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Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects

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

Deadline for manuscript submissions: 20 May 2024 | Viewed by 5148

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Dr. Tunde Szatmari

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Guest Editor

Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Public Health Centre, 1097 Budapest, Hungary
Interests: radiobiology; bystander effects; cancer research; extracellular vesicles; in vitro and in vivo models; biodosimetry

Special Issue Information

Dear Colleagues,

Applications of ionizing radiation – particularly medical applications as therapeutic and diagnostic tools – expanded in the last decades. Radiotherapy is still one of the main primary treatment options for most tumor types. However, it is associated with significant challenges, due to the fact that it is not a tumor-tissue specific treatment, leading to normal tissue cytotoxicity and increases the risk of new neoplasms. Moreover, radiation induced non-targeted effects, such as bystander effects significantly modulate direct effects of radiotherapy. Radioresistance of cancer cells and radiosensitivity of healthy cells can also hamper the efficiency of radiotherapy. Additionally, occupational health hazards associated with ionizing radiation exist and the potential of nuclear accidents still represents a significant threat to public health. Therefore, the assessment of the acute and late biological effects of ionizing radiation, the mechanisms governing these effects as well as the radioprotection issues are still in the focus of researchers. Further research is needed for instance in the identification of new molecular and cellular agents and pathways governing the development of radiation injuries and propagation of the radiation effects; in the prediction of radiosensitivity (new biomarkers); in the assessment of cell damaging effects of radiation.

The evaluation of the effects of ionizing radiation evolved substantially over time. For decades, the most intensively studied radiobiological consequence of ionizing radiation was the DNA damage. Lately it is known that the non-targeted effects of radiation also contribute to biological effects and other molecules and cytoplasmic organelles other than the nucleus can also be affected by the radiation. A relatively new agent which has proven to mediate non-targeted effects and especially the radiation induced bystander effects are the extracellular vesicles.

This Special Issue aims to publish studies that can provide new insights in cellular or molecular responses to ionizing radiation and their underlying mechanisms, identification of new biomarkers or new methodologies. We also welcome reviews in appropriate topics.

Dr. Tunde Szatmari
Guest Editor

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Keywords

ionizing radiation
cytoplasmic targets of radiation
radiation induced bystander effects
extracellular vesicles
dna damage and repair
biomarkers
miRNA
proteomics
liquid biopsy
radiation carcinogenesis
radiation fibrosis

Published Papers (5 papers)

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Research

18 pages, 3319 KiB

Open AccessArticle

Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice

by Alexandra Jameus, Jessica Dougherty, Ramya Narendrula, Daniela Levert, Manon Valiquette, Jake Pirkkanen, Christine Lalonde, Patrice Bonin, Jeffrey D. Gagnon, Vasu D. Appanna, Sujeenthar Tharmalingam and Christopher Thome

Int. J. Mol. Sci. 2024, 25(6), 3339; https://doi.org/10.3390/ijms25063339 - 15 Mar 2024

Viewed by 600

Abstract

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1–3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage. Full article

(This article belongs to the Special Issue Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects)

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17 pages, 4590 KiB

Open AccessArticle

Chronic Ouabain Targets Pore-Forming Claudin-2 and Ameliorates Radiation-Induced Damage to the Rat Intestinal Tissue Barrier

by Alexander G. Markov, Alexandra A. Livanova, Arina A. Fedorova, Violetta V. Kravtsova and Igor I. Krivoi

Int. J. Mol. Sci. 2024, 25(1), 278; https://doi.org/10.3390/ijms25010278 - 24 Dec 2023

Viewed by 886

Abstract

Ionizing radiation (IR) causes disturbances in the functions of the gastrointestinal tract. Given the therapeutic potential of ouabain, a specific ligand of the Na,K-ATPase, we tested its ability to protect against IR-induced disturbances in the barrier and transport properties of the jejunum and colon of rats. Male Wistar rats were subjected to 6-day intraperitoneal injections of vehicle or ouabain (1 µg/kg/day). On the fourth day of injections, rats were exposed to total-body X-ray irradiation (10 Gy) or a sham irradiation. Isolated tissues were examined 72 h post-irradiation. Electrophysiological characteristics and paracellular permeability for sodium fluorescein were measured in an Ussing chamber. Histological analysis and Western blotting were also performed. In the jejunum tissue, ouabain exposure did not prevent disturbances in transepithelial resistance, paracellular permeability, histological characteristics, as well as changes in the expression of claudin-1, -3, -4, tricellulin, and caspase-3 induced by IR. However, ouabain prevented overexpression of occludin and the pore-forming claudin-2. In the colon tissue, ouabain prevented electrophysiological disturbances and claudin-2 overexpression. These observations may reveal a mechanism by which circulating ouabain maintains tight junction integrity under IR-induced intestinal dysfunction. Full article

(This article belongs to the Special Issue Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects)

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17 pages, 1890 KiB

Open AccessArticle

Proton Compared to X-Irradiation Induces Different Protein Profiles in Oral Cancer Cells and Their Derived Extracellular Vesicles

by Inga Solgård Juvkam, Olga Zlygosteva, Mateusz Sitarz, Bernd Thiede, Brita Singers Sørensen, Eirik Malinen, Nina Jeppesen Edin, Tine Merete Søland and Hilde Kanli Galtung

