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  • br Hypothesis The hypothesis is that AhR in skin diseases


    Hypothesis The hypothesis is that AhR in skin diseases could be an objective of study for future dermatological therapies. Both stimulation and inhibition of the receptor might have significant influences on neoplastic or inflammatory skin diseases. However, at present the functions of AhR are unclear and often contradictory and the consequences of pharmacological altered balance of the receptor are poorly understood. In broad terms, we can say that in healthy skin, AhR signalling driven by endogenous ligands contributes to keratinocyte differentiation, skin barrier function, skin pigmentation, and mediates oxidative stress [1], [14]. On the other hand, in xenobiotic AhR ligand-exposed skin canonical signalling may become cdc42 and lead to a set of adverse effects as the generation of reactive oxygen species (ROS) and dysregulation of proteins involved in cell division, differentiation, migration, and apoptosis [3], [14], [32]. This may lead to metabolic activation of pre-carcinogens, extracellular matrix (ECM) degradation, inflammation and anti-apoptosis and thus to skin cancer development and extrinsic skin aging [1]. In chronically inflamed skin disease, such as psoriasis, atopic dermatitis or vitiligo, AhR expression appears to be aberrantly induced, probably via pro-inflammatory transcription factors, such as NF-κB [33]. This may lead to silencing or out competing of canonical AhR signalling and consequently to alterations of the gene expression profile in the skin. Simultaneously, the chronic inflammatory state might implement non-canonical AHR signalling pathways. [1], [31], [34]. Therefore, this seems to be a promising target for future treatment of cutaneous malignancy or inflammatory diseases that are among the most frequent human pathologies. Moreover, clarifying its functions could also lead to better understand the mechanism of action of some old drugs, such as coal tar, that, due to their chemical characteristics, may interfere with AhR and are cheap. On the other hand, defining the role of the receptor as a mediator between the environment and skin diseases can also lead to the adoption of environmental prevention measures. We herein list the current knowledge about the receptor involvement in certain skin diseases, highlighting some therapeutic proposals emerged from the literature. For these purposes, further studies on molecular mechanism that underlie the functions af AhR are needed, as well as clinical trials regarding the most promising drugs.
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    Introduction Recently the pollution of dioxin and dioxin-like compounds has come to light, in that certainly these chemicals have been shown to be toxic to the environment and to humans. These compounds are almost exclusively produced as industrial products or byproducts which include polychlorinated dibenzodioxins (PCDDs), dibenzofurans (PCDFs), polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and dioxin-like biphenyls (DL-PCBs). They accumulate in the environment and are enriched through the food chain because of their long half-life (Sinkkonen and Paasivirta, 2000). Thus, they can be widely detected in the environment (e.g., food, water, air, soils and sediments.) and in human (e.g., milk and serum) (Srogi, 2008; Zober et al., 1992). A number of epidemiological and experimental studies have shown that these compounds have diverse adverse health effects (Birnbaum et al., 2003; Greim, 1997; Van den Berg et al., 2006; Taylor et al., 2013; Bertazzi et al., 2001), such as liver toxicity, developmental and reproductive toxicity to immune system dysfunction. These effects have shown to be mediated by activation of aryl hydrocarbon receptor (AhR). The inactivated AhR is usually located in cytoplasm, it enters into nucleus once being activated, which then binds to dioxin-responsive elements (DREs) in the upstream promoter region of a diverse battery of genes and regulates their expression. The gene alterations in response to the activation of AhR pathway result in various biological and toxicological effects in different species and tissues (Furness and Whelan, 2009; Marinković et al., 2010).