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Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 15352

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Special Issue Editors

Dr. Mauro Belli

E-Mail Website
Guest Editor

Independent Researcher, 00185 Rome, Italy
Interests: radiation biology; radiation effects; DNA damage; DNA repair; charged particles; radiation protection; low doses; radiation therapy; hadrontherapy; radiation epigenetics
Special Issues, Collections and Topics in MDPI journals

Dr. Maria Antonella Tabocchini

E-Mail Website
Guest Editor

Istituto Nazionale di Fisica Nucleare (INFN), Sezione Roma 1, 00185 Rome, Italy
Interests: radiation biology; radiation effects; DNA damage; DNA repair; charged particles; radiation protection; low doses; radiation therapy; hadrontherapy; radiation epigenetics

Special Issue Information

Dear Colleagues,

The biological effects of ionizing radiation are a subject of great interest both in radiation protection and in medicine. Ionizing radiation is a powerful tool for medical applications, e.g., in cancer diagnosis and treatment. However, in spite of these great benefits, it is considered a “double-edged sword” because of its undesired, harmful side effects.

In all cases, the underlying basic mechanisms are almost always assumed to be related to the “radiation damage” in the DNA of irradiated cells, while there is now substantial and increasing evidence of non-DNA targeted effects. For example, bystander/abscopal effects and adaptive response, which are likely related to epigenetic mechanisms, may have a significant role in radiation response, including carcinogenesis, and should also be considered in treatment optimization in radiotherapy. In effect, there is growing interest in exploiting epigenetic regulation by combining epi-drugs with radiotherapy. A better understanding of radiation-induced epigenetic effects is required to develop this type of precision medicine.

Non-DNA targeted effects appear to be related and involved in a variety of cellular responses to ionizing radiation, including mitochondrial and extranuclear modifications and triggering of cellular defense mechanisms.

Although many DNA- and non-DNA targeted effects have a common origin in the reactive oxygen species generated by ionizing radiation, their dependence on the characteristic of radiation exposure may be significantly different.

This Special Issue is focused on collecting significant works, including original research, reviews, and commentaries, aimed at elucidating the cellular and molecular mechanisms of non-DNA targeted effects of ionizing radiation useful not only for advancing knowledge in radiation biology but also for applications in radiation therapy and radiation protection.

A possible, but not exhaustive, list of important and promising topics is:

Radiation-induced extranuclear modifications of cellular defense mechanisms, including mitochondrial related aspects;
Non-DNA targeted and epigenetic mechanisms involved in cancer and noncancer effects;
Modulation of immune/inflammatory response by epigenetic mechanisms;
Role of radiation linear energy transfer and of chronic, low-dose-rate, radiation exposure in non-DNA targeted effects and epigenetic response;
Epigenetic markers useful in radiation therapy and radiation protection;
Rationale for combinations of epi-drugs and radiotherapy.

Dr. Mauro Belli
Dr. Maria Antonella Tabocchini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ionizing radiation
radiotherapy
radiation protection
low dose/low-dose rate
linear energy transfer
non-DNA targeted effects
epigenetics
abscopal effects
bystander effect
genome instability
adaptive response
DNA repair
chromatin structure
non-coding RNA
microRNA
epi-drugs

Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 6111 KiB

Open AccessArticle

Transcriptome Analysis by RNA Sequencing of Mouse Embryonic Stem Cells Stocked on International Space Station for 1584 Days in Frozen State after Culture on the Ground

by Kayo Yoshida, Megumi Hada, Masami Hayashi, Akane Kizu, Kohei Kitada, Kiyomi Eguchi-Kasai, Toshiaki Kokubo, Takeshi Teramura, Hiromi Hashizume Suzuki, Hitomi Watanabe, Gen Kondoh, Aiko Nagamatsu, Premkumar Saganti, Masafumi Muratani, Francis A. Cucinotta and Takashi Morita

Int. J. Mol. Sci. 2024, 25(6), 3283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063283 - 14 Mar 2024

Viewed by 660

Abstract

As a space project, in “Stem Cells” by the Japan Aerospace Exploration Agency (JAXA), frozen mouse ES cells were stored on the International Space Station (ISS) in the Minus Eighty Degree Laboratory Freezer for ISS (MELFI) for 1584 days. After taking these cells back to the ground, the cells were thawed and cultured, and their gene expressions were comprehensively analyzed using RNA sequencing in order to elucidate the early response of the cells to long-time exposure to space radiation consisting of various ionized particles. The comparisons of gene expression involved in double-stranded break (DSB) repair were examined. The expressions of most of the genes that were involved in homologous recombination (HR) and non-homologous end joining (NHEJ) were not significantly changed between the ISS-stocked cells and ground-stocked control cells. However, the transcription of Trp53inp1 (tumor protein 53 induced nuclear protein-1), Cdkn1a (p21), and Mdm2 genes increased in ISS-stocked cells as well as Fe ion-irradiated cells compared to control cells. This suggests that accumulated DNA damage caused by space radiation exposure would activate these genes, which are involved in cell cycle arrest for repair and apoptosis in a p53-dependent or -independent manner, in order to prevent cells with damaged genomes from proliferating and forming tumors. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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Review

