scholarly journals Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Science ◽  
2012 ◽  
Vol 335 (6064) ◽  
pp. 104-108 ◽  
Author(s):  
Badri G. Modi ◽  
Jason Neustadter ◽  
Elisa Binda ◽  
Julia Lewis ◽  
Renata B. Filler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Langerhans Cells ◽  
Polyaromatic Hydrocarbons ◽  
Chemical Carcinogenesis ◽  
Human Keratinocytes ◽  
Underlying Mechanism ◽  
Tumor Resistance ◽  
Complex Relation ◽  
Cell Immunity ◽  
Pah Metabolism

Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

scholarly journals Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Weiqiang Huang ◽  
Longshan Zhang ◽  
Mi Yang ◽  
Xixi Wu ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Gene Set Enrichment Analysis ◽  
Cancer Associated Fibroblasts ◽  
Western Blot Assay ◽  
Damage Level ◽  
Radiation Resistant

Abstract Background Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. Methods Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. Results We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. Conclusions Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.

scholarly journals UVB protective effects of Sargassum horneri through the regulation of Nrf2 mediated antioxidant mechanism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eui Jeong Han ◽  
Seo-Young Kim ◽  
Hee-Jin Han ◽  
Hyun-Soo Kim ◽  
Kil-Nam Kim ◽  
...  
Keyword(s):  
Skin Barrier ◽  
Human Keratinocytes ◽  
Underlying Mechanism ◽  
Ultraviolet B ◽  
Sargassum Horneri ◽  
Cellular Damage ◽  
Protective Effects ◽  
Skin Damage ◽  
Antioxidant Mechanism ◽  
Induced Apoptosis

AbstractThe present study aimed to evaluate the protective effect of a methanol extract of Sargassum horneri (SHM), which contains 6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (HTT) and apo-9′-fucoxanthinone, against ultraviolet B (UVB)-induced cellular damage in human keratinocytes and its underlying mechanism. SHM significantly improved cell viability of UVB-exposed human keratinocytes by reducing the generation of intracellular reactive oxygen species (ROS). Moreover, SHM inhibited UVB exposure-induced apoptosis by reducing the formation of apoptotic bodies and the populations of the sub-G1 hypodiploid cells and the early apoptotic cells by modulating the expression of the anti- and pro-apoptotic molecules, Bcl-2 and Bax, respectively. Furthermore, SHM inhibited NF-κB p65 activation by inducing the activation of Nrf2/HO-1 signaling. The cytoprotective and antiapoptotic activities of SHM are abolished by the inhibition of HO-1 signaling. In further study, SHM restored the skin dryness and skin barrier disruption in UVB-exposed human keratinocytes. Based to these results, our study suggests that SHM protects the cells against UVB-induced cellular damages through the Nrf2/HO-1/NF-κB p65 signaling pathway and may be potentially useful for the prevention of UVB-induced skin damage.

scholarly journals Blocking DNA Damage Repair May Be Involved in Stattic (STAT3 Inhibitor)-Induced FLT3-ITD AML Cell Apoptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuxuan Luo ◽  
Ying Lu ◽  
Bing Long ◽  
Yansi Lin ◽  
Yanling Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Dna Damage Repair ◽  
Underlying Mechanism ◽  
Internal Tandem Duplication ◽  
Mrna Sequencing ◽  
Damage Repair ◽  
Flt3 Inhibitors ◽  
Flt3 Internal Tandem Duplication

The FMS-like tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD) mutation can be found in approximately 25% of all acute myeloid leukemia (AML) cases and is associated with a poor prognosis. The main treatment for FLT3-ITD-positive AML patients includes genotoxic therapy and FLT3 inhibitors, which are rarely curative. Inhibiting STAT3 activity can improve the sensitivity of solid tumor cells to radiotherapy and chemotherapy. This study aimed to explore whether Stattic (a STAT3 inhibitor) affects FLT3-ITD AML cells and the underlying mechanism. Stattic can inhibit the proliferation, promote apoptosis, arrest cell cycle at G0/G1, and suppress DNA damage repair in MV4-11cells. During the process, through mRNA sequencing, we found that DNA damage repair-related mRNA are also altered during the process. In summary, the mechanism by which Stattic induces apoptosis in MV4-11cells may involve blocking DNA damage repair machineries.

scholarly journals Healthcare Workers Occupationally Exposed to Ionizing Radiation Exhibit Altered Levels of Inflammatory Cytokines and Redox Parameters

