Radiation-induced Bystander Effects Research Articles

Radiation-induced bystander effect on the brain after fractionated spinal cord irradiation of aging rats

We investigated the influence of the so-called bystander effect on metabolic and histopathological changes in the rat brain after fractionated spinal cord irradiation. The study was initiated with adult Wistar male rats (n = 20) at the age of 9 months. The group designated to irradiation (n = 10) and the age-matched control animals (n = 10) were subjected to an initial measurement using in vivo proton magnetic resonance spectroscopy (1H MRS) and magnetic resonance imaging (MRI). After allowing the animals to survive until 12 months, they received fractionated spinal cord irradiation with a total dose of 24 Gy administered in 3 fractions (8 Gy per fraction) once a week on the same day for 3 consecutive weeks. 1H MRS and MRI of brain metabolites were performed in the hippocampus, corpus striatum, and olfactory bulb (OB) before irradiation (9-month-old rats) and subsequently 48 h (12-month-old) and 2 months (14-month-old) after the completion of irradiation. After the animals were sacrificed at the age of 14 months, brain tissue changes were investigated in two neurogenic regions: the hippocampal dentate gyrus (DG) and the rostral migratory stream (RMS). By comparing the group of 9-month-old rats and individuals measured 48 h (at the age of 12 months) after irradiation, we found a significant decrease in the ratio of total N-acetyl aspartate to total creatine (tNAA/tCr) and gamma-aminobutyric acid to tCr (GABA/tCr) in OB and hippocampus. A significant increase in myoinositol to tCr (mIns/tCr) in the OB persisted up to 14 months of age. Proton nuclear magnetic resonance (1H NMR)-based plasma metabolomics showed a significant increase in keto acids and decreased tyrosine and tricarboxylic cycle enzymes. Morphometric analysis of neurogenic regions of 14-month-old rats showed well-preserved stem cells, neuroblasts, and increased neurodegeneration. The radiation-induced bystander effect more significantly affected metabolite concentration than the distribution of selected cell types.

ATR signaling controls the bystander responses of human chondrosarcoma cells by promoting RAD51-dependent DNA repair.

Radiation-induced bystander effect (RIBE) frequently is seen as DNA damage in unirradiated bystander cells, but the repair processes initiated in response to that DNA damage are not well understood. RIBE-mediated formation of micronuclei (MN), a biomarker of persistent DNA damage, was previously observed in bystander normal fibroblast (AG01522) cells, but not in bystander human chondrosarcoma (HTB94) cells. The molecular mechanisms causing this disparity are not clear. Herein, we investigate the role of DNA repair in the bystander responses of the two cell lines. Cells were irradiated with X-rays and immediately co-cultured with un-irradiated cells using a trans-well insert system in which they share the same medium. The activation of DNA damage response (DDR) proteins was detected by immunofluorescence staining or Western blotting. MN formation was examined by the cytokinesis-block MN assay, which is a robust method to detect persistent DNA damage. Immunofluorescent foci of γH2AX and 53BP1, biomarkers of DNA damage and repair, revealed a greater capacity for DNA repair in HTB94 cells than in AG01522 cells in both irradiated and bystander populations. Autophosphorylation of ATR at the threonine 1989 site was expressed at a greater level in HTB94 cells compared to AG01522 cells at the baseline and in response to hydroxyurea treatment or exposure to 1 Gy of X-rays. An inhibitor of ATR, but not of ATM, promoted MN formation in bystander HTB94 cells. In contrast, no effect of either inhibitor was observed in bystander AG01522 cells, indicating that ATR signaling might be a pivotal pathway to preventing the MN formation in bystander HTB94 cells. Supporting this idea, we found an ATR-dependent increase in the fractions of bystander HTB94 cells with pRPA2 S33 and RAD51 foci. A blocker of RAD51 facilitated MN formation in bystander HTB94 cells. Our results indicate that HTB94 cells were likely more efficient in DNA repair than AG01522 cells, specifically via ATR signaling, which inhibited the bystander signal-induced MN formation. This study highlights the significance of DNA repair efficiency in bystander cell responses.

Radiation-induced Bystander Effects on Glioblastoma Tumor Cells via NMDA Receptor Signaling.

