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Introduction: Natural products can be used as radioprotector agents because of containing phenolic compounds and several flavonoids with antioxidant properties. When the normal cells are exposed to ionizing radiation, they generate free radicals and reactive oxygen species that can cause damage in DNA, which leads to cellular dysfunction or even cell death. However, it is necessary to identify new radioprotective agents to protect normal cells. Ferulago angulata (F. angulata), a medicinal plant, can be used as a new radioprotective agent. Purpose: In this study, the radioprotective effect of F. angulata was evaluated against genotoxicity and oxidative stress induced by ionizing radiation in human blood lymphocytes. Methods: The antioxidant activity of F. angulata was assayed using FRAP and DPPH methods. Then, the human blood samples were incubated with F. angulata at different concentrations (25, 50, 100, and 200 μM) and subsequently exposed to IR at a dose of 2Gy. The radioprotective effect of F. angulata on the exposed cells was assessed by the micronucleus (MN) method. Also, biomarkers of oxidative stress in the exposed cells were evaluated by malondialdehyde (MDA) and superoxide dismutase (SOD) methods. Results: Our findings showed that F. angulata reduced the frequency of MN induced by IR in exposed cells. At a 200 μM concentration of F. angulata, the maximum reduction in the frequency of MN (63.11%) was observed that demonstrated a high degree of radioprotection. Afterward, pretreatment at 200 μM concentration of F. angulata inhibited oxidative stress in irradiated lymphocytes, leading to a reduction in MN frequency and MDA levels while SOD activity was enhanced in the exposed cells. Conclusion: F. angulata as a natural radioprotective agent can protect normal cells against reactive oxygen species and genetic damage induced by IR.

Ionizing radiation (IR) brings many health problems to humans, causing damage to the digestive system, hematopoietic system, and immune system. Natural compounds derived from plants have attracted widespread attention due to their low toxicity. Here, we found that 3,4,5-O-tricaffeoylquinic acid (tCQA) extracted from natural plant Azolla imbricata could significantly alleviate the systemic damage in mice caused by IR. In order to further explore the molecular mechanism of the radioprotective effect of tCQA, in vitro experiments confirmed that tCQA could attenuate the cytotoxic effect of IR on the colonic epithelial cell line NCM460 and alleviate the IR-induced mitochondrial dysfunction characterized by the decrease of mitochondrial transmembrane potential, ROS production, and caspase-dependent apoptosis. In addition, the generation of ROS induced by H2 O2 could also be reversed by tCQA. Then, Western blot demonstrated that tCQA could reverse the MAPK signaling pathway activated by IR. However, the inhibitory effect of tCQA on JNK and P38 levels activated by the JNK agonist anisomycin is not obvious; meanwhile, tCQA could inhibit the activation of JNK/P38 induced by H2 O2 , which suggests that tCQA might inhibit the JNK/P38 signaling pathway by reducing ROS. In short, tCQA inhibits the generation of ROS caused by IR, and then regulates the activity of caspase in the mitochondrial pathway by inhibiting the JNK/P38 signaling pathway, thereby alleviating the apoptosis of NCM460. This research provides an experimental basis for the development of new types of radioprotective agents for medical diagnosis and radiotherapy.

Background As we know, radiotherapy plays an irreplaceable role in the clinical management on solid tumors. However, due to the non-specific killing effects of ionizing radiation, normal tissues damages would be almost simultaneous inevitably. Therefore, ideal radioprotective agents with high efficiency and low toxicity are always desirable. In this work, atomically precise Ag14 clusterzymes were developed, and their applications in radioprotection were studied in vitro and in vivo for the first time. Methods The ultra-small glutathione supported Ag14 clusterzymes were synthesized by convenient sodium borohydride (NaBH4) reduction of thiolate-Ag (I) complexes and then they were purified by desalting columns. The enzyme-like activity and antioxidant capacity of Ag14 clusterzymes have been tested by various commercial kits, salicylic acid method and electron spin resonance (ESR). Next, they were incubated with L929 cells to evaluate whether they could increase cell viability after γ-ray irradiation. And then Ag14 clusterzymes were intravenously injected into C57 mice before 7 Gy whole-body γ-ray irradiation to evaluate the radioprotection effects in vivo. At last, the in vivo toxicities of Ag14 clusterzymes were evaluated through biodistribution test, hematological details, serum biochemical indexes and histological test in female Balb/c mice with intravenous injection of Ag14 clusterzymes. Results Our studies suggested atomically precise Ag14 clusterzymes were potential radioprotectants. Ag14 clusterzymes exhibited unique superoxide dismutase (SOD)-like activity, strong anti-oxidative abilities, especially on •OH scavenging. The Ag14 clusterzymes could effectively improve cell viability through eliminating ROS and prevent DNA damages in cells dealt with γ-ray irradiation. In vivo experiments showed that Ag14 clusterzymes could improve the irradiated mice survival rate by protecting hematological systems and repairing tissue oxidative stress damage generated by γ-ray irradiation. In addition, bio-distribution and toxicological experiments demonstrated that the ultrasmall Ag14 clusterzymes could be excreted quickly from the body by renal clearance and negligible toxicological responses were observed in mice up to 30 days. Conclusion In summary, atomically precise, ultrasmall and water soluble Ag14 clusterzymes with SOD-like activity were successfully developed and proved to be effective both in vitro and in vivo for radioprotection. Furthermore, with atomically precise molecular structure, Ag14 clusterzymes, on aspect of the catalytic and optical properties, may be improved by structure optimization on atom-scale level for other applications in disease diagnosis and treatment. Graphical Abstract