Antioxidants ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 12 ◽  
Author(s):  
Iman M. Ahmad ◽  
Maher Y. Abdalla ◽  
Tiffany A. Moore ◽  
Lisa Bartenhagen ◽  
Adam J. Case ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Healthcare Workers ◽  
Immune Modulation ◽  
Oxidative Dna Damage ◽  
Underlying Mechanism ◽  
Increased Risk ◽  
Exposed Workers ◽  
Immune Alterations ◽  
Occupationally Exposed

Studies have shown an increased risk for a variety of cancers, specifically brain cancer, in healthcare workers occupationally exposed to ionizing radiation. Although the mechanisms mediating these phenomena are not fully understood, ionizing radiation-mediated elevated levels of reactive oxygen species (ROS), oxidative DNA damage, and immune modulation are likely involved. A group of 20 radiation exposed workers and 40 sex- and age-matched non-exposed control subjects were recruited for the study. We measured superoxide (O2•−) levels in whole blood of healthcare workers and all other measurements of cytokines, oxidative DNA damage, extracellular superoxide dismutase (EcSOD) activity and reduced/oxidized glutathione ratio (GSH/GSSG) in plasma. Levels of O2•− were significantly higher in radiation exposed workers compared to control. Similarly, a significant increase in the levels of interleukin (IL)-6, IL-1α and macrophage inflammatory protein (MIP)-1α in radiation exposed workers compared to control was observed, while there was no significance difference in the other 27 screened cytokines. A significant positive correlation was found between MIP-1α and O2•− levels with no correlation in either IL-6 or IL-1α. Further, a dose-dependent relationship with significant O2•− production and immune alterations in radiation exposed workers was demonstrated. There was no statistical difference between the groups in terms of oxidative DNA damage, GSH/GSSG levels, or EcSOD activity. Although the biologic significance of cytokines alterations in radiation exposed workers is unclear, further studies are needed for determining the underlying mechanism of their elevation.

scholarly journals MORC2 regulates DNA damage response through a PARP1-dependent pathway

2019 ◽  
Vol 47 (16) ◽  
pp. 8502-8520 ◽  
Author(s):  
Lin Zhang ◽  
Da-Qiang Li
Keyword(s):  
Dna Damage ◽  
Zinc Finger ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

scholarly journals Analyses of the Secondary Particle Radiation and the DNA Damage It Causes to Human Keratinocytes

2011 ◽  
Vol 52 (6) ◽  
pp. 685-693 ◽  
Author(s):  
Emily A. LEBEL ◽  
Adam RUSEK ◽  
Michael B. SIVERTZ ◽  
Kin YIP ◽  
Keith H. THOMPSON ◽  
...  
Keyword(s):  
Dna Damage ◽  
Secondary Particle ◽  
Human Keratinocytes ◽  
Particle Radiation

scholarly journals Skin Treatment with Pulsed Monochromatic UVA1 355 Device and Computerized Morphometric Analysis of Histochemically Identified Langerhans Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-6
Author(s):  
Nicola Zerbinati ◽  
Federica Riva ◽  
Marco Paulli ◽  
Pier Camillo Parodi ◽  
Alberto Calligaro
Keyword(s):  
Dna Damage ◽  
Solid State ◽  
Langerhans Cells ◽  
Narrow Band ◽  
Band Emission ◽  
Passive Filters ◽  
Metal Halide Lamps ◽  
Skin Samples ◽  
Immunohistochemical Identification ◽  
New Machine

Fluorescent or metal halide lamps are widely used in therapeutic applications in dermatological diseases, with broadband or narrow band emission UVA/UVA1 (320–400 nm) obtained with suitable passive filters. Recently, it has been possible for us to use a new machine provided with solid state source emitting pulsed monochromatic UVA1 355 nm. In order to evaluate the effects of this emission on immunocells of the skin, human skin samples were irradiated with monochromatic 355 nm UVA1 with different energetic fluences and after irradiation Langerhans cells were labeled with CD1a antibodies. The immunohistochemical identification of these cells permitted evaluating their modifications in terms of density into the skin. Obtained results are promising for therapeutical applications, also considering that a monochromatic radiation minimizes thermic load and DNA damage in the skin tissues.

Opposed arsenite-mediated regulation of p53-survivin is involved in neoplastic transformation, DNA damage, or apoptosis in human keratinocytes

Toxicology ◽  
2012 ◽  
Vol 300 (3) ◽  
pp. 121-131 ◽  
Author(s):  
Yuan Li ◽  
Rongrong Jiang ◽  
Yue Zhao ◽  
Yuan Xu ◽  
Min Ling ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neoplastic Transformation ◽  
Human Keratinocytes
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