Jump to: Research

23 pages, 2348 KiB

Open AccessReview

A Review of Numerical Models of Radiation Injury and Repair Considering Subcellular Targets and the Extracellular Microenvironment

by Nousha Afshari, Igor Koturbash, Marjan Boerma, Wayne Newhauser, Maria Kratz, Jeffrey Willey, Jacqueline Williams and Jeffery Chancellor

Int. J. Mol. Sci. 2024, 25(2), 1015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25021015 - 13 Jan 2024

Viewed by 863

Abstract

Astronauts in space are subject to continuous exposure to ionizing radiation. There is concern about the acute and late-occurring adverse health effects that astronauts could incur following a protracted exposure to the space radiation environment. Therefore, it is vital to consider the current tools and models used to describe and study the organic consequences of ionizing radiation exposure. It is equally important to see where these models could be improved. Historically, radiobiological models focused on how radiation damages nuclear deoxyribonucleic acid (DNA) and the role DNA repair mechanisms play in resulting biological effects, building on the hypotheses of Crowther and Lea from the 1940s and 1960s, and they neglected other subcellular targets outside of nuclear DNA. The development of these models and the current state of knowledge about radiation effects impacting astronauts in orbit, as well as how the radiation environment and cellular microenvironment are incorporated into these radiobiological models, aid our understanding of the influence space travel may have on astronaut health. It is vital to consider the current tools and models used to describe the organic consequences of ionizing radiation exposure and identify where they can be further improved. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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42 pages, 3804 KiB

Open AccessReview

Quantum Biology and the Potential Role of Entanglement and Tunneling in Non-Targeted Effects of Ionizing Radiation: A Review and Proposed Model

by Bruno F. E. Matarèse, Andrej Rusin, Colin Seymour and Carmel Mothersill

Int. J. Mol. Sci. 2023, 24(22), 16464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242216464 - 17 Nov 2023

Cited by 1 | Viewed by 5421

Abstract

It is well established that cells, tissues, and organisms exposed to low doses of ionizing radiation can induce effects in non-irradiated neighbors (non-targeted effects or NTE), but the mechanisms remain unclear. This is especially true of the initial steps leading to the release of signaling molecules contained in exosomes. Voltage-gated ion channels, photon emissions, and calcium fluxes are all involved but the precise sequence of events is not yet known. We identified what may be a quantum entanglement type of effect and this prompted us to consider whether aspects of quantum biology such as tunneling and entanglement may underlie the initial events leading to NTE. We review the field where it may be relevant to ionizing radiation processes. These include NTE, low-dose hyper-radiosensitivity, hormesis, and the adaptive response. Finally, we present a possible quantum biological-based model for NTE. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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51 pages, 2623 KiB

Open AccessReview

Low-Dose Non-Targeted Effects and Mitochondrial Control

by Dietrich Averbeck

Int. J. Mol. Sci. 2023, 24(14), 11460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411460 - 14 Jul 2023

Cited by 7 | Viewed by 2504

Abstract

Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and “spontaneous” cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O₂⁻ and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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14 pages, 799 KiB

Open AccessReview

A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome

by Alan Cocchetto, Colin Seymour and Carmel Mothersill

Int. J. Mol. Sci. 2023, 24(7), 6022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076022 - 23 Mar 2023

Cited by 1 | Viewed by 3173

Abstract

Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE). Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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19 pages, 2055 KiB

Open AccessReview

Low Dose and Non-Targeted Radiation Effects in Environmental Protection and Medicine—A New Model Focusing on Electromagnetic Signaling

by Carmel Mothersill, Alan Cocchetto and Colin Seymour

Int. J. Mol. Sci. 2022, 23(19), 11118; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911118 - 21 Sep 2022

Cited by 2 | Viewed by 1868

Abstract

The role of signalling in initiating and perpetuating effects triggered by deposition of ionising radiation energy in parts of a system is very clear. Less clear are the very early steps involved in converting energy to chemical and biological effects in non-targeted parts of the system. The paper aims to present a new model, which could aid our understanding of the role of low dose effects in determining ultimate disease outcomes. We propose a key role for electromagnetic signals resulting from physico-chemical processes such as excitation decay, and acoustic waves. These lead to the initiation of damage response pathways such as elevation of reactive oxygen species and membrane associated changes in key ion channels. Critically, these signalling pathways allow coordination of responses across system levels. For example, depending on how these perturbations are transduced, adverse or beneficial outcomes may predominate. We suggest that by appreciating the importance of signalling and communication between multiple levels of organisation, a unified theory could emerge. This would allow the development of models incorporating time, space and system level to position data in appropriate areas of a multidimensional domain. We propose the use of the term “infosome” to capture the nature of radiation-induced communication systems which include physical as well as chemical signals. We have named our model “the variable response model” or “VRM” which allows for multiple outcomes following exposure to low doses or to signals from low dose irradiated cells, tissues or organisms. We suggest that the use of both dose and infosome in radiation protection might open up new conceptual avenues that could allow intrinsic uncertainty to be embraced within a holistic protection framework. Full article

(This article belongs to the Special Issue Radiation-Induced Non-DNA-Targeted Effects Relevant to Radiation Protection and Medicine)

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