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Home All issues Volume 59 / No 4 (October - December 2024) Radioprotection, 59 4 (2024) 287-295 Full HTML
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Radioprotection
Volume 59, Number 4, October - December 2024
Page(s) 287 - 295
DOI https://doi.org/10.1051/radiopro/2024032
Published online 13 December 2024

© J. Yan and D. Li, Published by EDP Sciences, 2024

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 Introduction

With the evolution of society, nuclear technology has found applications in various fields including medicine, the military and nuclear power instead of one terminology. This transition from a singular application to a multifaceted usage has spurred significant progress across all walks of life. Despite the strides made and given that nuclear energy itself is still considered risky in condition of inadequate compliance of instructions, we could never underestimate its detriments. Nowadays, with the escalating global incidence of cancer worldwide, radiotherapy (RT) is introduced to cancer patients during their treatment more often, thus the likelihood of radiation damage ensue. The problems stemming from radiation have garnered heightened attention, making the prevention and treatment of the radiation-induced damage become a hot topic of discussion (Arnold, 2022).

In addition to being directly acting on DNA, ionizing radiation (IR) also leads to superfluous production of reactive oxygen species (ROS), such as hydroxyl radicals, singlet oxygen, and hydrogen peroxide, which, in turn, causes damage to pivotal cellular contents including DNA, RNA, proteins and lipids, leading to necrosis and apoptosis, ultimately resulting in cell death. Approximately two-thirds of radiation-induced damage attributes to ROS, which continues to be generated post-irradiation (Brown et al., 2010).

Radiotherapy is now commonly used in the realm of cancer treatment, with roughly half of cancer patients undergoing this procedure. Higher doses of radiation within a reasonable range are frequently needed to maximize the eradication of cancer cells in the irradiated area, but high doses of RT may cause severe toxicity in adjacent tissues and organs (De Ruysscher et al., 2019). Biological effects caused by radiation exposure could be divided into two categories according to the dose of radiation: relatively higher dose of radiation could cause acute radiation syndrome and the following delayed effect of acute radiation exposure, while lower dose of radiation is inclined to chronic radiation injury (Ray et al., 2014). Receiving high-dose (>2 Gy) total-body irradiation (TBI) in a relatively short time may lead to acute radiation syndrome (ARS), which represents a collection of symptoms such as nausea, vomiting, fatigue, fever, diarrhea and seizures. And these symptoms typically manifest with minutes to weeks after the exposure. While the injury lingers, placing survivors of ARS at risk of delayed effect of acute radiation exposure (DEARE), which occurs months to years after radiation exposure and may cause a range of chronic illness, such as injury in pulmonary tissue, hepatic tissue, kidney tissue, cardiovascular tissue, reproductive tissue and oral cavity as well as salivary glands, giving rise to corresponding symptoms (Dainiak et al., 2011; DiCarlo et al., 2011; Gasperetti et al., 2021; Wu and Orschell, 2023). Chronic radiation injuries may elevate the risk of cardiac toxicity, cognitive impairment, reproductive disorders, deformity and impairments to bone and teeth growth, hair loss and secondary malignancy, genetic mutations and carcinogenesis. Therefore, the identification of active and effective radiation protection agents against ionizing radiation is crucial to mitigate the radiation hazard of radioactive accidents (De Ruysscher et al., 2019; Tapio et al., 2021).

Selenium (Se), an essential microelement, and its compounds, along with their metabolites, play vital roles in numerous of biological functions (Green, 2018). As one of the highly regulated proteins, selenoproteins are instrumental in preventing and modulating several clinical outcomes and diseases, including cancer, diabetes, Alzheimer’s disease, mental disorders, cardiovascular disorders, fertility impairments, inflammation, and infections (including SARS-CoV-2) (Barchielli et al., 2022). Additionally, selenium has long been considered as radiation − protective agent in the field of radiobiology since 1969 (Michalke, 2018). By upregulating the absorption and utilization of cysteine, the biosynthesis of glutathione, detoxificating reactive oxygen free radicals, and protecting of polyunsaturated fatty acids and cholesterol molecules free from peroxidation, selenium takes its role in radiation protection. In short, the antioxidation, anti-inflammatory effect and DNA stabilizing formed the protective effects of selenium against DNA damage induced by radiation (Bartolini et al., 2020).

This review seeks to elucidate part of the potential abilities of selenium together with its compounds and metabolites including selenomethionine [C5H11NO2Se] (Se-Met) (Fig. 1A), sodium selenite [Na2SeO3] (Fig. 1B) and Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one](Eb) (Fig. 1C) to act as radioprotectants, and present selenium as a reliable radioprotective agent for scientists and companies seeking effective solutions in this domain (Fig. 2, Tab. 1).

thumbnail Fig. 1

Chemical structures of compounds and metabolites of selenium. (A) Selenomethionine [C5H11NO2Se] (Se-Met); (B) Sodium selenite[Na2SeO3]; (C) Ebselen [2-phenyl- 1,2-benzisoselenazol-3(2H)-one] (Eb).
thumbnail Fig. 2

Simple conclusion of Selenium and its various forms including selenomethionine, Ebselen, and sodium selenite acting as radioprotective agents to different body systems. Eb, Ebselen; Se-L-Met, Seleno-L-Methionine.
Table 1

Selenium and selenium-containing compounds and metabolites to function as valuable radioprotective adjuvants. Se-L-Met, Seleno-L-Methionine; Eb, Ebselen; Se-NPs, selenium nanoparticles.