Proton therapy has been widely applied on treating inaccessible and inoperable tumors, such as tumors deep within the brain or close to the critical brain stem. Nevertheless, the damaging effect of radiation for central nervous system (CNS) tumors is difficult to be confined within the irradiated region and has led to decline of neurological function in especially children with congenital CNS tumors. Currently, the involvement of n-methyl-d-aspartate (NMDA) receptors or secretary cytokines and chemokines in proton-induced bystander effects remains unclear. To understand the modulatory effects of NMDA receptor inhibition on the survival and proliferation of glioblastoma-derived cells, mesenchymal-like U373 cells were applied along with U87 neural glioblastoma cells for single doses of proton radiation at different LET in the presence or absence of pretreatment with memantine and/or collimation. Under collimation, neuronal tumor cells that are not directly irradiated (i.e., bystander cells) encounter similar biological effects potentially through cell coupling and synaptic transmission. Furthermore, whether proton LET plays a role in the mediation of bystander effect awaits to be elucidated. From this study, synaptic transmission was found to play differential roles in the proliferation of U373 and U87 cells after exposure to collimated radiation. Also, radiation-induced cell proliferation at the late stage was more correlated with bystander cell survival than early manifested γH2AX foci, suggesting that proton-induced glutamatergic synapse may act as a more important contributor than proton-induced direct effect on DNA double-stranded breaks to the late-stage responses of glioblastoma cells.

The influence of radiation-induced bystander effect in osteoblasts mediated by plasma-derived extracellular vesicles (EVs)

ObjectivesHead and neck tumor patients may develop post-radiotherapy diseases after radiotherapy treatment. And radiotherapy can elicit radiation-induced bystander effect, wherein extracellular vesicles (EVs) play a crucial role. For normal parts of the body that have not been directly irradiated, the effect of EVs on them needs to be further explored. This study aims to investigate the functions of plasma-derived EVs in regulating normal osteoblasts during radiation-induced bystander effects. Methods and materialsRat plasma-derived EVs were isolated and identified firstly, followed by an evaluation of their intracellular biological effects on normal osteoblasts in vitro. Transcriptome sequencing analysis and confirmations were performed to identify potential mechanisms. ResultsIrradiated plasma-derived EVs were found to enhance osteoblast proliferation, migration, and cell cycle progression, concurrently suppressing the expression of osteogenesis-related genes and proteins. Furthermore, these EVs attenuated the expression of osteogenesis and oxidative stress resistance related genes, while upregulating the PI3K-AKT pathway and intracellular reactive oxygen species in osteoblasts. ConclusionsIrradiated plasma-derived EVs could alter the biological effects in osteoblasts, which is closely associated with the levels of GPX1 and the PI3K-AKT signaling pathway. This suggests that plasma-derived EVs serve as a crucial factor contributing to radiation-induced bystander effect in osteoblasts.

Irradiated engineered tumor cell-derived microparticles remodel the tumor immune microenvironment and enhance antitumor immunity

Radiotherapy (RT), administered to roughly half of all cancer patients, occupies a crucial role in the landscape of cancer treatment. However, expanding the clinical indications of RT remains challenging. Inspired by the radiation-induced bystander effect (RIBE), we used the mediators of RIBE to mimic RT. Specifically, we discovered that irradiated tumor cell-released microparticles (RT-MPs) mediated the RIBE and had immune activation effects. To further boost the immune activation effect of RT-MPs to achieve cancer remission, even in advanced stages, we engineered RT-MPs with different cytokine and chemokine combinations by modifying their production method. After comparing the therapeutic effect of the engineered RT-MPs invitro and invivo, we demonstrated that tIL-15/tCCL19-RT-MPs effectively activated antitumor immune responses, significantly prolonged the survival of mice with malignant pleural effusion (MPE), and even achieved complete cancer remission. When tIL-15/tCCL19-RT-MPs were combined with PD-1 monoclonal antibody (mAb), a cure rate of up to 60% was achieved. This combination therapy relied on the activation of CD8+ Tcells and macrophages, resulting in the inhibition of tumor growth and the establishment of immunological memory against tumor cells. Hence, our research may provide an alternative and promising strategy for cancers that are not amenable to conventional RT.

