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15 pages, 2298 KiB

Open AccessArticle

Transcriptional Inflammatory Signature in Healthy Donors and Different Radiotherapy Cancer Patients

by Gráinne O’Brien, Malgorzata Kamuda, Lourdes Cruz-Garcia, Mariia Polozova, Ales Tichy, Marketa Markova, Igor Sirak, Oldrich Zahradnicek, Piotr Widłak, Lucyna Ponge, Joanna Polanska and Christophe Badie

Int. J. Mol. Sci. 2024, 25(2), 1080; https://doi.org/10.3390/ijms25021080 - 16 Jan 2024

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Abstract

Cancer and ionizing radiation exposure are associated with inflammation. To identify a set of radiation-specific signatures of inflammation-associated genes in the blood of partially exposed radiotherapy patients, differential expression of 249 inflammatory genes was analyzed in blood samples from cancer patients and healthy [...] Read more.

Cancer and ionizing radiation exposure are associated with inflammation. To identify a set of radiation-specific signatures of inflammation-associated genes in the blood of partially exposed radiotherapy patients, differential expression of 249 inflammatory genes was analyzed in blood samples from cancer patients and healthy individuals. The gene expression analysis on a cohort of 63 cancer patients (endometrial, head and neck, and prostate cancer) before and during radiotherapy (24 h, 48 h, ~1 week, ~4–8 weeks, and 1 month after the last fraction) identified 31 genes and 15 up- and 16 down-regulated genes. Transcription variability under normal conditions was determined using blood drawn on three separate occasions from four healthy donors. No difference in inflammatory expression between healthy donors and cancer patients could be detected prior to radiotherapy. Remarkably, repeated sampling of healthy donors revealed an individual endogenous inflammatory signature. Next, the potential confounding effect of concomitant inflammation was studied in the blood of seven healthy donors taken before and 24 h after a flu vaccine or ex vivo LPS (lipopolysaccharide) treatment; flu vaccination was not detected at the transcriptional level and LPS did not have any effect on the radiation-induced signature identified. Finally, we identified a radiation-specific signature of 31 genes in the blood of radiotherapy patients that were common for all cancers, regardless of the immune status of patients. Confirmation via MQRT-PCR was obtained for BCL6, MYD88, MYC, IL7, CCR4 and CCR7. This study offers the foundation for future research on biomarkers of radiation exposure, radiation sensitivity, and radiation toxicity for personalized radiotherapy treatment. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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15 pages, 1848 KiB

Open AccessArticle

Short-Term and Long-Term Effects after Exposure to Ionizing Radiation and Visible Light on Retina and Retinal Pigment Epithelium of Mouse Eye

by Tatiana Feldman, Marina Yakovleva, Dina Utina and Mikhail Ostrovsky

Int. J. Mol. Sci. 2023, 24(23), 17049; https://doi.org/10.3390/ijms242317049 - 01 Dec 2023

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Abstract

A comparative in vivo study of the effects of ionizing radiation (accelerated protons) and visible light (400–700 nm) on the retina and retinal pigment epithelium (RPE) of the mouse eye was carried out. Using the methods of fluorescence spectroscopy and high-performance liquid chromatography [...] Read more.

A comparative in vivo study of the effects of ionizing radiation (accelerated protons) and visible light (400–700 nm) on the retina and retinal pigment epithelium (RPE) of the mouse eye was carried out. Using the methods of fluorescence spectroscopy and high-performance liquid chromatography (HPLC), we analyzed the relative composition of retinoids in chloroform extracts obtained from the retinas and RPEs immediately after exposure of animals to various types of radiation and 4.5 months after they were exposed and maintained under standard conditions throughout the period. The fluorescent properties of chloroform extracts were shown to change upon exposure to various types of radiation. This fact indicates the accumulation of retinoid oxidation and degradation products in the retina and RPE. The data from fluorescence and HPLC analyses of retinoids indicate that when exposed to ionizing radiation, retinoid oxidation processes similar to photooxidation occur. Both ionizing radiation and high-intensity visible light have been shown to be characterized by long-term effects. The action of any type of radiation is assumed to activate the mechanism of enhanced reactive oxygen species production, resulting in a long-term damaging effect. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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13 pages, 1648 KiB