2 Selenium

Selenium is an important microelement that exists primarily in plants and animals in two chemical forms: organic and inorganic. The selenium content in foods varies, most of which occurs in a protein-combination way, while fruits and vegetables generally contain relatively lower levels. The primary organic selenium compound is selenomethionine [C5H11NO2Se] (Se-Met), a natural amino acid incorporating selenium, and the most common inorganic selenium supplement is inorganic salts, with sodium selenite [Na2SeO3] being the most widely known (Kieliszek and Błażejak, 2016; Kieliszek and Serrano Sandoval, 2023; Yang et al., 2017). The predominant way for human body to intake of selenium is through daily dietary sources and integrate into selenoproteins in the form of selenocysteine. Being involved in several processes, selenoproteins are historically regarded as a primary focus of related studies. Selenium has been wildly acknowledged to contribute to the reduction of oxidative stress through different selenoproteins including thioredoxin reductase (TrxR), glutathione peroxidase (GSH-Px, GPx) and others (Sieber et al., 2009). Notably, GPx is one of which has been studied in depth and extensively (Mangiapane et al., 2014; Rayman, 2012). Fenech et al. discussed the protective role of microelements supplements from DNA damage in humans with selenium considered as a prevention of oxidative stress and inflammation. Meanwhile biological effects that are not mediated by selenoproteins have drawn the scientists’ attention, specifically safeguarding of DNA by preventing damages as well as promoting repairment, which may be the main reason for why selenium is regarded as a radioprotective agent. Researchers worldwide recently have substantiated that selenium do have promising radioprotective effect in different organs (Fenech et al., 2023).

Selenium and Vitamin-E are both regarded as efficient antioxidants and are affordable for most patients. Rostami et al. performed their study and 15 volunteers were divided into 3 different groups treated with selenium, Vitamin-E, and the combination of both, respectively. 2 whole blood samples were collected at each sampling time, one of which was used as non-irradiated control and another was irradiated with 2 Gy of 6 MV X-rays. Results indicated that both selenium and Vitamin-E effectively reduced the incidence of micronuclei and the total micronuclei values 1 hour after finishing oral supplementation were decreased by more than 40% comparing with similarly irradiated whole blood collected at the beginning, specifically in the combined treatment group, the total micronuclei values were reduced by 50% (Rostami et al., 2016).

Beyond the involvement of selenium in the process of spermatogenesis, previous studies have proven that it can also improve sperm motility and semen quality (Moslemi and Zargar, 2011). Given its vulnerability to environmental toxic agents, even regular therapeutic dose of radiotherapy (RT) may have detrimental impact on spermatogenesis system. Bagheri et al. conducted their experiments by feeding mice selenium and zinc before radiation and evaluated the radioprotective effect through histopathological results. The findings revealed that both selenium and zinc supplementation before radiation could reverse the reduction of spermatogonia. Notably, apart from the edema, selenium could reverse the damage caused by 2 Gy of γ irradiation including spermatogenic arrest, atrophy of seminiferous tubules, thickening of basal lamina, leydig cell hyperplasia, epididymis decreased sperm density and epididymis vacuolatio, meanwhile selenium showed no toxicity to spermatogenesis in comparison with the mice without radiation treatment. During the assessment of histopathological results, zinc not only exhibited less radioactive protective effect for its protective ability merely to basal lamina and epididymis but also caused damage to seminiferous tubules. And strikingly, zinc treatment without radiation induced damage in epididymis (Bagheri et al., 2019).

3 Selenomethioine

Selenomethionine [C5H11NO2Se] (Se-Met) is deemed to be an appropriate supplemental form of selenium for its outstanding bioavailability and low toxicity in comparison to other selenium compounds (Wang et al., 2007). With the presence of both selenium and methionine, Seleno-L-Methionine (Se-L-Met) is the L-isomer of Se-Met and both of which could act as potent antioxidants and scavenge ROS.

A study designed by Fisher et al. explored the protective effects of selenium against DNA damages, revealing that the selenium supplementation in the form of Se-L-Met at a relatively physiological and nontoxic concentration could increase the levels of p53 and redox factor-1 (Ref-1) proteins, meanwhile p53 cysteine residues 275 and/or 277 were reduced, being consilient with former studies (Pluquet and Hainaut, 2001). P53 cysteine residues 275 and/or 277 are specifically crucial for the binding of p53 and downstream effector gene sequences, meanwhile Ref-1 was essential for selenium signal transduction to p53 (Seo et al., 2002). Breast cancer susceptibility gene 1 (Brca1) is a tumor suppressor gene being involved in the repair of DNA damage (Jasin, 2002). Se-L-Met may effectively influence related processes. Their further study suggested that the protective effect of Se-L-Met did not extend to Brca1-deficient fibroblasts from UV-radiation, indicating that in addition to p53 and Ref-1, Brca1 may also be considered to take an important place in the DNA protection enhanced by Se-L-Met (Fischer et al., 2006).

Previous studies have reported that Se-Met could efficiently inhibit the formation of lipid peroxy radicals, preventing lipid peroxidation (Dowlath et al., 2021). Guo et al. had demonstrated in their research that Se-Met, composing over 90% of selenium content, acts as the primary form of selenium in Se-rich yeast peptide fractions. By scavenging the free radical and inhibiting the lipid peroxidation, Se-rich peptide fraction together with yeast extract enzyme (abbreviated as sSeP) presents its remarkable synergistic antioxidant in vitro. Experiments in vivo also manifested its significant antioxidant activity through abating malonaldehyde (MDA) as well as increasing GPx, had shown significant antioxidant activity in vivo. Furthermore, the application of sSeP on shaved dorsal skin of UVB-irridated mice could significantly alleviated morphological changes (including drier skin, redness, edema formation and increased scaly wrinkle) as well as histopathological changes (mainly epidermis thickness). Additionally, sSeP was testified to enhance the expression of aquaporin-3 and attenuate the phosphorylation of p38 MAPK in H2O2-treated HaCaT cells (a human epidermal keratinocytes cell line), providing a potential mechanism for sSeP to alleviate UVB-induced oxidative damages in skin of mice (Guo et al., 2020).

