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  • 1
    Language: English
    In: PLoS ONE, 01 January 2018, Vol.13(9), p.e0204318
    Description: BACKGROUND AND OBJECTIVES:Microneedling therapy is a widely used technique in dermatology. However, little is known about the underlying molecular effects of this therapy on extracellular matrix remodeling, wound healing, and inflammation. The aim of this study was to examine morphological and molecular changes caused by microneedling treatment in a standardized in vitro full-thickness 3D model of human skin. MATERIALS AND METHODS:A microneedling device was used to treat full-thickness 3D skin models. Specimens were harvested at specified time points and qRT-PCR and microarray studies were performed. Frozen sections were examined histologically. RESULTS:Microneedling treatment caused morphological changes in the skin model resulting in an almost complete recovery of the epidermis five days after treatment. Microarray analysis identified an upregulation of genes that are associated with tissue remodeling and wound healing (e.g. COL3A1, COL8A1, TIMP3), epithelial proliferation and differentiation (KRT13, IGF1), immune cell recruitment (CCL11), and a member of the heat shock protein family (HSPB6). On the other hand, we detected a downregulation of pro-inflammatory cytokines (e.g. IL1α, IL1β, IL24, IL36γ, IL36RN), and antimicrobial peptides (e.g. S100A7A, DEFB4). These data were confirmed by independent RT-PCR analyses. CONCLUSION:We present for the first time the direct molecular effects of microneedling therapy on epidermal keratinocytes and dermal fibroblasts using a standardized 3D skin model. Treatment resulted in histological alterations and changed the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling. This data suggests that skin microneedling plays a role in dermal remodeling, increases epidermal differentiation, and might also have a direct effect on collagen synthesis. These findings may increase our understanding of the molecular mechanisms of human skin repair induced by microneedling therapy and will allow comparisons with competing applications, such as ablative laser therapies.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(1), p.e0146325
    Description: INTRODUCTION:Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling. RESULTS:We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment. CONCLUSION:We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in 'silent' metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Science of the Total Environment, 15 November 2018, Vol.642, pp.1429-1438
    Description: Polychlorinated biphenyls (PCBs) are well- known man-made persistent environmental pollutants and endocrine disruptors. As a result of mass production in the past, background levels of these compounds can be measured in human blood worldwide. In 2010 high internal levels of PCBs were discovered in workers of a transformer-recycling company in Germany. Our aim was to measure, whether the expression of CYP1A1, CYP1B1, and IL-1β is dysregulated in peripheral blood mononuclear cells (PBMCs) of the exposed individuals (n = max 308). Further, we measured the regulation of CYP1A1, CYP1B1, AHRR (aromatic hydrocarbon receptor repressor) and IL-1β in skin samples of 25 workers with elevated plasma PCB levels using quantitative PCR (q-RT-PCR). We found a significant correlation between the regulation of IL-1β in skin samples and lipid adjusted PCB levels. In the PBMCs, the expression levels of CYP1A1, CYP1B1 and IL-1β decreased over time with decreasing PCB plasma levels. The upregulation of the cytokine IL-1β in exposed individuals with higher PCB plasma levels warrants further investigation in order to examine its role in the pathophysiology of autoimmune disorders and tumor promotion.
    Keywords: Polychlorinated Biphenyls ; Biomarker ; Gene Regulation ; Marker Genes ; Occupational Exposure ; Ahr ; Rt-Pcr ; Cyp1a1 ; Cyp1b1 ; Il-1β ; Dioxins ; Environmental Sciences ; Biology ; Public Health
    ISSN: 0048-9697
    E-ISSN: 1879-1026
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  • 4
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, February 2017, Vol.31(2), pp.526-543
    Description: The response of the skin to harmful environmental agents is shaped decisively by the status of the immune system. Keratinocytes constitutively express and secrete the chemokine-like mediator, macrophage migration inhibitory factor (MIF), more strongly than dermal fibroblasts, thereby creating a MIF gradient in skin. By using global and epidermis-restricted Mif-knockout (Mif and K14-Cre; Mif) mice, we found that MIF both recruits and maintains antigen-presenting cells in the dermis/epidermis. The reduced presence of antigen-presenting cells in the absence of MIF was associated with accelerated and increased formation of nonmelanoma skin tumors during chemical carcinogenesis. Our results demonstrate that MIF is essential for maintaining innate immunity in skin. Loss of keratinocyte-derived MIF leads to a loss of control of epithelial skin tumor formation in chemical skin carcinogenesis, which highlights an unexpected tumor-suppressive activity of MIF in murine skin.-Brocks, T., Fedorchenko, O., Schliermann, N., Stein, A., Moll, U. M., Seegobin, S., Dewor, M., Hallek, M., Marquardt, Y., Fietkau, K., Heise, R., Huth, S., Pfister, H., Bernhagen, J., Bucala, R., Baron, J. M., Fingerle-Rowson, G. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin.