Open AccessArticle

Biomarkers to Predict Lethal Radiation Injury to the Rat Lung

by Meetha Medhora, Feng Gao, Tracy Gasperetti, Jayashree Narayanan, Heather Himburg, Elizabeth R. Jacobs, Anne V. Clough, Brian L. Fish and Aniko Szabo

Int. J. Mol. Sci. 2023, 24(6), 5627; https://doi.org/10.3390/ijms24065627 - 15 Mar 2023

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Abstract

Currently, there are no biomarkers to predict lethal lung injury by radiation. Since it is not ethical to irradiate humans, animal models must be used to identify biomarkers. Injury to the female WAG/RijCmcr rat has been well-characterized after exposure to eight doses of [...] Read more.

Currently, there are no biomarkers to predict lethal lung injury by radiation. Since it is not ethical to irradiate humans, animal models must be used to identify biomarkers. Injury to the female WAG/RijCmcr rat has been well-characterized after exposure to eight doses of whole thorax irradiation: 0-, 5-, 10-, 11-, 12-, 13-, 14- and 15-Gy. End points such as SPECT imaging of the lung using molecular probes, measurement of circulating blood cells and specific miRNA have been shown to change after radiation. Our goal was to use these changes to predict lethal lung injury in the rat model, 2 weeks post-irradiation, before any symptoms manifest and after which a countermeasure can be given to enhance survival. SPECT imaging with ^99mTc-MAA identified a decrease in perfusion in the lung after irradiation. A decrease in circulating white blood cells and an increase in five specific miRNAs in whole blood were also tested. Univariate analyses were then conducted on the combined dataset. The results indicated that a combination of percent change in lymphocytes and monocytes, as well as pulmonary perfusion volume could predict survival from radiation to the lungs with 88.5% accuracy (95% confidence intervals of 77.8, 95.3) with a p-value of < 0.0001 versus no information rate. This study is one of the first to report a set of minimally invasive endpoints to predict lethal radiation injury in female rats. Lung-specific injury can be visualized by ^99mTc-MAA as early as 2 weeks after radiation. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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17 pages, 4107 KiB

Open AccessArticle

Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice

by Hua Guan, Wen Zhang, Dafei Xie, Yuehua Nie, Shi Chen, Xiaoya Sun, Hongling Zhao, Xiaochang Liu, Hua Wang, Xin Huang, Chenjun Bai, Bo Huang, Pingkun Zhou and Shanshan Gao

Int. J. Mol. Sci. 2023, 24(4), 4020; https://doi.org/10.3390/ijms24044020 - 16 Feb 2023

Cited by 4 | Viewed by 1745

Abstract

Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. [...] Read more.

Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. In this study, we investigated the effect, role, and radioprotective significance of cytosolic mitochondrial DNA (mtDNA) and its associated cGAS signaling on hematopoietic injury induced by IR in vitro culture cells and in vivo total body irradiated mice in this study. The results demonstrated that γ-ray exposure increases the release of mtDNA into the cytosol to activate cGAS signaling pathway, and the voltage-dependent anion channel (VDAC) may contribute to IR-induced mtDNA release. VDAC1 inhibitor DIDS and cGAS synthetase inhibitor can alleviate bone marrow injury and ameliorate hematopoietic suppression induced by IR via protecting hematopoietic stem cells and adjusting subtype distribution of bone marrow cells, such as attenuating the increase of the F4/80⁺ macrophage proportion in bone marrow cells. The present study provides a new mechanistic explanation for the radiation non-target effect and an alternative technical strategy for the prevention and treatment of hematopoietic acute radiation syndrome. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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15 pages, 4416 KiB