Brown et al. demonstrated that antioxidant food supplementation including Se-L-Met could scavenge ROS after total-body irradiation (TBI), and improve DNA damage and apoptosis in bone marrow cells (Brown et al., 2010). Bagheri et al. assessed chromosome damage through the micronuclei test, revealing that comparing to the control group, 2 Gy irradiated rats manifest a significant increase in micronucleus frequency, which could be markedly decreased by preadministration with Se-L-Met. And in contrast with the control group, the impact of ionizing radiation (IR) to cell proliferation could be significantly suppressed with the preconditioning of Se-L-Met. Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione], a natural pigment with broad economic value and pharmacological effects, is widely known for its anti-inflammatory and antioxidant potential, and is also considered to be protective from DNA damage caused by radiation (Srinivasan et al., 2006). By controlling the variables, Bagheri et al. also confirmed that the combined form of Se-L-Met and curcumin outperformed the effects of Se-L-Met or curcumin alone (Bagheri et al., 2017).

Usually, RT will not result in severe damages to lung immediately but further influences including pneumonitis and fibrosis may contribute to the limited dose of RT for malignant tumors of organs in the chest area. These two pathological changes are related to the changes of inflammatory factors and cytokines caused by chronic oxidative stress. Previous studies proved that IL-4 plays an instrumental role in late effects of radiation-induced lung injuries as potent pro-fibrotic cytokines, and mainly causes the constant production of ROS after IR. Being related to the oxidation process in the body and involved in the inflammatory response, dual oxidase 1 (Duox1) and dual oxidase 2 (Duox2) are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. IL-4 could upregulate interleukin-4 receptor subunit alpha-1 (IL4Ra1), thus stimulating Duox1 and Duox2 and ultimately mediate the continuous production of H2O2 (Raad, 2013). Ameziane et al. had demonstrated that the upregulation of IL-4 after irradiation could induce the expression of dual oxidases including Duox1 and Duox2, thus leading to the chronic production of ROS and instability of genome (Ameziane-El-Hassani et al., 2015). Amini et al. evaluated the regulatory effect of Se-L-Met on the aforementioned genes and the protective effect to the lungs after local irradiation to the chest of rats. Results showed that the serum level of IL-4 increased markedly as well as the expression of IL4Ra1, Duox1 and Duox2 after irradiation. The levels of IL4Ra1, Duox1 and Duox2 were significantly upregulated after exposing to 15 Gy radiation and could be reversed by supplementation of Se-L-Met. Histopathological analysis also showed that Se-L-Met could markedly attenuate the filtration of macrophages and lymphocytes together with the vascular and alveolar thickening and fibrosis, during which the JAK1-STAT6 cascade induced by IL-4 stimulation may take a leading role (Amini et al., 2019).

Myriad evidences have proved that IR may lead to the increase of incidence of cardiovascular diseases (Boerma et al., 2016; Najafi et al., 2018), including carotid and coronary artery disorders, blood supply impairment to heart muscles, pericarditis and atherosclerosis (Stewart et al., 2006). The chronic excretion of pro-fibrotic and pro-inflammatory cytokines plays an instrumental role in the aggravation of cardiovascular diseases after irradiation for the stimulation of chronic production of ROS during the progression of inflammation and fibrosis (Farhood et al., 2019). Joseph L. Unthank et al. demonstrated that a significant reduction of the endothelial cells in coronary arteries was observed in mice 4 months after TBI at 8.53 or 8.72 Gy of γ radiation, and persisted through 18 months (Unthank et al., 2019). Amini et al. revealed that γ radiation exposed locally to chest area of rats could lead to increased expression levels of IL4Ra1, Duox1 and Duox2, meanwhile treatment before and after 15 Gy γ local radiation with the combination of curcumin and Se-L-Met could decrease the expression all three significantly. Among which the change of Duox1 level is most obvious for its expression reduced to lower than 2-fold in treated rats (Amini et al., 2018), indicating the potential of Se-L-Met together with curcumin to alleviate radiation-induced injuries (Basnet and Skalko-Basnet, 2011).

4 Ebselen

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] (Eb), a synthesized multifunctional lipid-soluble selenium-containing compound, is recognized as an inhibitor of TrxRs, could functionally simulate GPx to protect cells free from ROS-induced injuries thus demonstrating its significant radioprotective effect (Briviba et al., 1998; Cardoso et al., 2017; Tak and Park 2009). Additionally, Eb also exhibits a broad range of biological activities, including anti-atherosclerotic, anti- inflammatory, anti-SARS-CoV-2, and anti-cancer properties (Barchielli et al., 2022; Thabet et al., 2023).

Thabet et.al have demonstrated that Eb has anti-arthritic and radioprotective effects in an arthritic irradiated model (Thabet et al., 2023). Eb, by abating ROS, could enhance the antioxidant system thus reducing the peroxidation of serum and synovial tissue, meanwhile inhibit the activation of NOD-like receptor protein-3 (NLRP-3), thereby impeding caspase-1/IL-1β/receptor activator of nuclear factor κB ligand (RANKL)/nuclear factor-κB (NF-κB) pathway. Arthritic irradiated rats treated with Eb exhibited a superior ability to limit ROS comparing with rats without Eb, highlighting the protection of Eb against oxidative stress. Antioxidant system also exhibited a upregulation by activities of superoxide dismutase (SOD), catalase (CAT) and GPx, along with the level of glutathione (GSH) in serum and synovial in the Eb-treated group compared to the untreated group (Thabet et al., 2023). Recent experiments and studies have shown that the up-regulation of NLRP3 inflammasome has a substantial impact on radiation damage, including oral mucositis, skin, lung, intestine and other systems (Wei et al., 2019). Considering the notable inhibition of the activation of NLRP3 that Eb manifests, it is possible that Eb could present a potential protective effect on different radiation-induced organ damages, however further studies both in vivo and in vitro are necessary to support this point.

Tewari et al. have demonstrated that Eb could positively regulate DNA damage repair response by restoring decreased expression of mismatch repair (MMR) proteins. In their study, showing no effect on either mutL homolog 1 (MLH1) or mutS homolog 2 (MSH2) expression in A172 cells, Eb could restore the decreased levels of them both in TNFα treated cells, meanwhile in T98G cells, the decreased level of MSH2 was also elevated. Knowing that Eb could abate the pro-inflammatory mediators as well as ROS from TNFα treated cells, along with its ability of increasing the expression of MMR protein, Eb may curtail the accumulation of genetic instability, indicating that Eb could act as radioprotector during glioma treatment, while further demonstration in future study is warranted (Tewari et al., 2009).

