Variation of selected genotoxic and epigenetic markers due to therapeutic exposure to PAHs and ultraviolet radiation.

BACKGROUND: Goeckerman therapy (GT) of psoriasis involves dermal application of crude coal tar containing polycyclic aromatic hydrocarbons (PAHs) and exposure to ultraviolet radiation (UVR). Little is known about GT influence on DNA epigenetics. OBJECTIVE: The study aim was to discover epigenetic mechanisms altered by the exposure related to the GT of psoriasis. METHODS: Observed group of patients with plaque psoriasis (n = 23) was treated by GT with 3 % CCT. Before and after GT, we analyzed the levels of benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts (BPDE-DNA), p53 protein in serum, 5-methylcytosine (5-mC, global DNA methylation), and methylation in selected CpG sites of p53 gene. RESULTS: We found a significant increase in the levels of BPDE-DNA (p < 0.01) and serum levels of p53 protein (p < 0.01) after GT, and an insignificant decrease in the percentage of 5-mC in peripheral blood DNA. Methylation of p53 CpG sites was affected neither by psoriasis nor by GT. The study confirmed good effectiveness of GT (significantly reduced psoriasis area and severity index; p < 0.001). CONCLUSION: Our findings indicate that there is a significantly increased genotoxic hazard related to the exposure of PAHs and UV radiation after GT of psoriasis. However, global DNA methylation and p53 gene methylation evade the effect of GT, as they remained unchanged (Tab. 4, Fig. 3, Ref. 50).

From Dyestuff Chemistry to Cancer Theranostics: The Rise of Rylenecarboximides.

Fighting cancer with the means of chemistry remains a tremendous challenge and defines a pressing societal need. Compounds based on synthetic organic dyes have long been recognized as vital tools for cancer diagnosis and therapy (theranostics). Fluorescence and photoacoustic imaging of cancer as well as cancer treatment protocols such as photodynamic and photothermal therapy are all photobased technologies that require chromophores. However, a serious drawback of most chromophoric molecules is photobleaching over the course of their use in biological environments, which severely compromises the desired theranostic effects. At this point, rylenecarboximide (RI) dyes with ultrahigh photostability hold enormous promise. RI stands for a homologous series of dyes consisting of an aromatic core and carboximide auxochromic groups. They possess high molar extinction coefficients and finely tunable photophysical properties. RIs such as perylenebiscarboxylic acid monoimide (PMI), perylenetetracarboxylic acid diimide (PDI), terrylenetetracarboxylic acid diimide (TDI), and quaterrylene tetracarboxylic acid diimide (QDI) have attracted great scientific attention as colorants, components of organic photovoltaics and organic field-effect transistors, as well as tools for biological applications. PDI has appeared as one of the most widely studied RI dyes for fluorescence bioimaging. Our recent breakthroughs including chemotherapy with PDI-based DNA intercalators and photothermal therapy guided by photoacoustic imaging using PDI, TDI, or QDI, define urgent needs for further scientific research and clinical translation. In this Account, we tackle the relationship between chemical structures and photophysical and pharmacologic properties of RIs aiming at new contrast and anticancer agents, which then lay the ground for further biomedical applications. First, we introduce the design concepts for RIs with a focus on their structure-property relationships. Chemical structure has an enormous impact on the fluorescent, chemotoxic, photodynamic, and photothermal performance of RIs. Next, based on the resulting performance criteria, we employ RIs for fluorescence and photoacoustic cancer imaging as well as cancer therapies. When carrying electron donating substituents, PDIs and PMIs possess high fluorescence quantum yield and red-shifted emission which qualifies them for use in cancer fluorescence imaging. Also, some fluorescent PDIs are combined with chemodrugs or developed into DNA intercalators for chemotherapy. PDI-based photosensitizers are prepared by "heavy atom" substitution, showing potential for photodynamic therapy. Further, photothermal agents using PDI, TDI, and QDI with near-infrared absorption and excellent photothermal conversion efficiency offer high promise in photothermal cancer therapy monitored by photoacoustic imaging. Finally, looking jointly at the outstanding properties of RIs and the demands of current biomedicine, we offer an outlook toward further modifications of RIs as a powerful and practical platform for advanced cancer theranostics as well as treatment of other diseases.

Review of the mechanism of action of coal tar in psoriasis.

PURPOSE: Crude coal tar and its derivatives have been used in modern medicine for the treatment of psoriasis since at least 1925 as part of the Goeckerman regimen. To this day, coal tar remains a safe and highly effective option for the treatment of psoriasis vulgaris. However, the mechanism by which coal tar has its therapeutic effect is unknown. This review summarizes current knowledge of the mechanism by which coal tar has its therapeutic effect in the treatment of psoriasis vulgaris. MATERIAL AND METHODS: A Pubmed search was conducted on March 13, 2017 for relevant English language journal articles on the subject and were relevant journal articles were included in this review. RESULTS: Crude coal tar consists of thousands of ingredients, many of which are unidentified. Of these ingredients, the most research has gone into analyzing polycyclic aryl hydrocarbons. These hydrocarbons are thought to be the most likely component of crude coal tar that leads to its effects in psoriasis. Of the aryl hydrocarbons, carbazole has been the most well studied in psoriasis and is hypothesized as being responsible for the treatment efficacy of crude coal tar. CONCLUSIONS: Polycyclic aryl hydrocarbons, and specifically carbazole, are thought to be the mechanism by which crude coal tar has its effect in psoriasis. However, further research is warranted to fully characterize the mechanism of action of crude coal tar, with the potential to create new therapies for psoriasis.