Understanding how MSCs reverse radiation-induced fibrosis: HGF vs. TGF-B1

Understanding how MSCs reverse radiation-induced fibrosis: HGF <i>vs.</i> TGF-B1

Primary cilium participates in radiation-induced bystander effects through TGF-β1 signaling.

Many studies have indicated that tumor growth factor-beta (TGF-β) signaling mediates radiation-induced bystander effects (RIBEs). The primary cilium (PC) coordinates several signaling pathways including TGF-β signaling to regulate diverse cellular processes. But whether the PC participates in TGF-β induced RIBEs remains unclear.The cellular levels of TGF-β1 were detected by western blot analysis and the secretion of TGF-β1 was measured by ELISA kit. The ciliogenesis was altered by CytoD treatment, STIL siRNA transfection, IFT88 siRNA transfection, or KIF3a siRNA transfection, separately, and was detected by western blot analysis and immunofluorescence staining. G0 /G1 phase cells were arrested by serum starvation and S phase cells were induced by double thymidine block. The TGF-β1 signaling was interfered by LY2109761, a TGF-β receptor 1 (TβR1) inhibitor, or TGF-β1 neutral antibody. The DNA damages were induced by TGF-β1 or radiated conditional medium (RCM) from irradiated cells and were reflected by p21 expression, 53BP1 foci, and γH2AX foci.Compared with unirradiated control, both A549 and Beas-2B cells expressed and secreted more TGF-β1 after carbon ion beam or X-ray irradiation. RCM collected from irradiated cells or TGF-β1 treatment caused an increase of DNA damage in cocultured unirradiated Beas-2B cells while blockage of TGF-β signaling by TβR1 inhibitor or TGF-β1 neutral antibody alleviates this phenomenon. IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-β1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G0 /G1 phase cells which showed higher PC formation rate.This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-β1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs.

The COX-2/PGE2 Response Pathway Upregulates Radioresistance in A549 Human Lung Cancer Cells through Radiation-Induced Bystander Signaling.

This study aimed to determine the mechanism underlying the modulation of radiosensitivity in cancer cells by the radiation-induced bystander effect (RIBE). We hypothesized that the RIBE mediates cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in elevating radioresistance in unirradiated cells. In this study, we used the SPICE-QST microbeam irradiation system to target 0.07-0.7% cells by 3.4-MeV proton microbeam in the cell culture sample, such that most cells in the dish became bystander cells. Twenty-four hours after irradiation, we observed COX-2 protein upregulation in microbeam-irradiated cells compared to that of controls. Additionally, 0.29% of the microbeam-irradiated cells exhibited increased cell survival and a reduced micronucleus rate against X-ray irradiation compared to that of non-microbeam irradiated cells. The radioresistance response was diminished in both cell groups with the hemichannel inhibitor and in COX-2-knockout cells under cell-to-cell contact and sparsely distributed conditions. The results indicate that the RIBE upregulates the cell radioresistance through COX-2/PGE2 intercellular responses, thereby contributing to issues, such as the risk of cancer recurrence.

LC3 Accelerated Brain-Lung Axis Abscopal Effects after Fractionated Whole-Brain Radiation by Promoting Motoneurons to Secrete Periostin.

The effect of autophagy on the radiation-induced bystander effect (RIBE) invivo is unclear. Here, the whole brains of microtubule-associated protein 1A/1B-light chain 3 (LC3) and C57BL/6 (B6) mice were irradiated once (10 Gy)(IR1), given 3 fractions in three weeks (IR3), or 6 fractions in six weeks (IR6). The median survival of LC3 mice was 56.5 days, and that of B6 mice was 65 days after IR6. LC3 mice showed more congestion and fibrosis in the lung after the IR3 and IR6 irradiation protocols than B6 mice. Quantitative proteomics of serum samples and lung RNA sequencing of the LC3 group showed that the common most clustered pathway of the IR3 group was the elastic fiber formation pathway, which contained Periostin (POSTN). POSTN in the motoneurons increased with increasing number of radiation fractions in LC3 mice. A 1 μg/g POSTN neutralizing antibody reduced the lung fibrosis of LC3 mice exposed to IR3 by one-third, and significantly prolonged the survival time of LC3 mice exposed to IR6. LDN-214117 and LRRK2-in-1 were the best two of sixteen transforming growth factor-beta1 (TGF-β) receptor and autophagy mediators to decrease Postn mRNA. These data led us to conclude that LC3 accelerated motoneuron secretion of POSTN and aggravated the RIBE in the lung after brain irradiation.

Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects

Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects

Radiation-Induced Bystander Effect via GRID Radiotherapy and Medium Transfer in the A-375 Human Melanoma Cancer Cell Line: An In-vitro Study

Purpose: The goal of this research was to investigate the bystander effect in the A-375 cell line under the GRID therapy technique. In GRID therapy, due to direct and indirect cell damage after high-dose radiation, evaluation of Radiation-Induced Bystander Effects (RIBE) is of the most importance for investigating the risk of therapy.&#x0D; Materials and Methods: The potential role of RIBE was evaluated with different doses of 6 MeV electron radiation and different incubation times after irradiation using two methods; GRID therapy and medium transfer. Colony Formation Assay (CFA) and MTT test were used to detect the mentioned effects. Alpha and beta parameters were calculated from the cell survival curve by the quadratic-linear model.&#x0D; Results: The result showed that the survival fraction significantly decreases by increasing the radiation dose for both bystander and irradiated cells. However, a decrease in the number of colony-forming cells caused by electron radiation greater than 4MeV to target cells was significantly increased compared with bystander cells (P &lt; 0.05). While increasing the incubation time after exposure to an electron beam, it had no significant effect on cell survival fraction (P &gt; 0.05). Furthermore, the RIBE level in non-target cells increased up to a dose of 4Gy, but decreased significantly at doses higher than 4Gy. This result in high doses confirmed that a negative feedback mechanism was responsible for reducing the RIBE response.&#x0D; Conclusion: Based on the results, we can state there are classic radiation-induced bystander effects in A-375 monolayer exposed by GRID therapy and medium transfer technique, which can play an important role in pre-clinical and clinical studies.

Astragaloside IV protects LO2 cells from oxidative damage caused by radiation-induced bystander effect through Akt/Nrf2 pathway.

The protective effects of astragaloside IV (ASIV) on various diseases are well known, but its potential impact on radiation-induced bystander effect (RIBE) has remained unclear. This study aimed to explore the protective mechanism of ASIV against oxidative damage caused by RIBE in LO2 cells. To construct the RIBE model, the conditioned medium from HepG2 cells irradiated with radiation was transferred to nonirradiated LO2 cells. LY294002, a commonly used phosphatidylinositol 3-kinase/Akt pathway inhibitor, was added to LO2 cells 1h before exposing HepG2 cells to radiation. LO2 cells were then collected for analyses after RIBE exposure. The study found that ASIV significantly improved cell proliferation and promoted the recovery of mitochondrial membrane potential while reducing the rate of apoptosis. Western blot analyses demonstrated that ASIV upregulated B-cell lymphoma 2 and downregulated B-cell lymphoma 2-related X protein and cleaved-caspase 3. Measurement of reactive oxygen species, superoxide dismutase, glutathione peroxidase, and malondialdehyde levels showed that ASIV effectively restored the oxidative stress state induced by RIBE. Additionally, immunofluorescence and western blots analyses confirmed that ASIV enhanced the translocation of Nrf2 to the nucleus and activated downstream nicotinamide adenine dinucleotide phosphate: quinine oxidoreductase 1 and heme oxygenase 1. Importantly, Akt pathway inhibitor repressed ASIV-induced activation of Nrf2 and its protective effect against RIBE. This study demonstrates that ASIV protects LO2 cells against oxidative damage caused by RIBE through activation of the Akt/Nrf2 pathway.