The pretreatment with 5 µM Eb for 2h significantly increased the viability of U937 cells exposed to 2 Gy γ radiation comparing to the untreated cells and decreased the increased dihydroethidium (DHE) fluorescence (Tak and Park, 2009). Eb pretreatment could significantly inhibit oxidative stress by decreasing the level of MDA which was 3 times higher after 20 Gy γ radiation in untreated cells. The fluorescence probe studies, including 1,3-Bis(diphenylphosphino)propane (DPPP) for lipid peroxidation and 8-OH-dG for DNA damage in vivo and in vitro, demonstrated that Eb could protect DNA from oxidative damages induced by IR. In comparison with the untreated cells, the pretreatment of Eb could lessen the amount of apoptotic cells after 2 Gy γ radiation. The induction of the mitochondria permeability transition (MPT) is related to the opening of large pores in the membranes of mitochondria, which takes an important role in apoptosis, during which ROS act as stimuli that change MPT, thus fluorescence probe JC-1 was chosen to observe the change of MPT. Results showed that the pretreatment of Eb could markedly suppress the disruption in the mitochondrial membrane potential induced by 2 Gy γ radiation. While the oxidant-sensitive probe, DHR 123 was chosen to estimate the levels of intracellular peroxides in the mitochondria of U937 cells, and results showed that the pretreatment of 5 µM Eb could significantly reduce the mitochondrial fluorescence in comparison with the untreated cells, suggesting that Eb could protect mitochondria from oxidative damages. Male mice treated orally with Eb at 10 mg/kg per day for 2 weeks also manifested a significant protective effect on liver morphological changes after 8 Gy of TBI comparing to the control group treated with DMSO (Tak and Park, 2009).

5 Sodium selenite

Sodium selenite [Na2SeO3] has long been recognized as one of the most redox-active selenium compounds and exhibiting potent anticancer properties, and notably, sodium selenite is considered to generate ROS which is contrary to the consensus that selenium is an antioxidant. Its high biological activity is attributed to its ability to primarily enhance the expression of selenoproteins, thus sodium selenite may not be inherently antioxidant until incorporated into selenoproteins with oxidoreductase functions (Misra et al., 2015; Spallholz, 1994).

Iodine-131 (131I) is an effective treatment against thyroid cancer which is considered as one of the most common tumors of the endocrine system. Beyond the intake of the thyroid tissue, salivary glands could also accumulate radioiodine through the sodium iodide symporter (NIS). Due to the high proportion of radio-sensitive serous acinar cells, parotid glands are especially vulnerable to radiation (Choi et al., 2013; De La Vieja et al., 2000). Individuals undergoing high-dose treatment of 131I may suffer temporary or permanent dysfunction of salivary glands accompanied by symptomatic sialadenitis, thus leading to severe impact to quality of life (An et al., 2013). Selenium has been demonstrated to be radioprotective on parotid glands against γ radiation and on the blood cells against 131I radiation in animal studies (Tuji et al., 2010). Son et al. performed a prospective study that contains 2 groups of thyroid cancer patients post-total thyroidectomy, 8 patients were divided in each group for 131I treatment. Both serum amylase level and salivary gland scintigraphy manifested the protective effect of sodium selenite against salivary glands after 131I therapy (Son et al., 2017.).

Puspitasari et al. proved that the sodium selenite could increase GPx-1 activity in a dose- and time-dependent manner. The administration of a 50nM sodium selenite solution to checkpoint kinase 1 (CHECK-1) non-cancerous human esophageal cells for 72 h could induce the highest activity of GPx-1. With the supplementation of 50 nM sodium selenite, cell viability at 72 h after irradiation significantly increased, and the percentage of sub-G1 phase cells markedly reduced comparing to the group treated with 2 Gy X-ray irradiation alone. These findings suggest that sodium selenite supplementation before irradiation could protect cells from irradiation-induced damage and reduce the percentage of apoptotic cells. Poly ADP-Ribose Polymerase (PARP) protein was chosen for further experiments as a principal biomarker for apoptosis. 2 Gy irradiated cells with supplementation of 50 nM sodium selenite showed increased expression levels of cleaved PARP proteins comparing to cells treated with irradiation only, although not statically significant. This indicates that sodium selenite may have the potential to inhibit irradiation-induced apoptosis in non-cancerous cells (Puspitasari et al., 2017).

The concept of osteoradionecrosis (ORN) was first described by Regaud in 1922, referring to the late effect observed in individuals under RT for head and neck cancers (O’Dell and Sinha, 2011). In addition to the impact on appearance, ORN severely affects the deglutition and linguistic function. Although the perception of the pathogenesis of ORN is not yet unified, most researchers attribute it to the fibroatrophic process featuring in early inflammation and subsequent fibrosis and remodeling caused by radiation(Frankart et al., 2021). Yamasaki et al. reported that 40 days after the 15 Gy X-ray radiation in head and neck region, all rats were anaesthetized and underwent bilateral extraction of mandibular first molars. Bone microarchitecture parameters, including total volume, bone volume, bone volume fraction (bone volume/total volume), trabecular number, trabecular thickness and trabecular separation were assessed 15 days and 30 days after surgery, respectively. Statistically higher trabecular separation was observed in rats treated with radiation, while a statistically higher value of the trabecular number evaluation was displayed in irradiated rats intraperitoneally administrated with sodium selenite (0.8 mg/kg) 15 days after the tooth extraction. However, sodium selenite did not manifest a significant radioprotective effect in the assessment of bone microarchitecture 30 days after surgery in this experiment. Therefore, it might be fair to indicate that sodium selenite could be considered as a potential radioprotective adjuvant during locally radiation therapy with further confirmatory experiments (Yamasaki et al., 2019).