Open AccessArticle

IGFL2-AS1, a Long Non-Coding RNA, Is Associated with Radioresistance in Colorectal Cancer

by Jeeyong Lee, Da Yeon Kim, Younjoo Kim, Ui Sup Shin, Kwang Seok Kim and Eun Ju Kim

Int. J. Mol. Sci. 2023, 24(2), 978; https://doi.org/10.3390/ijms24020978 - 04 Jan 2023

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Abstract

Precise prediction of radioresistance is an important factor in the treatment of colorectal cancer (CRC). To discover genes that regulate the radioresistance of CRCs, we analyzed an RNA sequencing dataset of patient-originated samples. Among various candidates, IGFL2-AS1, a long non-coding RNA (lncRNA), exhibited [...] Read more.

Precise prediction of radioresistance is an important factor in the treatment of colorectal cancer (CRC). To discover genes that regulate the radioresistance of CRCs, we analyzed an RNA sequencing dataset of patient-originated samples. Among various candidates, IGFL2-AS1, a long non-coding RNA (lncRNA), exhibited an expression pattern that was well correlated with radioresistance. IGFL2-AS1 is known to be highly expressed in various cancers and functions as a competing endogenous RNA. To further investigate the role of IGFL2-AS1 in radioresistance, which has not yet been studied, we assessed the amount of IGFL2-AS1 transcripts in CRC cell lines with varying degrees of radioresistance. This analysis showed that the more radioresistant the cell line, the higher the level of IGFL2-AS1 transcripts—a similar trend was observed in CRC samples. To directly assess the relationship between IGFL2-AS1 and radioresistance, we generated a CRC cell line stably expressing a small hairpin RNA (shRNA) targeting IGFL2-AS1. shRNA-mediated knockdown of IGFL2-AS1 decreased radioresistance and cell migration in vitro, establishing a functional role for IGFL2-AS1 in radioresistance. We also showed that downstream effectors of the AKT pathway played crucial roles. These data suggest that IGFL2-AS1 contributes to the acquisition of radioresistance by regulating the AKT pathway. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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17 pages, 2982 KiB

Open AccessArticle

Cell Type-Specific Patterns in the Accumulation of DNA Damage Following Multifractional Radiation Exposure

by Pamela Akuwudike, Adrianna Tartas, Milagrosa López-Riego, Iuliana Toma-Dasu, Andrzej Wojcik and Lovisa Lundholm

Int. J. Mol. Sci. 2022, 23(21), 12861; https://doi.org/10.3390/ijms232112861 - 25 Oct 2022

Cited by 1 | Viewed by 1105

Abstract

Predicting the risk of second malignant neoplasms is complicated by uncertainties regarding the shape of the dose–response relationship at high doses. Limited understanding of the competitive relationship between cell killing and the accumulation of DNA lesions at high doses, as well as the [...] Read more.

Predicting the risk of second malignant neoplasms is complicated by uncertainties regarding the shape of the dose–response relationship at high doses. Limited understanding of the competitive relationship between cell killing and the accumulation of DNA lesions at high doses, as well as the effects of other modulatory factors unique to radiation exposure during radiotherapy, such as dose heterogeneity across normal tissue and dose fractionation, contribute to these uncertainties. The aim of this study was to analyze the impact of fractionated irradiations on two cell systems, focusing on the endpoints relevant for cancer induction. To simulate the heterogeneous dose distribution across normal tissue during radiotherapy, exponentially growing VH10 fibroblasts and AHH-1 lymphoblasts were irradiated with 9 and 12 fractions (VH10) and 10 fractions (AHH-1) at 0.25, 0.5, 1, or 2 Gy per fraction. The effects on cell growth, cell survival, radiosensitivity and the accumulation of residual DNA damage lesions were analyzed as functions of dose per fraction and the total absorbed dose. Residual γH2AX foci and other DNA damage markers (micronuclei, nuclear buds, and giant nuclei) were accumulated at high doses in both cell types, but in a cell type-dependent manner. The competitive relationship between cell killing and the accumulation of carcinogenic DNA damage following multifractional radiation exposure is cell type-specific. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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21 pages, 3750 KiB