SPACE RADIATION-INDUCED BYSTANDER EFFECT IN ESTIMATING THE CARCINOGENIC RISK DUE TO GALACTIC COSMIC RAYS

Space radiobiology is an interdisciplinary science that examines the biological effects of ionizing radiation on humans involved in aerospace missions. The knowledge of the risk assessment of the health hazard related to human space exploration is crucial to reducing damages induced to astronauts from Galactic Cosmic Rays (GCRs) and sun-generated radiation. GCRs have been identified as one of the primary sources of radiation exposure in space. In this context, an accurate characterization of the possible risk of carcinogenesis induced by exposure to GCRs particles is mandatory for safe human space exploration, and one of the most crucial open problems is the contribution to carcinogenesis due to the effects on the cells directly and not directly irradiated, indicated as Target Effects (TEs) and Non-Target Effects (NTEs), respectively. It is accepted that the detrimental effects of ionizing radiation are not restricted only to the irradiated cells but also to non-irradiated distant cells manifesting various biological effects. Tumor Prevalence (TP) is often used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. This paper reports the status of the research on this topic at the INFN Roma Sapienza Alpha Magnetic Spectrometer (AMS) research group, where is in progress an extensive study about the risk evaluation of the NTEs that the GCRs radiation will imply when added to the TE. A theoretical framework is presented for TP-induced NTEs modeling, ready to be used with the data collected from the AMS02 detector. Finally, a possible example of the use of the tool is shown for an accurate estimate of the tumor prevalence function of the exposure period for different typical space protons energies.

Radiation-induced bystander effect and its clinical implications.

For many years, targeted DNA damage caused by radiation has been considered the main cause of various biological effects. Based on this paradigm, any small amount of radiation is harmful to the organism. Epidemiological studies of Japanese atomic bomb survivors have proposed the linear-non-threshold model as the dominant standard in the field of radiation protection. However, there is increasing evidence that the linear-non-threshold model is not fully applicable to the biological effects caused by low dose radiation, and theories related to low dose radiation require further investigation. In addition to the cell damage caused by direct exposure, non-targeted effects, which are sometimes referred to as bystander effects, abscopal effects, genetic instability, etc., are another kind of significant effect related to low dose radiation. An understanding of this phenomenon is crucial for both basic biomedical research and clinical application. This article reviews recent studies on the bystander effect and summarizes the key findings in the field. Additionally, it offers a cross-sectional comparison of bystander effects caused by various radiation sources in different cell types, as well as an in-depth analysis of studies on the potential biological mechanisms of bystander effects. This review aims to present valuable information and provide new insights on the bystander effect to enlighten both radiobiologists and clinical radiologists searching for new ways to improve clinical treatments.

Investigation of presence and impact of radiation-induced bystander effect in Acheta domesticus

Purpose Radiation-induced bystander effect (RIBE), a non-targeted effect of ionizing radiation in which non-irradiated individuals behave as if they have been irradiated after interactions with irradiated individuals, has been well documented in vertebrates. However, little research has been done investigating RIBE in terrestrial insects, this paucity of invertebrate RIBE leads to lack of knowledge on invertebrates living in fallout and exclusion zones. This paper aims to better understand the impacts of RIBE on terrestrial insects. Methods and materials: House crickets who have interacted with irradiated crickets were examined to investigate population effects of ionizing radiation exposure to better understand RIBE in insects. Results The results demonstrated RIBE in crickets and found that cohabitated males had higher growth rate (mg/day) when compared to non-cohabitated males. Further, cohabitated males and females matured significantly faster with no significant difference in maturation weight than non-cohabitated populations. Experiment with adult irradiated crickets found saturability of bystander signals and similar shifts in maturation parameters. These results highlight that bystander signals can impacted development and maturation in crickets. Conclusion Given long-term impacts of RIBE in insects, these results may have significant implications for interactions between insects inhabiting fringe nuclear exclusion zones and those outside of it.

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

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.

X-rays-Induced Bystander Effect Consists in the Formation of DNA Breaks in a Calcium-Dependent Manner: Influence of the Experimental Procedure and the Individual Factor.