Sieber et al. found that with the supplementation of 100 µg/day of selenium in the form of sodium selenite or Se-L-Met, blood urea nitrogen (BUN) level of rats significantly decreased. 21 weeks after TBI, irradiated rats on sodium selenite-supplemented water showed no interstitial fibrosis and only minimal mesangiolysis in histopathological analysis while irradiated rats on standard drinking water showed severe histological abnormalities aforementioned (Sieber et al., 2009). 2 years later, they conducted further experiments and demonstrated that 2 months after TBI, BUN level of rats with supplementation of drinking water with selenium at 150 or 200 µg/d significantly decreased comparing to rats with standard drinking water. 4 months after TBI, there’s no difference in serum BUN level between irradiated rats with supplement of sodium selenium (200 µg/d) and normal controls. Interestingly, with the supplement of 200 µg/d for 4 months, sodium selenite acted better as a kidney protective adjuvant than Se-L-Met due to its superior activity in reducing BUN level. Sodium selenite also manifested better protective effect than Se-L-Met, as it could mitigate histopathological abnormalities including cysts, sclerosed glomeruli, interstitial fibrosis, and glomerular mesangiolysis in the kidneys (Sieber et al., 2011).

Muecke et al. initiated their phase III clinical trials and one purpose of which was to estimate the radioprotective effect of sodium selenite. 81 patients suffering from uterine or cervical cancer were admitted into the trial and 39 patients were administrated sodium selenite supplementation during their RT process. During the trial, radiation-induced diarrhea, being regarded as one of the most relevant side-effects of aforementioned cancers that partly impact the quality of life, was assessed to determine whether it could be reduced by the supplementation of sodium selenite. Studies revealed that the levels of selenium were elevated both in whole blood and in serum, and the incidence of common toxicity criteria (CTC) Grade 2 diarrhea was significantly reduced in patients treated with sodium selenite comparing to the control group without supplementation. Notably, there was a tendency that the patients with higher Se status tolerated the radiotherapy better than the ones with relative Se deficiency (Muecke et al., 2010, 2014, 2018).

Verma et al. conducted their experiments to assess the protection of low-dose sodium selenite, administrated multiple times, against TBI in mice. 4 groups were designed: sham control, sodium selenite control, radiation control, and combined treatment group. The irradiated groups received 4 µg/kg PBS (for control group) or sodium selenite through intraperitoneal administration for 5 consecutive days before and 3 times/week after TBI till the end of experiment. Results indicated that although low-dose of sodium selenite did not exhibit significant protective function from the destruction of shortening of villi in the intestinal lumen induced by 8 Gy γ radiation comparing to the untreated mice, the level of lipid peroxidation was significantly decreased. Comet assays in peripheral leukocytes were conducted and results showed that lose-dose of sodium selenite could significantly mitigate the DNA damage induced by 5 Gy γ radiation at both early and later time points (Verma et al., 2017).

The kidneys are particularly vulnerable to radiation and even moderate dose of radiation whether locally or whole-bodily radiated, resulting in the deterioration of renal function (El-Ghazaly et al., 2017). And selenium has been reported to have protective effects against cadmium-induced nephropathy (Bagheri et al., 2019). A previous study has proved that selenium nanoparticles (Se-NPs) possess potential anti-inflammatory effects in radiated mice. Increased levels of renal function biomarkers in the serum of 8 Gy radiated mice including creatinine, urea, cystatin-c and beta-2-microglobulin (β2M) were all significantly decreased after intraperitoneal injection of sodium selenite and Se-NPs, meanwhile activities of SOD and GPx were both normalized. Among which Se-NPs manifested higher ability than sodium selenite. Renal selenium content decreased after γ radiation dose-dependently. Notably, both the supplementation of Se-NPs and sodium selenite showed an equivalent ability to tremendously suppress the extent of histopathologic changes to 8 Gy radiated mice including glomerular sclerosis, focal glomerular necrosis and tublar epithelium necrosis to almost normal range. Additionally, both Se-NPs and sodium selenite have almost the same protective potential against pathologic changes (Karami et al., 2018).

6 Conclusion

Nuclear technology has profoundly impacted our daily lives, which provides convenience while also poses potential hazards that, if mishandled, can lead to irrevocable consequences. To wield this double-edged sword responsibly requires thoughtful consideration of the risks involved and the implementation of corresponding solutions. Although radiotherapy has offered a renewed hope for individuals once suffered from cancer, it brings along challenges associated with radiation-induced problems that need to be addressed. Both acute radiation syndrome and delayed effect of acute radiation exposure are far-reaching and may significantly impact various of organs and ultimately diminishing the overall quality of life. The mechanisms underlying radiation-induced injury encompass direct and indirect impacts, with the recognized hazards of ROS are widely recognized. Consequently, the antioxidants are being investigated and used as radioprotective adjuvants. Selenium, along with its compounds and metabolites, has long been considered as an affordable and potent antioxidant, and researchers worldwide have conducted myriad experiments to demonstrate the radioprotective effect of selenium in various forms, and the results are quite affirmative. It is not arbitrary to indicate that selenium-containing compounds and metabolites could be recommended as radioprotective adjuvants for individuals undergoing radiotherapy, given their remarkable protective effects on different organs and cells.

Most studies in this review, which include research on various types of cells, animals, and humans, added Se (in the form of selenium and its compounds and metabolites) before radiation, while only one study used Se as a remedial supplement (Table 1). It is well established that Se can act as a radioprotective adjuvant, however, the appropriate dosage and optimal timing for supplementation, along with the most effective type of Se supplementation still require further rigorous comparative studies.

Funding

This research did not receive any specific funding.

Conflicts of interest

The authors declare that they have no conflict of interest.

Data availability statement

All relevant data are within the paper.

Author contribution statement

Jiangyue Yan : Conceptualization, writing original draft ; Dan Li : Investigation and Supervision.