Ionizing radiation (IR) is widely used in the diagnosis and treatment of various cancers. However, IR can cause damage to human health by producing reactive oxygen species. Lactococcus lactis is a type of microorganism that is beneficial to human health and has a strong antioxidant capacity. In this study, the protective effect of normal and IR-induced L. lactis IL1403 cell-free extracts (CFE and IR-CFE, respectively) against oxidative damage in vitro and the radioprotective effect of IR-CFE in vivo was evaluated using 60Coγ-induced oxidative damage model in mice. Results showed that IR-CFE exhibited a stronger oxidative damage-protective effect than CFE for L. lactis IL1403 under H2O2 in vitro. Moreover, IR-CFE also showed strong radioprotective effect on hepatocyte cells (AML-12) under radiation condition, and the effect was better than that of CFE. Animal experiment indicated that IR-CFE could reduce the IR-induced damage to the hematopoietic system by increasing the number of white blood cells and red blood cells in peripheral blood of irradiated mice. It was also observed that IR-CFE could markedly alleviate the 60Coγ-induced oxidative stress via increasing the activities of superoxide dismutase and glutathione peroxidase, enhancing the levels of glutathione, and decreasing the contents of malondialdehyde in serum, liver, and spleen. In addition, IR-CFE also could reduce the activities of alanine transaminase and aspartate aminotransferase in serum, thereby reducing radiation damage to the liver. These results suggested that IR-CFE could be considered as potential candidates for natural radioprotective agents. This study provides a theoretical basis for improving the application of lactic acid bacteria.

Purpose: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. Methods: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. Results: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. Conclusion: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.

Objective To develop an UPLC-MS/MS method for the accurate quantification of Estriol (E3), a new radioprotective agent, and observe the variation in pharmacokinetic characteristics of E3 after irradiation. As a hormone drug, the gender differences of E3 metabolism were also concerned here. Methods Various chromatographic and mass spectrometric conditions of E3 were optimized. The specificity, linearity, precision and accuracy of UPLC-MS/MS method were validated. Twenty SD rats, half male and half female, were administered with intramuscular (im) injection of 2.7 ​mg/kg E3, and then divided randomly into two groups, sham-irradiated group (Con) and irradiated group (IR). IR group was irradiated to 7 ​Gy of γ-rays. Blood samples were collected at different times post-irradiation and E3 concentrations were detected. The changes of concentration-time variation and pharmacokinetic parameters for E3 after irradiation were investigated, together with metabolic differences between male and female rats. Results The range of the calibration curve of UPLC-MS/MS for E3 was 1.00–200.0 ​ng/mL. Con group reached maximum concentration (Cmax) (77.57 ​± ​18.71) ng/mL at (0.68 ​± ​0.29) h (Tmax) after im injection. The drug concentration-time profiles and pharmacokinetic parameters of E3 were consistent before and after irradiation. The areas under time curve (AUC0-t) of E3 were (353 ​± ​74) h·ng/mL for Con group, and (299 ​± ​74) h·ng/mL for IR group (P ​> ​0.05). There were also no statistical differences in pharmacokinetic parameters between female and male rats. The elimination half-lifes (T1/2) of males and females were (3.02 ​± ​0.68) h and (3.01 ​± ​0.42) h in Con group, and (3.64 ​± ​0.51) h and (3.38 ​± ​0.60) h in IR group, respectively (P ​> ​0.05). Conclusion A rapid and sensitive UPLC-MS/MS method for determination of E3 was established. The pharmacokinetic characteristics of E3 in rat were not affected by 7 ​Gy irradiation and gender differences. This study provided a theoretical basis for the development and application of new radiation injury treatment drug.