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

TL-2 attenuates ß-amyloid induced neuronal apoptosis through the AKT/GSK-3ß/ß-catenin pathway.

ß-amyloid (Aß)-mediated neuronal apoptosis contributes to the progression of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether Dalesconol B (TL-2), a potent immunosuppressive agent with an unusual carbon skeleton, could inhibit Aß-induced apoptosis in vitro and in vivo and to explore the underlying mechanisms. Aß(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. TL-2 was able to cross the blood-brain barrier and attenuate memory deficits in the AD mice. TL-2 also inhibited Aß(1-42)-induced neuronal apoptosis in vitro and in vivo. In addition, TL-2 could activate the AKT/GSK-3ß pathway, and inhibition of AKT and activation of GSK-3ß partially eliminated the neuroprotective effects of TL-2. Furthermore, TL-2 induced the nuclear translocation of ß-catenin and enhanced its transcriptional activity through the AKT/GSK-3ß pathway to promote neuronal survival. These results suggest that TL-2 might be a potential drug for AD treatment.

Genotoxic and apoptotic effects of Goeckerman therapy for psoriasis.

BACKGROUND: Goeckerman therapy (GT) for psoriasis is based on cutaneous application of crude coal tar [polycyclic aromatic hydrocarbons (PAH)] and exposure to ultraviolet radiation (UVR). PAH and UVR are mutagenic, carcinogenic and immunotoxic agents that promote apoptosis. METHODS: We evaluated dermal absorption of PAH as well as the genotoxic and apoptotic effects of GT in 20 patients with psoriasis, by determining numbers of chromosomal abnormalities in peripheral lymphocytes, and levels of 1-hydroxypyrene (1-OHP), p53 protein and soluble FasL (sFasL) in urine and/or blood, before and after GT. Psoriasis Area and Severity Index (PASI) score was used to evaluate clinical efficacy of GT. RESULTS: Compared with pre-treatment levels, there was a significant increase in urine 1-OHP, indicating a high degree of dermal absorption of PAH (P < 0.01). We also found a significant increase in the number of chromosomal abnormalities in peripheral blood lymphocytes (P < 0.001), suggesting that GT is genotoxic; significantly increased p53 protein in plasma (P < 0.05), an indicator of cell response to DNA damage; and significantly increased sFasL in serum (P < 0.01), an indicator of apoptosis. The PASI score was significantly decreased after GT (P < 0.001), confirming clinical benefit of this treatment. CONCLUSION: Our results demonstrate high dermal absorption of PAH during GT and provide evidence that GT promotes genotoxicity and apoptosis.

Cytogenetic and immunological changes after dermal exposure to polycyclic aromatic hydrocarbons and UV radiation.

Goeckerman's therapy (GT), which combines exposure to coal tar (polycyclic aromatic hydrocarbons - PAHs) and UV radiation (UV) is often used as the first option for treatment of psoriasis. However, PAHs and UV represent mutagenic, carcinogenic and immunotoxic agents. Therefore GT can represent a health risk for the patients. The group under observation consisted of thirty patients undergoing GT. Before and after the treatment, blood samples were collected and chromosomal aberrations and selected immunological markers were determined. The relationships between chromosomal aberrations and immunological markers and the extent (duration) of exposure to GT were evaluated. The Psoriasis Area and Severity Index (PASI) score confirmed the high efficacy of GT. However, significantly elevated levels of chromosomal aberrations of peripheral lymphocytes were also found after the therapy (p<0.001). The levels of chromosomal abnormalities correlated to the extent and the total duration of exposure to PAHs (r = 0.682, p<0.01 and r = 0.605, p<0.05). After the therapy, significantly decreased levels of IgE, IgM isotypes of immunoglobulin, alpha(2)-macroglobulin and transferrin together with beta(2)-microglobulin were found. From the immunological markers listed above only the decreased level of alpha(2)-macroglobulin correlated to the extent of exposure to PAHs (r = -0.568, p<0.05). No correlation was found between chromosomal aberrations, significantly changed immunological markers and the duration of UV exposure. Our study revealed that GT has a significant impact on both genetic and immunological parameters of psoriatic patients. The results indicate that GT could increase genotoxic risk and modulates immunity of treated patients.

Coal tar, pine tar and sulfonated shale oil preparations: comparative activity, efficacy and safety.

BACKGROUND: Tar and sulfonated shale oil preparations are used in the treatment of a variety of inflammatory skin diseases, including psoriasis vulgaris; due to the high polycyclic aromatic hydrocarbon (PAH) content of tars, a possible relationship with cancer in humans has been postulated. On the other hand, the purity of sulfonated shale oils concerning PAHs guarantees a good tolerability during dermatologic therapy. AIM: In this review, it is attempted to compare activity, efficacy and safety of coal tar, pine tar and sulfonated shale oil preparations which currently play a role in dermatologic treatment. RESULTS AND CONCLUSIONS: Primary sources of PAHs in the normal human environment are forest fires, cigarette smoke and combustion of fossil fuels for heating and energy. Thermal processing of fossil substances is also required for the production of tars and sulfonated shale oils. Due to individual manufacturing techniques, tars and sulfonated shale oils differ completely in their chemical composition. Still, sulfonated shale oils are often falsely grouped as tars because of their related origin and similar dermatologic indications. There is at least limited evidence of the activity and efficacy of various tars as well as sulfonated shale oil preparations in different frequent inflammatory skin diseases. This includes psoriasis vulgaris and atopic eczema of glabrous as well as hairy skin. There is still some concern about the long-term tolerability of tar preparations at least in some contexts. This, however, does not apply to sulfonated shale oil preparations. Consequently, at least their use should still be considered a rational drug treatment in dermatology.