    Keywords: Cd44 ; Cd74 ; Dmba/Tpa ; Chemokine ; Skin Carcinogenesis ; Macrophage Migration-Inhibitory Factors -- Metabolism ; Skin -- Cytology ; Skin Neoplasms -- Chemically Induced
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 5
    Language: English
    In: Experimental Dermatology, Sept, 2015, Vol.24(9), p.663(6)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/exd.12704/abstract Byline: Sebastian Huth, Ruth Heise, Claudia S. Vetter-Kauczok, Claudia Skazik, Yvonne Marquardt, Katharina Czaja, Ruth Knuchel, Hans F. Merk, Edgar Dahl, Jens M. Baron Keywords: hyaluronan; inflammatory skin diseases; ITIH5 knockout mouse; ITIH5; murine 3D skin model Abstract Inter-[alpha]-trypsin inhibitors are protease inhibitors that are thought to be important regulators in various acute-phase processes. They are composed of one light chain (bikunin) and different heavy chains (ITIHs). The only function known so far of ITIHs is the covalent linkage to hyaluronan (HA). As there is virtually no knowledge on the distribution and function of ITIH proteins in skin tissue, we performed a systematic characterization of ITIH expression in healthy and diseased skin. Using GeneChip.sub.[R] Human Exon 1.0 ST expression profiling, we found that ITIH5 represents the major ITIH family member expressed in human skin. Moreover, the use of quantitative reverse transcription PCR and a customized ITIH5-specific antibody indicated that ITIH5 is predominantly produced by dermal fibroblasts. Immunohistochemical analysis revealed a clearly detectable ITIH5 protein expression in normal skin. Interestingly, ITIH5 expression was significantly up-regulated in inflammatory skin diseases. Furthermore, 3D skin models employing murine Itih5.sub.-/- epidermal keratinocytes and dermal fibroblasts as well as skin specimens of Itih5.sub.-/- mice revealed a significantly altered epidermal structure compared to wild-type controls. Hence, we can strengthen the presumption that ITIH5 may constitute a novel regulatory molecule of the human skin that could play an important role in inflammation via its interaction with HA. Article Note: Equal first authors. Equally contributing senior authors.
    Keywords: Proteases -- Analysis ; Proteins -- Analysis ; Trypsin -- Analysis ; Skin Diseases -- Analysis ; Protease Inhibitors -- Analysis ; Hyaluronic Acid -- Analysis ; Skin -- Analysis
    ISSN: 0906-6705
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  • 6
    Language: English
    In: Archives of biochemistry and biophysics, 2011, Vol.508(2), pp.212-216
    Description: The multidrug resistance related proteins (MRPs) function as efflux transporters of a variety of large organic anions or their conjugates. In recent studies we demonstrated that antigen-presenting cells express a specific pattern of MRPs. MRP-mediated efflux activity of human monocyte-derived dendritic cells (moDCs) was analyzed using an in vitro transport assay. The efflux transport of radiolabeled contact allergens was inhibited using the specific MRP inhibitor indomethacin. Treatment with indomethacin increased intracellular concentration of [³H] eugenol and [³H] isoeugenol in moDCs. In addition by using MRP1 expressing inside-out membrane vesicles we revealed that the transport of eugenol is mediated by MRP1. Human DCs were employed to assess the sensitizing potential of contact allergens and alters their cytokine gene expression profile. Hence, to survey the functionality of indomethacin after stimulation with contact allergens IL-8 and TRIM16 regulation was measured by a DC-based in vitro assay. Incubation with isoeugenol after pre-treatment with indomethacin leads to increased IL-8 and TRIM16 gene expression. These results strongly support the functional role of MRPs in the active efflux of contact allergens also in antigen-presenting cells like moDCs, a novel mechanism which could possibly play a role in the pathogenesis of contact allergy. ; p. 212-216.
    Keywords: Anions ; Indomethacin ; In Vitro Studies ; Dendritic Cells ; Pathogenesis ; Tritium ; Active Transport ; Humans ; Radiolabeling ; Interleukin-8 ; Hypersensitivity ; Pretreatment ; Transporters ; Multiple Drug Resistance ; Allergens ; Eugenol ; Gene Expression
    ISSN: 0003-9861
    Source: AGRIS (Food and Agriculture Organization of the United Nations)
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  • 7
    Language: English
    In: Skin Pharmacology and Physiology, February 2017, Vol.29(6), pp.281-290
    Description: Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of tasisulam and lead to further clinical trials in metastatic melanoma.