According to leading experts, the vast arsenal of radioprotective agents available in the world today does not fully meet modern practical needs, both in the field of radiation protection, and in the prevention and treatment of complications of radiotherapy. The purpose of the study was to evaluate the effect of the salt-forming acids type on the radioprotective activity of NOS inhibitor T1023. The chemical part of this study included methods of chemical synthesis, physicochemical and elemental analysis. Pharmacological part – assessment of acute toxicity using V.B. Prozorovsky express method and the study of radioprotective activity using Till and McCulloch method based on the ability of mice hematopoietic cells to form spleen colonies after irradiation. The number of endogenous hematopoietic spleen colonies were assessed on the 8th day after total exposure to gamma-irradiation at a dose of 6 Gy in six independent experiments. As a result of directed chemical synthesis, six new derivatives of T1023 – salts of N-isobutanoyl-S-isopropylisothiourea have been developed, identified and characterized. The results of studying the safety and radioprotective activity of the synthesized compounds showed that changes in the salt-forming acid don’t significantly influence the toxicity: all studied compounds are in the 3rd class of toxicity and hazard. At the same time, it was found that the replacement of the salt-forming acid significantly influenced the severity of the radioprotective effect. For some of these compounds radioprotective efficacy is comparable to or exceeds the efficacy of the initial compound T1023. It is important to note that these new compounds were used in lower, more save doses than T1023. The results suggest promising further development of NOS inhibitors – isothiourea derivatives as radioprotective agents.

—The possibilities of improving medical protectors administered by inhalation for urgent assistance in emergency situations are discussed in this paper. The advantages of this method of administration are characterized, and the expediency of using portable dry powder inhalers as a technical means of drug delivery is substantiated. The sources containing information on the inhalation use of drugs from various pharmacological groups has been examined. Radioprotective agents (cystamine, indraline, naphthyzine), radioprotective agents for prophylactic use (estradiol), means of preventing and arresting the primary reaction to radiation (ondansetron, metoclopramide, metacin), radiomitigators (analogs of granulocyte colony stimulating factor (G-CSF), growth hormone, betaleukin), and incorporated binding agents radionuclides (pentacin) should be considered as the most promising medical preparations for inhalation under exposure to radiation factors. This is determined by the presence of effective inhalation forms approved for medical use and registered in the Russian Federation, as well as their technological feasibility.

Radionuclide tritium is widely used in the nuclear energy production industry and creates a threat to human health through radiation exposure. Herein, the radioactive elimination and radioprotective effect of hydrogen-rich water (HRW), a potential antioxidant with various medical applications, on tritiated water (HTO) exposure, was studied in vitro and in vivo. Results showed that intragastric administration of HRW effectively promoted the elimination of urinary tritium, decreased the level of serum tritium and tissue-bound tritium (OBT), and attenuated the genetic damage of blood cells in mice exposed to HTO (18.5 MBq/kg). Pretreatment with HRW effectively reduces tritium accumulation in HTO-treated human blood B lymphocyte AHH-1 cells. In addition, the anti-oxidative properties of HRW could attenuate the increased intracellular ROS (such as O2•-, •OH and ONOO−), resulting in reversing the exhaustion of cellular endogenous antioxidants (reduced GSH and SOD), decreasing lipid peroxidation (MDA), relieving DNA oxidative damage, and depressing cell apoptosis and cytotoxicity induced by HTO exposure. In conclusion, HRW is expected to be an effective radioactive elimination agent through the competition effect of isotope exchange or a radioprotective agent by scavenging free radicals induced by HTO exposure.

In mass casualty events involving radiation exposure, there is a substantial unmet need for identifying and developing an orally bioavailable agent that can be used to protect the hematopoietic stem cell pool and regenerate hematopoiesis after radiation injury. Dimethyl sulfoxide (DMSO), a free-radical scavenger, has shown therapeutic benefits in many preclinical and clinical studies. This study investigates the radioprotective effects of DMSO on oral administration. Single dose of oral DMSO administrated before irradiation conferred 100% survival of C57BL6/J mice receiving otherwise lethal as well as super-lethal radiation dose, with wide radioprotective time frame (from 15min to 4h). Oral DMSO not only protected radiation-induced acute hematopoietic stem and progenitor cell (HSPC) injury, but also ameliorated long-term BM suppression following irradiation in mice. Mechanistically, DMSO directly protected HSPC survival after irradiation in vitro and in vivo, whereas no radioprotective effect was seen in MLL-AF9-induced leukemia cells. Unexpectedly, DMSO treatment did not inhibit radiation-induced HSPC apoptosis, and the HSPC survival from Trp53-and PUMA-deficient mice after irradiation was also protected by DMSO. In conclusion, our findings demonstrate the radioprotective efficacy of oral DMSO. Given its oral efficacy and little toxicity, DMSO is an attractive candidate for human use in a wide variety of settings, including nuclear accidents and medical radiation.