Int. J. Mol. Sci. 2023, 24(23), 16983; https://doi.org/10.3390/ijms242316983 - 30 Nov 2023

Viewed by 900

Abstract

Extracellular vesicles (EVs) are membrane-bound particles released from cells, and their cargo can alter the function of recipient cells. EVs from X-irradiated cells have been shown to play a likely role in non-targeted effects. However, EVs derived from proton irradiated cells have not yet been studied. We aimed to investigate the proteome of EVs and their cell of origin after proton or X-irradiation. The EVs were derived from a human oral squamous cell carcinoma (OSCC) cell line exposed to 0, 4, or 8 Gy from either protons or X-rays. The EVs and irradiated OSCC cells underwent liquid chromatography–mass spectrometry for protein identification. Interestingly, we found different protein profiles both in the EVs and in the OSCC cells after proton irradiation compared to X-irradiation. In the EVs, we found that protons cause a downregulation of proteins involved in cell growth and DNA damage response compared to X-rays. In the OSCC cells, proton and X-irradiation induced dissimilar cell death pathways and distinct DNA damage repair systems. These results are of potential importance for understanding how non-targeted effects in normal tissue can be limited and for future implementation of proton therapy in the clinic. Full article

(This article belongs to the Special Issue Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects)

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16 pages, 4461 KiB

Open AccessArticle

Toward a Transportable Cell Culture Platform for Evaluating Radiotherapy Dose Modifying Factors

by Nicholas Carlson, Carrie D. House and Mauro Tambasco

Int. J. Mol. Sci. 2023, 24(21), 15953; https://doi.org/10.3390/ijms242115953 - 03 Nov 2023

Viewed by 1079

Abstract

The current tools for validating dose delivery and optimizing new radiotherapy technologies in radiation therapy do not account for important dose modifying factors (DMFs), such as variations in cellular repair capability, tumor oxygenation, ultra-high dose rates and the type of ionizing radiation used. These factors play a crucial role in tumor control and normal tissue complications. To address this need, we explored the feasibility of developing a transportable cell culture platform (TCCP) to assess the relative biological effectiveness (RBE) of ionizing radiation. We measured cell recovery, clonogenic viability and metabolic viability of MDA-MB-231 cells over several days at room temperature in a range of concentrations of fetal bovine serum (FBS) in medium-supplemented gelatin, under both normoxic and hypoxic oxygen environments. Additionally, we measured the clonogenic viability of the cells to characterize how the duration of the TCCP at room temperature affected their radiosensitivity at doses up to 16 Gy. We found that

(78 \pm 2) %

of MDA-MB-231 cells were successfully recovered after being kept at room temperature for three days in 50% FBS in medium-supplemented gelatin at hypoxia (

0.4 \pm 0.1) %

pO₂, while metabolic and clonogenic viabilities as measured by ATP luminescence and colony formation were found to be

(58 \pm 5) %

and

(57 \pm 4)

%, respectively. Additionally, irradiating a TCCP under normoxic and hypoxic conditions yielded a clonogenic oxygen enhancement ratio (OER) of

1.4 \pm 0.6

and a metabolic OER of

1.9 \pm 0.4

. Our results demonstrate that the TCCP can be used to assess the RBE of a DMF and provides a feasible platform for assessing DMFs in radiation therapy applications. Full article

(This article belongs to the Special Issue Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects)

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13 pages, 2582 KiB

Open AccessArticle

Cytokine Levels in Saliva Are Associated with Salivary Gland Fibrosis and Hyposalivation in Mice after Fractionated Radiotherapy of the Head and Neck

by Olga Zlygosteva, Inga Solgård Juvkam, Hans Christian D. Aass, Hilde K. Galtung, Tine M. Søland, Eirik Malinen and Nina F. J. Edin

Int. J. Mol. Sci. 2023, 24(20), 15218; https://doi.org/10.3390/ijms242015218 - 16 Oct 2023

Viewed by 1109

Abstract

Cytokines are mediators of inflammation that could lead to fibrosis. The aim was to monitor cytokine levels in saliva and serum after locally fractionated radiotherapy of the head and neck in mice and investigate associations with salivary gland fibrosis and hyposalivation. C57BL/6 mice were randomized to sham or X-ray irradiation of 66 Gy in 10 fractions over 5 days. Blood and saliva were collected on days −7, 5, 35, 80, and 105 following cytokine analysis. The harvested submandibular salivary gland was assessed for the presence of fibrosis. Decision tree regression analysis was used to investigate whether cytokine levels could predict late endpoints in terms of hyposalivation or fibrosis. Significant formation of fibrosis in gland tissue and reduced saliva production was found after irradiation. The pro-inflammatory cytokines IL-1α, TNF, TIMP1, G-CSF, KC, and MIP-1α showed increased levels in saliva in irradiated mice and a strong correlation with late endpoints. The decision tree analysis largely separated controls from irradiated animals, with IL-1α being the strongest predictor. Pro-inflammatory cytokines in saliva, but not in serum, were associated with late endpoints. This indicates that cytokine expression in saliva is a good biomarker for local salivary gland damage with IL-1α as the strongest single predictor. Full article

(This article belongs to the Special Issue Novel Molecular and Cellular Biology Approaches in the Assessment of Radiation Effects)

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