References

  • Ameziane-El-Hassani R, Talbot M, De Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart J-M, De Deken X, et al. 2015. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc. Natl. Acad. Sci. 112 (16): 5051–5056. [CrossRef] [PubMed] [Google Scholar]
  • Amini P, Kolivand S, Saffar H, Rezapoor S, Motevaseli E, Najafi M, Nouruzi F, Shabeeb D, Musa AE. 2019. Protective effect of selenium-L-methionine on radiation-induced acute pneumonitis and lung fibrosis in rat. Curr Clin Pharmacol 14: 157–164. [CrossRef] [PubMed] [Google Scholar]
  • Amini P, Rezapoor S, Shabeeb D, Musa AE, Najafi M, Motevaseli E. 2018. Evaluating the protective effect of a combination of curcumin and selenium-L-methionine on radiation induced dual oxidase upregulation. Pharmaceut Sci 24 (4): 340–345. [Google Scholar]
  • An Y-S., Yoon J-K., Lee SJ, Song H-S., Yoon S-H., Jo K-S. 2013. Symptomatic late-onset sialadenitis after radioiodine therapy in thyroid cancer. Ann Nucl Med 27 (4): 386–391. [CrossRef] [PubMed] [Google Scholar]
  • Arnold C. 2022. Theranostics could be big business in precision oncology. Nat Med 28 (4): 606–608. [CrossRef] [PubMed] [Google Scholar]
  • Bagheri H, Salajegheh A, Javadi A, Amini P, Shekarchi B, Shabeeb D, Eleojo Musa A, Najafi M. 2019. Radioprotective effects of zinc and selenium on mice spermatogenesis. J Biomed Phys Eng. doi:10.31661/jbpe.v0i0.957 [Google Scholar]
  • Bagheri, H, Saeed R, Masoud N, Elahe M, Babak S, Mohsen C, and Hossein M. 2017. “Protection Against Radiation-Induced Micronuclei in Rat Bone Marrow Erythrocytes by Curcumin and Selenium L-Methionine.” 43(6): 645–52 [Google Scholar]
  • Bagheri H, Rezapour S, Najafi M, Motevaseli E, Shekarchi B, Cheki M, Mozdarani H. 2018. Protection against radiation-induced micronuclei in rat bone marrow erythrocytes by curcumin and selenium L-methionine. Iran J Med Sci 43 (6): 645. [PubMed] [Google Scholar]
  • Barchielli G, Capperucci A, Tanini D. 2022. The role of selenium in pathologies: an updated review. Antioxidants 11 (2): 251. [CrossRef] [PubMed] [Google Scholar]
  • Bartolini D, Tew KD, Marinelli R, Galli F, Wang GY. 2020. Nrf2‐modulation by seleno‐hormetic agents and its potential for radiation protection. BioFactors 46 (2): 239–245. [CrossRef] [PubMed] [Google Scholar]
  • Basnet P, Skalko-Basnet N. 2011. Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules 16 (6): 4567–4598. [Google Scholar]
  • Boerma M, Sridharan V, Mao X-W., Nelson GA, Cheema AK, Koturbash I, Singh SP, Tackett AJ, Hauer-Jensen M. 2016. Effects of ionizing radiation on the heart. Mutation Res/Rev Mutat Res 770: 319–327. [CrossRef] [Google Scholar]
  • Briviba K, Kissner R, Koppenol WH, Sies H. 1998. Kinetic study of the reaction of glutathione peroxidase with peroxynitrite. Chem Res Toxicol 11 (12): 1398–1401. [CrossRef] [PubMed] [Google Scholar]
  • Brown SL, Kolozsvary A, Liu J, Jenrow KA, Ryu S, Kim JH. 2010. Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality. Radiat Res 173 (4): 462–468. [CrossRef] [PubMed] [Google Scholar]
  • Cardoso BR, Hare DJ, Bush AI, Roberts BR. 2017. Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry 22 (3): 328–335. [Google Scholar]
  • Choi J-S., Park IS, Kim S-K., Lim J-Y., Kim Y-M. 2013. Morphometric and functional changes of salivary gland dysfunction after radioactive iodine ablation in a murine model. Thyroid 23 (11): 1445–1451. [CrossRef] [PubMed] [Google Scholar]
  • Dainiak N, Gent RN, Carr Z, Schneider R, Bader J, Buglova E, Chao N et al. 2011. Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems. Disaster Med Public Health Preparedness 5 (3): 183–201. [CrossRef] [PubMed] [Google Scholar]
  • De La Vieja A, Dohan O, Levy O, Carrasco N. 2000. Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology. Physiolog Rev 80 (3): 1083–1105. [CrossRef] [PubMed] [Google Scholar]
  • De Ruysscher D, Niedermann G, Burnet NG, Siva S, Lee AWM, Hegi-Johnson F. 2019. Radiotherapy toxicity. Nat Rev Disease Primers 5 (1): 13. [CrossRef] [Google Scholar]
  • DiCarlo AL, Maher C, Hick JL, Hanfling D, Dainiak N, Chao N, Bader JL, Norman ColemanC, Weinstock DM. 2011. Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation. Disaster Med Public Health Prepared 5(S1): S32– S44. [CrossRef] [PubMed] [Google Scholar]
  • Dowlath MJH, Karuppannan SK, Sinha P, Dowlath NS, Arunachalam KD, Ravindran B, Chang SW, Nguyen-Tri P, Duc Nguyen D. 2021. Effects of radiation and role of plants in radioprotection: a critical review. Sci Total Environ 779: 146431. [CrossRef] [PubMed] [Google Scholar]
  • El-Ghazaly MA, Fadel N, Rashed E, El-Batal A, Kenawy SA. 2017. Anti-inflammatory effect of selenium nanoparticles on the inflammation induced in irradiated rats. Can J Physiol Pharmacol 95 (2): 101–110. [CrossRef] [PubMed] [Google Scholar]
  • Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Salehi E, Nashtaei MS, Shabeeb D et al. 2019. Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation. J Cell Commun Signal 13 (1): 3–16. [CrossRef] [PubMed] [Google Scholar]