Environmental factors like ionizing radiation induced generation of reactive oxygen species (ROS) cause macromolecular damage under physiological conditions. Proteins are the potential targets of ROS induced oxidative damage because of their abundance and their critical functions in the biological systems. The present study investigates the protective potential of ethyl pyruvate (EP) against ionizing radiation induced oxidative damage of bovine serum albumin (BSA) using spectroscopic, biochemical and SDS-PAGE techniques. Spectroscopic data shows that EP prevents the build up of protein damage markers like bityrosine formation and oxidation of tryptophan. Protein melting studies shows that the melting temperature (Tm) of the irradiated protein does not change significantly in the presence of EP. Biochemical assays indicate that ionizing radiation causes the generation of carbonyls and malondialdehyde and the loss of thiol content in proteins that is prevented by EP. The SDS-PAGE profile of gamma irradiated BSA shows the radioprotective effect of EP. These results indicate the radiation induced oxidative and molecular changes in the protein and that the EP protected the BSA from these modifications. Therefore, these results imply that EP has a good antiradical property and hence it can be proposed as a good radioprotective agent.

The high level of nuclear radiation threats in the modern world determines the need to find new means of pharmacological protection of the health of military personnel and civilians from the effects of ionizing radiation. Of particular scientific interest in this aspect are natural polyphenols as a promising basis for the development of newdrugs, radiomodifiers.Justification of the prospects of creating radioprotective agents based on compositions of plantpolyphenolic substances (PPS) and polysaccharides.The experiments were performed on 130 laboratory white rats-male of Wistar line sexually mature weighting 180-240 g. Animals once received a total X-ray dose equivalent to 4.25 Gy. The effects ofquercetin and patulaten to the processes of reparative regeneration under conditions of X-ray irradiation andagainst the background of butadione suppression were investigated. Indicators in the study groups were compared using the Student's t-test for independent samples; the differences were considered statistically significantat p0.05.The various biological properties of quercetin, in particular, the ability to bind hydroxyl radicals, is thepotential for developing radioprotective agents based on it. At the first stage of the study, the effect of PPS andtheir compositions with polysaccharides on reparative regeneration was studied against the background of its suppression in intact and irradiated animals. With the oral administration of PPS and their compositions with pectin towhite rats, 30 minutes before the administration of butadion, an increase in the processes of reparative regeneration in the cells of the covering epitheliumof the esophagus was observed. At the same time, quercetin granulescaused the most expressive effect, which increased the statistically significant value of the mitotic index by 78.5 %in relation to the group of animals injected with butadion. At the second stage of the study, the effect of polyphenolic substances and their compositions with pectin on the processes of reparative regeneration in intact and irradiated white rats was studied on a model of linear skin wounds. The prophylactic administration of quercetin granules and the treatment of wounds with 20 % sterile quercetin gel significantly accelerated the healing process.Experimental data indicate that quercetin granules have the ability to stimulate the processes of reparative regeneration, quercetin showed the greatest efficiency with simultaneous use inside and topically.The research results indicate the promise of developing radioprotective drugs that can stimulatereparative regeneration processes based on