment genes were not among them. The increased expression of keratins 5 and 10, markers of basal and suprabasal keratinocytes, respectively, in age spots suggests that the increased proliferation of basal keratinocytes combined with the decreased turnover of suprabasal keratinocytes leads to the exaggerated formation of rete ridges in lesional epidermis which in turn disrupts the normal processing of melanin upwards from the basal layer. Based on our results, we propose a model for the development of age spots that explains the accumulation of melanin and the development of extensive rete ridges in those hyperpigmented lesions.