  • Fenech MF, Bull CF, Jan-Willem Van Klinken B. 2023. Protective effects of micronutrient supplements, phytochemicals and phytochemical-rich beverages and foods against DNA damage in humans: a systematic review of randomized controlled trials and prospective studies. Adv Nutr: S2161831323013546. [Google Scholar]
  • Fischer JL, Lancia JK, Mathur A, Smith ML. 2006. Selenium protection from DNA damage involves a Ref1/P53/Brca1 protein complex. Anticancer Res. [Google Scholar]
  • Frankart AJ, Frankart MJ, Cervenka B, Tang AL, Krishnan DG, Takiar V. 2021. Osteoradionecrosis: exposing the evidence not the bone. Int J Radiat Oncol Biol Phys 109: 1206–1218. [CrossRef] [PubMed] [Google Scholar]
  • Gasperetti T, Miller T, Gao F, Narayanan J, Jacobs ER, Szabo A, Cox GN, et al. 2021. Polypharmacy to mitigate acute and delayed radiation syndromes. Front Pharmacol 12: 634477. [CrossRef] [PubMed] [Google Scholar]
  • Green DR. 2018. An element of life. Cell 172 (3): 389–390. [CrossRef] [PubMed] [Google Scholar]
  • Guo H, Guo S, Liu H. 2020. Antioxidant activity and inhibition of ultraviolet radiation-induced skin damage of selenium-rich peptide fraction from selenium-rich yeast protein hydrolysate. Bioorg Chem 105: 104431. [CrossRef] [PubMed] [Google Scholar]
  • Jasin M. 2002. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21 (58): 8981–8993. [CrossRef] [PubMed] [Google Scholar]
  • Karami M, Asri-Rezaei S, Dormanesh B, Nazarizadeh A. 2018. Comparative study of radioprotective effects of selenium nanoparticles and sodium selenite in irradiation-induced nephropathy of mice model. Int J Radiat Biol 94 (1): 17–27. [CrossRef] [PubMed] [Google Scholar]
  • Kieliszek M, Błażejak S. 2016. Current knowledge on the importance of selenium in food for living organisms: a review. Molecules 21 (5): 609. [CrossRef] [PubMed] [Google Scholar]
  • Kieliszek M, Serrano Sandoval SN. 2023. The importance of selenium in food enrichment processes: a comprehensive review. J Trace Elem Med Biol 79: 127260. [CrossRef] [PubMed] [Google Scholar]
  • Mangiapane E, Pessione A, Pessione E. 2014. Selenium and selenoproteins: an overview on different biological systems. Curr Protein Peptide Sci 15 (6): 598–607. [CrossRef] [Google Scholar]
  • Michalke B, ed. 2018. Selenium. Cham: Springer International Publishing. [Google Scholar]
  • Misra S, Boylan M, Selvam A, Spallholz J, Björnstedt M. 2015. Redox-active selenium compounds—from toxicity and cell death to cancer treatment. Nutrients 7 (5): 3536–3556. [CrossRef] [MathSciNet] [PubMed] [Google Scholar]
  • Moslemi MK, Ali Zargar S. 2011. Selenium-Vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate. Int J General Med 99. doi:10.2147/IJGM.S16275. [Google Scholar]
  • Muecke R, Micke O, Schomburg L, Buentzel J, Kisters K, Adamietz I, and on behalf S of F AKTE. 2018. Selenium in radiation oncology—15 years of experiences in Germany. Nutrients 10 (4): 483. [CrossRef] [PubMed] [Google Scholar]
  • Muecke R, Micke O, Schomburg L, Glatzel M, Reichl B, Kisters K, Schaefer U et al. 2014. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. Integr Cancer Therap 13 (6): 463–467. [CrossRef] [PubMed] [Google Scholar]
  • Muecke R, Schomburg L, Glatzel M, Berndt-Skorka R, Baaske D, Reichl B, Buentzel J et al. 2010. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 78 (3): 828–835. [CrossRef] [PubMed] [Google Scholar]
  • Najafi M, Motevaseli E, Shirazi A, Geraily G, Rezaeyan A, Norouzi F, Rezapoor S, Abdollahi H. 2018. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 94 (4): 335–356. [CrossRef] [PubMed] [Google Scholar]
  • O’Dell K, Sinha U. 2011. Osteoradionecrosis. Oral Maxillofac Surg Clin North Am 23 (3): 455–464. [CrossRef] [PubMed] [Google Scholar]
  • Pluquet O, Hainaut P. 2001. Genotoxic and non-genotoxic pathways of P53 induction. Cancer Lett 174 (1): 1–15. [CrossRef] [PubMed] [Google Scholar]
  • Puspitasari IM, Yamazaki C, Abdulah R, Putri M, Kameo S, Nakano T, Koyama H. 2017. Protective effects of sodium selenite supplementation against irradiation-induced damage in non-cancerous human esophageal cells. Oncol Lett 13 (1): 449–454. [CrossRef] [PubMed] [Google Scholar]
  • Raad H. 2013. Thyroid hydrogen peroxide production is enhanced by the Th2 cytokines, IL-4 and IL-13, through increased expression of the dual oxidase 2and its maturation FactorDUO XA2. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2012.09.003 [Google Scholar]
  • Ray K, Hudak K, Citrin D, Stick M. 2014. Biomarkers of radiation injury and response, in Biomarkers in Toxicology. Elsevier, pp. 673-687. [Google Scholar]
  • Rayman MP. 2012. Selenium and human health. The Lancet 379 (9822): 1256–1268. [CrossRef] [Google Scholar]
  • Rostami A, Moosavi SA, Changizi V, Ardakani AA. 2016. Radioprotective effects of selenium and vitamin-E against 6MV X-rays in human blood lymphocytes by micronucleus assay. Med J Islam Repub Iran 30. [Google Scholar]
  • Seo YR, Kelley MR, Smith ML. 2002. Selenomethionine regulation of P53 by a Ref1-dependent redox mechanism. Proc Natl Acad Sci 99 (22): 14548–14553. [CrossRef] [PubMed] [Google Scholar]