compositions of plant polyphenolic substances and polysaccharides invarious qualitative and quantitative ratios.Vysokyĭ riven' radiatsiĭno-iadernykh zagroz v suchasnomu sviti vyznachaie neobkhidnist' poshuku diievykh zasobiv farmakologichnogo zakhystu zdorov’ia viĭs'kovosluzhbovtsiv i tsyvil'nogo naselennia vid diï ionizuiuchogo vyprominiuvannia. Osoblyvyĭ naukovyĭ interes v ts'omu aspekti predstavliaiut' pryrodni polifenoly iak perspektyvni spolukydlia rozrobky farmpreparativ radiozakhysnoï diï.Meta. Obґruntuvannia perspektyv stvorennia zasobiv radiozakhysnoï diï na osnovi kompozytsiĭ roslynnykh polifenol'nykh spoluk (PFS)i polisakharydiv.Material ta metody. Eksperymenty provedeno na 130 laboratornykh bilykh statevozrilykh shchurakh-samtsiakh liniïWistar masoiu 180–240 g. Tvaryny odnorazovo otrymaly zagal'ne rentgenivs'ke oprominennia v dozi, ekvivalentniĭ 4,25 Gr. Doslidzhuvaly vplyv kvertsetynu i patulatenu na reparatyvnu regeneratsiiu na modeli liniĭnykhran shkiry na foni oprominennia ta na foni prygnichennia Butadionom. Pokaznyky v grupakh doslidzhennia porivniuvaly za dopomogoiu t-kryteriiu St'iudenta dlia nezalezhnykh vybirok; vidminnosti vvazhaly statystychno znachushchymy pry0,05.Rezul'taty doslidzhennia. Riznomanitni biologichni vlastyvosti kvertsetynu, zokrema spromozhnist' zv’iazuvatygidroksyl'ni radykaly, ie potentsialom dlia rozrobky na ĭogo osnovi radiozakhysnykh zasobiv. Pry peroral'nomuvvedenni polifenol'nykh spoluk ta ïkh kompozytsiĭ z pektynom bilym shchuram za 30 khv do vvedennia butadionu sposterigaly posylennia protsesiv reparatyvnoï regeneratsiï v klitynakh pokryvnogo epiteliiu stravokhodu. Pry ts'omunaĭbil'sh vyrazhenu diiu chynyly kvertsetynu granuly, iaki zbil'shuvaly statystychno dostovirnu velychynu mitotychnogo indeksu na 78,5 % porivniano z grupoiu tvaryn, iakym vvodyly butadion (kontrol'). Na drugomu etapidoslidzhennia vyvchavsia vplyv polifenol'nykh spoluk (PFS) ta ïkh kompozytsiĭ z pektynom na protsesy reparatyvnoï regeneratsiï u intaktnykh i oprominenykh bilykh shchuriv na modeli liniĭnykh ran shkiry. Profilaktychne vvedenniakvertsetynu granul i obrobka ran 20 % steryl'nym gelem kvertsetynu znachno pryskoriuvalo protses zagoienniaran. Eksperymental'ni dani svidchat' pro zdatnist' kvertsetynu granul posyliuvaty protsesy reparatyvnoï regeneratsiï, osoblyvo pry odnochasnomu zastosuvanni peroral'no i mistsevo.Vysnovky. Rezul'taty doslidzhen' vkazuiut' na perspektyvnist' rozrobky radiozakhysnykh preparativ, zdatnykhstymuliuvaty protsesy reparatyvnoï regeneratsiï na osnovi kompozytsiĭ roslynnykh polifenol'nykh spoluk ipolisakharydiv u riznykh iakisnykh i kil'kisnykh spivvidnoshenniakh.

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn2+ in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)2Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)2Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)2Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ± 0.14) compared to radiation alone group (1.60 ± 0.07) was observed. DT(GS)2Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)2Mn(II) with an average of 1546 ± 61 μm versus 763 ± 154 μm for radiation alone group. The present findings suggested DT(GS)2Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.

Anti-aging properties can be found in many compounds with radiation-protective effects. Such compounds include the following: bioflavonoids, some antioxidants (N-acetylcysteine), melatonin, some non-steroid anti-inflammatory agents and statins, angiotensin converting enzyme inhibitors, metformin, rapamycin, etc. The effects of the drugs can develop both in the case of their long-term use and in case of a single application against the background of acute exposure to ionizing radiation at lethal doses. At the same time, “classical” radiation-protective agents such as cystamine, amifostine, adrenergic alfa-blockers, and androgenic drugs were not revealed to have geroprotective properties, which may be due to their high toxicity.

