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      Profiling mRNA, miRNA and lncRNA expression changes in endothelial cells in response to increasing doses of ionizing radiation

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          Abstract

          Recent and past research have highlighted the importance of the endothelium in the manifestation of radiation injury. Our primary focus is on medical triage and management following whole body or partial-body irradiation. Here we investigated the usability of endothelial cells’ radiation response for biodosimetry applications. We profiled the transcriptome in cultured human endothelial cells treated with increasing doses of X-rays. mRNA expression changes were useful 24 h and 72 h post-radiation, microRNA and lncRNA expression changes were useful 72 h after radiation. More mRNA expressions were repressed than induced while more miRNA and lncRNA expressions were induced than repressed. These novel observations imply distinct radiation responsive regulatory mechanisms for coding and non-coding transcripts. It also follows how different RNA species should be explored as biomarkers for different time-points. Radiation-responsive markers which could classify no radiation (i.e., ‘0 Gy’) and dose-differentiating markers were also predicted. IPA analysis showed growth arrest-related processes at 24 h but immune response coordination at the 72 h post-radiation. Collectively, these observations suggest that endothelial cells have a precise dose and time-dependent response to radiation. Further studies in the laboratory are examining if these differences could be captured in the extracellular vesicles released by irradiated endothelial cells.

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          Most cited references40

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          Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

          Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
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            Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice.

            Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.
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              Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases.

              Exposure to ionizing radiation induces not only apoptosis but also senescence. While the role of endothelial cell apoptosis in mediating radiation-induced acute tissue injury has been extensively studied, little is known about the role of endothelial cell senescence in the pathogenesis of radiation-induced late effects. Senescent endothelial cells exhibit decreased production of nitric oxide and expression of thrombomodulin, increased expression of adhesion molecules, elevated production of reactive oxygen species and inflammatory cytokines and an inability to proliferate and form capillary-like structures in vitro. These findings suggest that endothelial cell senescence can lead to endothelial dysfunction by dysregulation of vasodilation and hemostasis, induction of oxidative stress and inflammation and inhibition of angiogenesis, which can potentially contribute to radiation-induced late effects such as cardiovascular diseases (CVDs). In this article, we discuss the mechanisms by which radiation induces endothelial cell senescence, the roles of endothelial cell senescence in radiation-induced CVDs and potential strategies to prevent, mitigate and treat radiation-induced CVDs by targeting senescent endothelial cells.
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                Author and article information

                Contributors
                aryankalayilm@mail.nih.gov
                ccoleman@mail.nih.gov
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                19 November 2022
                19 November 2022
                2022
                : 12
                : 19941
                Affiliations
                GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Radiation Oncology Branch, Center for Cancer Research, , National Cancer Institute (NCI), ; Bethesda, MD 20892 USA
                Article
                24051
                10.1038/s41598-022-24051-6
                9675751
                36402833
                24448b07-9d0a-46c2-8220-d15f4c9dc9db
                © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 April 2022
                : 9 November 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100012399, Biomedical Advanced Research and Development Authority;
                Award ID: XRC-16002
                Award ID: XRC-16002
                Award Recipient :
                Funded by: NIH, Intramural Research Program, National Cancer Institute, Center for Cancer Research
                Award ID: ZIA BC 010670
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2022

                Uncategorized
                predictive markers,non-coding rnas,transcriptomics
                Uncategorized
                predictive markers, non-coding rnas, transcriptomics

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