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Increase skin pigmentation to prevent and treat sun-related skin damage

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Tags: Personal Care

Natural sunlight generates UVA, UVB and UVC radiations. UVA, with wavelengths between 320 and 400nm, are responsible for increased pigmentation and indirect DNA damage via the production of reactive oxygen species (ROS). UVB span the 280-320nm wavelengths of the electromagnetic spectrum, induce direct DNA damage and are associated with sunburns. Over 95% of UVA and close to 10% of UVB reach the Earth’s surface while almost 100% of UVC (200-280nm) are filtered by the stratospheric ozone layer (Hawryluk et al., 2014). Ultraviolet radiations target macromolecules in the skin, notably nucleic acids, where they generate mutations. These mutations ultimately lead to the development of melanoma as well as other forms of skin cancer. Fortunately, several protective mechanisms, such as DNA repair, apoptosis, cell cycle arrest and production of pigments, exist to counteract the hazardous effects ultraviolet radiations may have on the skin.

Indeed, DNA damage in keratinocytes following UV exposure leads to the stabilization of the p53 tumor suppressor protein and the transcriptional activation by p53 of proopiomelanocortin (POMC), which can be enzymatically cleaved to yield α-melanocyte stimulating hormone (α-MSH). Binding of the latter to the melanocortin 1 receptor (MC1R) on melanocytes triggers pro-differentiation signals mediated by the second messenger cyclic AMP (cAMP). Cyclic AMP-mediated signals inhibit UV-induced apoptosis and promote melanin synthesis via transcriptional activation of pigment-regulating enzymes such as tyrosinase. Once generated, melanin pigments are packaged into melanosomes and are exported to keratinocytes where they localize over the nucleus to protect the skin and its genomic content against further ultraviolet-induced DNA damage (Chen et al., 2014). Modulation of cAMP levels by pharmacological induction of adenylate cyclases or inhibition of phosphodiesterases, hold promise as UV-independent mechanisms of increasing natural production of melanin and protection from UV damage to skin.

Cilostazol is a selective inhibitor of phosphodiesterase 3 (PDE3), a cAMP-degrading enzyme, and is currently used as a vasodilator, antithrombotic and cardiotonic agent. It has also been shown to inhibit NADPH oxidase activity and reduce in a significant manner the level of ROS. Since antioxidants help with the prevention of ultraviolet-induced skin aging, it was hypothesized that cilostazol can have similar effects against skin photoaging. Dr. Park and Dr. Choi, respectively from Kangwon National University and Inje University, led a team of scientists from different Korean universities and investigated the potential benefits of using cilostazol in ultraviolet-irradiated dermal fibroblasts. They demonstrated that cell toxicity was significantly reduced when cilostazol was added to ultraviolet-exposed dermal fibroblasts and that levels of ROS were maintained at a background level similar to that of the unstimulated samples when pre-treated with cilostazol and significantly decreased when post-treated with cilostazol. In addition, cilostazol prevented the increase in MMP-1 following irradiation and inhibited ultraviolet-induced collagen breakdown by attenuating the decrease in type I procollagen both at the mRNA and protein levels. Finally, they demonstrated that these effects were due to the inhibition of the MAPK and activator protein 1 (AP-1) pathways.

More recently, Dr. Wei and colleagues from Jinan University in China pushed the analysis further as they tried to have a better understanding of cilostazol’s functions in ultraviolet-damaged skin cells. They first looked at the melanin content in melanoma cells and noticed a two-to-three-fold augmentation in cells treated with cilostazol. Both expression and activity of tyrosinase were also markedly increased. They found that the transcription factor of tyrosinase, referred to as microphthalmia-associated transcription factor (MITF) and known as the main regulator of melanocyte differentiation and pigment production, was in fact also significantly up-regulated both at the mRNA and protein levels in cells treated with cilostazol. Using siRNA specifically targeting MITF, they proved that cilostazol-induced tyrosinase activity and melanin production depended on the expression of MITF. By inhibiting PDE3, cilostazol is known to elevate the levels of intracellular cAMP and promote the phosphorylation of the cAMP-response element-binding protein (CREB) via the PKA pathway. Using siRNA against CREB, the authors demonstrated that the increase in MITF following treatment with cilostazol was totally suppressed. These data suggest that cilostazol promotes the production of melanin by activating MITF via the PKA pathway and CREB. Altogether, these studies suggest that cilostazol may hold promise for ultraviolet-irradiated skin prevention and treatment. Further work is, however, required in order to demonstrate comparable beneficial effects in vivo.

Enzo Life Sciences offers a comprehensive portfolio for advancing your research in personal care and skin pigmentation including the most sensitive and complete colorimetric ELISA kits for quantification of intracellular or extracellular cAMP in a variety of sample types. In addition, Enzo offers antibodies, enzymatic assays, live cell analysis kits and other regulators of pigmentation, some of which are listed below:

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Reference:

  1. H. Chen, et al. UV signaling pathways within the skin. J. Invest. Dermatol. (2014) 134:2080.
  2. E.B. Hawryluk, et al. Effects of ultraviolet exposure behaviors on skin pigmentation and melanoma. Pigment. Dis. (2014) 1:2.
  3. B. Wei, et al. Cilostazol promotes production of melanin by activating the microphthalmia-associated transcription factor (MITF). Biochem. Biophys. Res. Commun. (2014) 443:617.
  4. B.C. Yu, et al. The effect of cilostazol on the expression of matrix metalloproteinase 1 and type 1 procollagen in ultraviolet-irradiated human dermal fibroblasts. Life Sci. (2013) 92:282.

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