    Keywords: Original Paper ; Tasisulam ; Melanoma ; Ly573636 ; Skmel23 Cell Line ; A375 Cell Line ; Chemotherapy ; Sulfonimidamide ; Antiproliferative Effect ; Medicine
    ISSN: 1660-5527
    E-ISSN: 1660-5535
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  • 8
    Language: English
    In: Archives of Biochemistry and Biophysics, 2011, Vol.508(2), pp.212-216
    Description: ► Indomethacin increased intracellular concentration of contact allergens in moDCs. ► Transport of eugenol is mediated by MRP-1. ► Indomethacin-and isoeugenol-dependent increase of IL-8 and TRIM16 expression. The multidrug resistance related proteins (MRPs) function as efflux transporters of a variety of large organic anions or their conjugates. In recent studies we demonstrated that antigen-presenting cells express a specific pattern of MRPs. MRP-mediated efflux activity of human monocyte-derived dendritic cells (moDCs) was analyzed using an transport assay. The efflux transport of radiolabeled contact allergens was inhibited using the specific MRP inhibitor indomethacin. Treatment with indomethacin increased intracellular concentration of [ H] eugenol and [ H] isoeugenol in moDCs. In addition by using MRP1 expressing inside-out membrane vesicles we revealed that the transport of eugenol is mediated by MRP1. Human DCs were employed to assess the sensitizing potential of contact allergens and alters their cytokine gene expression profile. Hence, to survey the functionality of indomethacin after stimulation with contact allergens IL-8 and TRIM16 regulation was measured by a DC-based assay. Incubation with isoeugenol after pre-treatment with indomethacin leads to increased IL-8 and TRIM16 gene expression. These results strongly support the functional role of MRPs in the active efflux of contact allergens also in antigen-presenting cells like moDCs, a novel mechanism which could possibly play a role in the pathogenesis of contact allergy.
    Keywords: Contact Allergens ; Dendritic Cell ; Multidrug Resistance Related Protein ; Transport ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0003-9861
    E-ISSN: 1096-0384
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  • 9
    Language: English
    In: Journal of Investigative Dermatology, June 2014, Vol.134(6), pp.1579-1588
    Description: Retinoids are known to affect skin cell proliferation and differentiation and are key molecules that target retinoid and retinoic acid receptors (RXRs and RARs), leading to physiological and pharmacologic effects. Our aim was to elucidate the role of the retinol-binding protein receptor STRA6, mediating cellular uptake of retinol, on skin structure and function. Our results indicate that STRA6 is constitutively expressed in human epidermal keratinocytes and dermal fibroblasts and is regulated via RAR/RXR-mediated pathways. HaCaT (Human adult low Calcium high Temperature) cells with stable STRA6 knockdown (STRA6KD) showed increased proliferation. Consistently, human organotypic 3D skin models using stable STRA6KD HaCaT cells showed a significantly thicker epidermis and enhanced expression of activation, differentiation, and proliferation markers. The effects were reversible after treatment with free retinol. Human skin reconstitution employing STRA6KD HaCaT cells leads to massive epithelial thickening under conditions in SCID mice. We propose that STRA6KD could lead to cellular vitamin A deficiency in keratinocytes. Consequently, STRA6 has a role for regulating retinoid homeostasis and in helping to program signaling that drives proliferation and differentiation of human skin cells. By its influence on hyperproliferation-associated differentiation, STRA6 could also have a role in skin regeneration and could be a target for pharmacological approaches to improve wound healing.
    Keywords: Medicine
    ISSN: 0022-202X
    E-ISSN: 1523-1747
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  • 10
    In: Experimental Dermatology, November 2014, Vol.23(11), pp.832-837
    Description: Retinoids such as all‐ retinoic acid () influence cell growth, differentiation and apoptosis and may play decisive roles in tumor development and progression. An essential retinoid‐metabolizing enzyme known as lecithin retinol acyltransferase () is expressed in melanoma cells but not in melanocytes catalysing the esterification of all‐ retinol (ol). In this study, we show that a stable knockdown () in the human melanoma cell line SkMel23 leads to significantly increased levels of the substrate ol and biologically active . restored cellular sensitivity to retinoids analysed in cell culture assays and melanoma 3D skin models. Furthermore, ‐induced gene regulatory mechanisms drive depletion of added ol in cells. analysis revealed a significant upregulation of retinoid‐regulated genes such as 26A1 and 6 in cells, suggesting their possible involvement in mediating retinoid resistance in melanoma cells. In conclusion, seems to be important for melanoma progression. We propose that reduction in ol levels in melanoma cells by leads to a disturbance in cellular retinoid level. Balanced expression and activity may provide protection against melanoma development and progression. Pharmacological inhibition of activity could be a promising strategy for overcoming retinoid insensitivity in human melanoma cells.
    Keywords: Melanoma ; Retinoid Resistance ; Retinoid Sensitivity ; Retinoids ; Vitamin A Metabolism
    ISSN: 0906-6705
    E-ISSN: 1600-0625
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