Luteolin is a flavonoid which is part of our daily nutrition in relatively low amounts (less than 1 mg/day). Nevertheless, some epidemiological studies suggest an inverse correlation between luteolin intake and the risk of some cancer types. Luteolin displays specific anti-inflammatory and anti-carcinogenic effects, which can only partly be explained by its anti-oxidant and free radical scavenging capacities. Luteolin can delay or block the development of cancer cells in vitro and in vivo by protection from carcinogenic stimuli, by inhibition of tumor cell proliferation, by induction of cell cycle arrest and by induction of apoptosis via intrinsic and extrinsic signaling pathways. When compared to other flavonoids, luteolin was usually among the most effective ones, inhibiting tumor cell proliferation with IC50 values between 3 and 50 µM in vitro and in vivo by 5 to 10 mg/kg i.p., intragastric application of 0.1–0.3 mg/kg/d, or as food additive in concentrations of 50 to 200 ppm. Luteolin has been shown to penetrate into human skin, making it also a candidate for the prevention and treatment of skin cancer.

Background Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed the role of contact sensitizer induced ROS production and concomitant changes in hyaluronic acid metabolism on CHS responses. Methodology/Principal Findings We analyzed in vitro and in vivo ROS production using fluorescent ROS detection reagents. HA fragmentation was determined by gel electrophoresis. The influence of blocking ROS production and HA degradation by antioxidants, hyaluronidase-inhibitor or p38 MAPK inhibitor was analyzed in the murine CHS model. Here, we demonstrate that organic contact sensitizers induce production of reactive oxygen species (ROS) and a concomitant breakdown of the extracellular matrix (ECM) component hyaluronic acid (HA) to pro-inflammatory low molecular weight fragments in the skin. Importantly, inhibition of either ROS-mediated or enzymatic HA breakdown prevents sensitization as well as elicitation of CHS. Conclusions/Significance These data identify an indirect mechanism of contact sensitizer induced innate inflammatory signaling involving the breakdown of the ECM and generation of endogenous danger signals. Our findings suggest a beneficial role for anti-oxidants and hyaluronidase inhibitors in prevention and treatment of ACD.

Reactive oxygen and nitrogen species (ROS/RNS) which may exist as radicals or nonradicals, as well as reactive sulfur species and reactive carbon species, play a major role in aging processes and in carcinogenesis. These reactive molecule species (RMS), often referred to as ‘free radicals' or oxidants, are partly by-products of the physiological metabolism. When RMS concentrations exceed a certain threshold, cell compartments and cells are injured and destroyed. Endogenous physiological mechanisms are able to neutralize RMS to some extent, thereby limiting damage. In the skin, however, pollutants and particularly UV irradiation are able to produce additional oxidants which overload the endogenous protection system and cause early aging, debilitation of immune functions, and skin cancer. The application of antioxidants from various sources in skin care products and food supplements is therefore widespread, with increasingly effective formulations being introduced. The harmful effects of RMS (aside from impaired structure and function of DNA, proteins, and lipids) are: interference with specific regulatory mechanisms and signaling pathways in cell metabolism, resulting in chronic inflammation, weakening of immune functions, and degradation of tissue. Important control mechanisms are: MAP-kinases, the aryl-hydrocarbon receptor (AhR), the antagonistic transcription factors nuclear factor-κB and Nrf2 (nuclear factor erythroid 2-related factor 2), and, especially important, the induction of matrix metalloproteinases which degrade dermal connective tissue. Recent research, however, has revealed that RMS and in particular ROS/RNS are apparently also produced by specific enzyme reactions in an evolutionarily adapted manner. They may fulfill important physiologic functions such as the activation of specific signaling chains in the cell metabolism, defense against infectious pathogens, and regulation of the immune system. Normal physiological conditions are characterized by equilibrium of oxidative and antioxidative mechanisms. The application of antioxidants in the form of 'cosmeceuticals' or systemic 'nutraceuticals' should aim to support a physiologically balanced oxidation status in the skin.

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Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense. Furthermore, anti-oxidative and anti-inflammatory activities of luteolin were described on keratinocytes and fibroblasts as well as on several immune cells (e.g., macrophages, mast cell, neutrophils, dendritic cells and T cells). Luteolin can suppress proinflammatory mediators (e.g., IL-1β, IL-6, IL-8, IL-17, IL-22, TNF-α and COX-2) and regulate various signaling pathway (e.g., the NF-κB, JAK-STAT as well as TLR signaling pathway). In this way, luteolin modulates many inflammatory processes of the skin. The present review summarizes the recent in vitro and in vivo research on luteolin in the field of skin aging and skin cancer, wound healing as well as inflammatory skin diseases, including psoriasis, contact dermatitis and atopic dermatitis.In conclusion, luteolin might be a promising molecule for the development of topic formulations and systemic agents against inflammatory skin diseases.

St. John's wort (Hypericum perforatum) has been intensively investigated for its antidepressive activity, but dermatological applications also have a long tradition. Topical St. John's wort preparations such as oils or tinctures are used for the treatment of minor wounds and burns, sunburns, abrasions, bruises, contusions, ulcers, myalgia, and many others. Pharmacological research supports the use in these fields. Of the constituents, naphthodianthrones (e.g., hypericin) and phloroglucinols (e.g., hyperforin) have interesting pharmacological profiles, including antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. In addition, hyperforin stimulates growth and differentiation of keratinocytes, and hypericin is a photosensitizer which can be used for selective treatment of nonmelanoma skin cancer. However, clinical research in this field is still scarce. Recently, sporadic trials have been conducted in wound healing, atopic dermatitis, psoriasis, and herpes simplex infections, partly with purified single constituents and modern dermatological formulations. St. John's wort also has a potential for use in medical skin care. Composition and stability of pharmaceutical formulations vary greatly depending on origin of the plant material, production method, lipophilicity of solvents, and storage conditions, and this must be regarded with respect to practical as well as scientific purposes.

Recent studies have shown that human bitter taste receptors (TAS2Rs) are not only expressed in mucous epithelial cells of the tongue, but also in epithelial cells of the colon, stomach and upper respiratory tract. These cell types come in close contact with external bitter compounds by ingestion or breathing. In the present work we addressed the question whether bitter taste receptors might also be expressed in cornified epithelial cells of the skin. Here, we show for the first time the expression of TAS2R1 and TAS2R38 in human skin. Double staining of HaCaT cells and primary keratinocytes demonstrated the colocalization of TAS2R1 and TAS2R38 with the adaptor protein α-gustducin that is essential for signal transduction upon ligand binding. To test if TAS2Rs in keratinocytes are functional, we stimulated HaCaT cells with diphenidol, a clinically used bitter-tasting antiemetic, or amarogentin, the bitterest plant substance, that binds TAS2Rs, including TAS2R1 and TAS2R38. Diphenidol and amarogentin induced calcium influx. Furthermore, in keratinocytes diphenidol and amarogentin stimulated the expression of the differentiation markers keratin 10, involucrin and transglutaminase. Therefore, apart from the known role in mucous membranes of the gastrointestinal tract, TAS2Rs are expressed in the epidermis and might play a role in keratinocyte differentiation.

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