  • Sieber F, Muir SA, Cohen EP, Fish BL, Mäder M, Schock AM, Althouse BJ, Moulder JE. 2011. Dietary selenium for the mitigation of radiation injury: effects of selenium dose escalation and timing of supplementation. Radiat Res 176 (3): 366–374. [CrossRef] [PubMed] [Google Scholar]
  • Sieber F, Muir SA, Cohen EP, North PE, Fish BL, Irving AA, Mäder M, Moulder JE. 2009. High-dose selenium for the mitigation of radiation injury: a pilot study in a rat model. Radiat Res 171 (3): 368–373. [CrossRef] [PubMed] [Google Scholar]
  • Son H, Lee SM, Yoon RG, Lee H, Lee I, Kim S, Chung WY, Lee JW. Effect of selenium supplementation for protection of salivary glands from iodine-131 radiation damage in patients with differentiated thyroid cancer. [Google Scholar]
  • Spallholz JE. 1994. On the nature of selenium toxicity and carcinostatic activity. Free Radical Biol Med 17 (1): 45–64. [CrossRef] [Google Scholar]
  • Srinivasan M, Rajendra Prasad N, Menon VP. 2006. Protective effect of curcumin on γ-radiation induced dna damage and lipid peroxidation in cultured human lymphocytes. Mutat Res/Genetic Toxicol Environ Mutagen 611 (1-2): 96–103. [CrossRef] [Google Scholar]
  • Stewart FA, Heeneman S, Te Poele J, Kruse J, Russell NS, Gijbels M, Daemen M. 2006. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE−/− mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol 168 (2): 649–658. [CrossRef] [PubMed] [Google Scholar]
  • Tak JK, Park J-W. 2009. The use of Ebselen for radioprotection in cultured cells and mice. Free Radic Biol Med 46 (8): 1177–1185. [CrossRef] [PubMed] [Google Scholar]
  • Tapio S, Little MP, Kaiser JC, Impens N, Hamada N, Georgakilas AG, Simar D, Salomaa S. 2021. Ionizing radiation-induced circulatory and metabolic diseases. Environ Int 146: 106235. [CrossRef] [PubMed] [Google Scholar]
  • Tewari R, Sharma V, Koul N, Ghosh A, Joseph C, Hossain SKU, Sen E. 2009. Ebselen abrogates TNFα induced pro-inflammatory response in glioblastoma. Mol Oncol 3 (1): 77–83. [Google Scholar]
  • Thabet NM, Abdel-Rafei MK, Amin MM. 2023. Fractionated whole body γ-irradiation aggravates arthritic severity via boosting NLRP3 and RANKL expression in adjuvant-induced arthritis model: the mitigative potential of Ebselen. Inflammopharmacology 31 (4): 1929–1949. [CrossRef] [PubMed] [Google Scholar]
  • Tuji FM, Pontual MLDA, Barros MLDA, De Almeida SM, Bóscolo FN. 2010. Ultrastructural assessment of the radioprotective effects of sodium selenite on parotid glands in rats. J Oral Sci 52 (3): 369–375. [CrossRef] [PubMed] [Google Scholar]
  • Unthank JL, Ortiz M, Trivedi H, Pelus LM, Sampson CH, Sellamuthu R, Fisher A et al. 2019. Cardiac and renal delayed effects of acute radiation exposure: organ differences in vasculopathy, inflammation, senescence and oxidative balance. Radiat Res 191 (5): 383. [CrossRef] [PubMed] [Google Scholar]
  • Verma P, Kunwar A, Indira Priyadarsini K. 2017. Effect of low-dose selenium supplementation on the genotoxicity, tissue injury and survival of mice exposed to acute whole-body irradiation. Biolog Trace Element Res 179 (1): 130–139. [CrossRef] [PubMed] [Google Scholar]
  • Wang H, Zhang J, Yu H. 2007. Elemental selenium at nano size possesses lower toxicity without compromising the fundamental effect on selenoenzymes: comparison with selenomethionine in mice. Free Radic Biol Med 42 (10): 1524–1533. [CrossRef] [PubMed] [Google Scholar]
  • Wei J, Wang H, Wang H, Wang B, Meng L, Xin Y, Jiang X. 2019. The role of NLRP3 inflammasome activation in radiation damage. Biomed Pharmacother 118: 109217. [CrossRef] [PubMed] [Google Scholar]
  • Wu T, Orschell CM. 2023. The delayed effects of acute radiation exposure (DEARE): Characteristics, mechanisms, animal models, and promising medical countermeasures. Int J Radiat Biol 99 (7): 1066–1079. [CrossRef] [PubMed] [Google Scholar]
  • Yamasaki MC, Cavalcante Fontenele R, Nejaim Y, Freitas DQ. 2019. Radioprotective effect of sodium selenite on mandible of irradiated rats. Br Dent J 30: 232–237. [CrossRef] [PubMed] [Google Scholar]
  • Yang R, Liu Y, Zhou Z. 2017. Selenium and selenoproteins, from structure, function to food resource and nutrition. Food Sci Technol Res 23 (3): 363–373. [CrossRef] [Google Scholar]

Cite this article as: Yan J, Li D. 2024. Protection during radiotherapy: selenium. Radioprotection 59(4): 287–295

All Tables

Table 1

Selenium and selenium-containing compounds and metabolites to function as valuable radioprotective adjuvants. Se-L-Met, Seleno-L-Methionine; Eb, Ebselen; Se-NPs, selenium nanoparticles.

In the text

All Figures

thumbnail Fig. 1

Chemical structures of compounds and metabolites of selenium. (A) Selenomethionine [C5H11NO2Se] (Se-Met); (B) Sodium selenite[Na2SeO3]; (C) Ebselen [2-phenyl- 1,2-benzisoselenazol-3(2H)-one] (Eb).
In the text
thumbnail Fig. 2

Simple conclusion of Selenium and its various forms including selenomethionine, Ebselen, and sodium selenite acting as radioprotective agents to different body systems. Eb, Ebselen; Se-L-Met, Seleno-L-Methionine.
In the text

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