Open AccessArticle

Human Peripheral Blood Mononucleocyte Derived Myeloid Committed Progenitor Cells Mitigate H-ARS by Exosomal Paracrine Signal

by Rishi Man Chugh, Payel Bhanja, Ximena Diaz Olea, Fang Tao, Kealan Schroeder, Ryan Zitter, Tanu Arora, Harsh Pathak, Bruce F. Kimler, Andrew K. Godwin, John M. Perry and Subhrajit Saha

Int. J. Mol. Sci. 2022, 23(10), 5498; https://doi.org/10.3390/ijms23105498 - 14 May 2022

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Abstract

Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the [...] Read more.

Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient’s hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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Review

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25 pages, 2120 KiB

Open AccessReview

3D Cell Models in Radiobiology: Improving the Predictive Value of In Vitro Research

by Francesca Antonelli

Int. J. Mol. Sci. 2023, 24(13), 10620; https://doi.org/10.3390/ijms241310620 - 25 Jun 2023

Cited by 2 | Viewed by 2000

Abstract

Cancer is intrinsically complex, comprising both heterogeneous cellular composition and extracellular matrix. In vitro cancer research models have been widely used in the past to model and study cancer. Although two-dimensional (2D) cell culture models have traditionally been used for cancer research, they [...] Read more.

Cancer is intrinsically complex, comprising both heterogeneous cellular composition and extracellular matrix. In vitro cancer research models have been widely used in the past to model and study cancer. Although two-dimensional (2D) cell culture models have traditionally been used for cancer research, they have many limitations, such as the disturbance of interactions between cellular and extracellular environments and changes in cell morphology, polarity, division mechanism, differentiation and cell motion. Moreover, 2D cell models are usually monotypic. This implies that 2D tumor models are ineffective at accurately recapitulating complex aspects of tumor cell growth, as well as their radiation responses. Over the past decade there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers, highlighting a complementary model for studies of radiation effects on tumors, especially in conjunction with chemotherapy. The introduction of 3D cell culture approaches aims to model in vivo tissue interactions with radiation by positioning itself halfway between 2D cell and animal models, and thus opening up new possibilities in the study of radiation response mechanisms of healthy and tumor tissues. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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18 pages, 1047 KiB

Open AccessReview

Tissue Reactions and Mechanism in Cardiovascular Diseases Induced by Radiation

by Xiao-Chang Liu and Ping-Kun Zhou

Int. J. Mol. Sci. 2022, 23(23), 14786; https://doi.org/10.3390/ijms232314786 - 26 Nov 2022

Cited by 5 | Viewed by 2371

Abstract

The long-term survival rate of cancer patients has been increasing as a result of advances in treatments and precise medical management. The evidence has accumulated that the incidence and mortality of non-cancer diseases have increased along with the increase in survival time and [...] Read more.

The long-term survival rate of cancer patients has been increasing as a result of advances in treatments and precise medical management. The evidence has accumulated that the incidence and mortality of non-cancer diseases have increased along with the increase in survival time and long-term survival rate of cancer patients after radiotherapy. The risk of cardiovascular disease as a radiation late effect of tissue damage reactions is becoming a critical challenge and attracts great concern. Epidemiological research and clinical trials have clearly shown the close association between the development of cardiovascular disease in long-term cancer survivors and radiation exposure. Experimental biological data also strongly supports the above statement. Cardiovascular diseases can occur decades post-irradiation, and from initiation and development to illness, there is a complicated process, including direct and indirect damage of endothelial cells by radiation, acute vasculitis with neutrophil invasion, endothelial dysfunction, altered permeability, tissue reactions, capillary-like network loss, and activation of coagulator mechanisms, fibrosis, and atherosclerosis. We summarize the most recent literature on the tissue reactions and mechanisms that contribute to the development of radiation-induced cardiovascular diseases (RICVD) and provide biological knowledge for building preventative strategies. Full article

(This article belongs to the Special Issue Molecular Research in Radiobiology 2.0)

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