Radiation-induced bystander effects (RIBE) describe the biological events occurring in non-targeted cells in the vicinity of irradiated ones. Various experimental procedures have been used to investigate RIBE. Interestingly, most micro-irradiation experiments have been performed with alpha particles, whereas most medium transfers have been done with X-rays. With their high fluence, synchrotron X-rays represent a real opportunity to study RIBE by applying these two approaches with the same radiation type. The RIBE induced in human fibroblasts by the medium transfer approach resulted in a generation of DNA double-strand breaks (DSB) occurring from 10 min to 4 h post-irradiation. Such RIBE was found to be dependent on dose and on the number of donor cells. The RIBE induced with the micro-irradiation approach produced DSB with the same temporal occurrence. Culture media containing high concentrations of phosphates were found to inhibit RIBE, while media rich in calcium increased it. The contribution of the RIBE to the biological dose was evaluated after synchrotron X-rays, media transfer, micro-irradiation, and 6 MeV photon irradiation mimicking a standard radiotherapy session: the RIBE may represent less than 1%, about 5%, and about 20% of the initial dose, respectively. However, RIBE may result in beneficial or otherwise deleterious effects in surrounding tissues according to their radiosensitivity status and their capacity to release Ca2+ ions in response to radiation.

Pollution of ionising radiation diagnostic dose and its targeted and non-targeted effects on human primary fibroblast cells

One of the key issues of current radiation research is the biological effect of low doses of X-ray, which can instigate to chromosomal damage in direct irradiated and bystander cells. Additionally, the direct irradiated and bystander cells demonstrate delayed damage responses within their progeny, underlying radiation-induced genomic instability (GI). In this study we tried to mimic the effects of diagnostic procedure doses of X-ray (0.5 rad) on human fibroblast cells, which are considered as a one of the environmental polluter. Human fibroblast cells were irradiated with 0.5 rad X-ray, which were considered the direct irradiated cells; whilst radiation-induced bystander effects (BE) were induced by media transfer. Both cell populations were propagated until 24 generations for delayed responses. The direct, bystander and their progeny cells were subjected to chromosomal analysis and comet assay to measure chromosomal and total DNA damage in these cells. Early response of chromosome damage was observed in the direct irradiated cells; however it was statistically insignificant. Bystander cells showed higher chromosomal damage than the irradiated cells; but it was insignificant compare to the corresponding control groups. Conversely, comet data demonstrated a significant DNA damage in both direct irradiated and bystander cells as initial responses. Interestingly, progeny of direct irradiated and bystander cells showed a significant chromosomal instability and DNA damage after 24 population doublings following irradiation. The findings suggested that the diagnostic procedure doses of X-ray could cause a profound chromosomal instability within human primary fibroblast cells; which are considered as a hallmark of carcinogenesis.

Radiation-induced Bystander Effect and Its Possible Countermeasures

Ionizing radiation has been indispensable to medical diagnosis. In cancer, radiation therapy or radiotherapy (RT) offers patients a better chance of survival. It destroys cancer by depositing high-energy radiation on the cancer tissues, though it may directly damage a few normal cells. Therefore, the total radiation dose is administered in fractionated modalities over weeks or months. However, experimental evidence indicates that the irradiated cancer cells subsequently release cytokines in the blood that enter into nearby unirradiated nuclei/cells through several signaling pathways and cause radiation-induced bystander effects (RIBEs) such as DNA damage, chromosomal instability, mutation, and apoptosis in them as side effects of RT. Recently, many combined therapeutic protocols consisting of a few natural and synthetic products have been proposed to minimize RIBEs. This article reviews the present understanding of RIBEs and their possible countermeasures. Besides, a new protocol of combined therapy of nanoparticle-based ion treatment (NIT) and RT to minimize RIBEs has been proposed.

Radiation and Diabetic Retinopathy: A Dark Synergy

Exacerbation of the vascular pathology in radiation retinopathy as a result of pre-existing diabetes has been recognized for many years, as reflected by clinical reports and a few early experimental studies. However, the underlying pathogenetic mechanisms for the synergistic interaction of radiation retinopathy (RR) and diabetic retinopathy (DR) have not been compared and evaluated for insight on this phenomenon. The present work draws attention to the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as common mediators of both conditions and sources of ongoing cellular injury in the radiation-induced bystander effect (RIBE) and the senescence-associated secretory phenotype (SASP). Chronic hyperglycemia-mediated oxidative stress and depleted antioxidant defense in diabetes, together with impaired DNA damage sensing and repair mechanisms, were identified as the primary elements contributing to the increased severity of RR in diabetic patients. We conclude that apart from strategic genetic mutations affecting the DNA damage response (DDR), diabetes represents the most significant common risk factor for vascular injury as a side effect of radiotherapy.