Introduction: The ionizing radiation exposure of the normal cell causes damage to DNA, which leads to cell dysfunction or even cell death. However, it is necessary to identify new radio protectives in order to protect normal cells. Sulindac sulfide (SS) is a metabolite of sulindac (a non-steroidal anti-inflammatory drug) known as a cyclooxygenase inhibitor. Free radicals and reactive oxygen species are generated in the IR-exposed cells. Also, the induced inflammation process causes damage in DNA. Purpose In this research, the radioprotective effect of SS was investigated against genotoxicity and lipid peroxidation induced by ionizing radiation in the human blood lymphocytes. Methods In this study, the human blood samples were pretreated with SS at different concentrations (10, 25, 50, 100 and 250 μM) and then were exposed to IR at a dose of 1.5 Gy. The micronucleus (MN) assay was used to indicate the radioprotective effects of SS on exposed cells. Total antioxidant activity of the SS was measured by using FRAP and DPPH assay. Also, the malondialdehyde (MDA) levels and the activity of superoxide dismutase (SOD) on the exposed cells were evaluated. Results It was found that SS decreased the percentage of MN induced by IR in exposed cells. Maximum reduction in the frequency of MN was observed at 250 μM of SS (87%) that provides the highest degree of protection against IR. On the other hand, pretreatment at 250 μM of SS inhibited IR-induced oxidative stress, which led to a decrease in the MN frequencies and MDA levels, while SOD activity showed an increase in the exposed cells. Conclusion It could be concluded that SS as a good radioprotective agent protects the human normal cells against the oxidative stress and genetic damage induced by IR.

Objectives: Gliclazide (GL) is widely used to reduce hyperglycemia in diabetic patients. The aim of this study was to investigate the protective effect of GL against chromosome damage induced by ionizing radiation in human blood lymphocytes. Methods: In this experimental study, peripheral blood samples were collected from human volunteers and treated with GL at various concentrations (5, 25, 50 or 100 μM) for three hours. Then samples were irradiated to X-ray (1.5 Gy). Blood samples were cultured with mitogenic stimulation. The frequencies of micronuclei in cytokinesis-blocked binucleated lymphocytes were determined in the different samples. The antioxidant activities of GL were assayed by two different methods as 1,1- diphenyl-2-picryl hydrazyl radical (DPPH) free radical scavenging and reducing antioxidant power assays. Results: GL significantly reduced the percentage of micronuclei in lymphocytes which were irradiated. The maximum radioprotection in the reduction of percentage of micronuclei in lymphocytes was observed at 100 μM of GL with 52% efficacy. GL exhibited excellent free radical scavenging activity and reducing power at concentration dependent activities. The IC50 values of GL were lower than ascorbic acid. Higher potencies were observed in the antioxidant activities for GL than ascorbic acid in both methods. Conclusion: This data exhibits that GL is a powerful radioprotective agent that could protect healthy cells against the chromosome damage induced by ionizing radiation through antioxidant activity. The radioprotective effect is new indication of GL for patients' protection against side effect induced by ionizing radiation.

In spite of carbon ion radiotherapy is a talented modality for malignant tumor patients, the radiation damage of normal tissues adjacent to tumor and the dysfunction of immune system limits therapeutic gain. Protecting immune system against carbon ion radiation-caused damage has the possibility to improve cancer treatment, but it is uncertain whether conventional radioprotective agents play a role in carbon ion radiation. To certify carbon ion caused immune dysfunction and assess the radioprotective effect of melatonin on immune system, animal experiments were performed in radiosensitive BALB/C mice. Here, we observed the bodyweight loss, death and apoptosis, abnormal T-cell distributions in immune system in carbon ion radiated mice. Pretreatment with melatonin could increase the index of thymus and spleen, reduce cell apoptosis in thymus and spleen, and attenuate the carbon ion radiation-caused imbalance of T lymphocytes and disorder of cytokines. These results suggest that melatonin can act as an effective protector against carbon ion radiation-caused immune dysfunction. Furthermore, we also found melatonin restored the activity of the antioxidant enzymes and reduced the level of lipid peroxidation in serum. These data have provided baseline information both for radiation workers and cancer patients to use melatonin as a radioprotector during the carbon ion radiation treatment.

Background:Radiotherapy is one of the treatment methods for cancers using ionizing radiations. About 70% of cancer patients undergo radiotherapy. Radiation effect on the skin is one of the main complications of radiotherapy and dose limiting factor. To ameliorate this complication, we used melatonin as a radioprotective agent due to its antioxidant and anti-inflammatory effects, free radical scavenging, improving overall survival after irradiation as well as minimizing the degree of DNA damage and frequency of chromosomal abrasions.Methods:Sixty male Wistar rats were randomly assigned to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). A single dose of 30 Gy gamma radiation was exposed to the right hind legs of the rats while 40 mg/ml of melatonin was administered 30 minutes before irradiation and 2 mg/ml once daily in the afternoon for one month till the date of rat’s sacrifice. Five rats from each group were sacrificed 4, 12 and 20 weeks after irradiation. Afterwards, their exposed skin tissues were examined histologically and biochemically.Results:In biochemical analysis, we found that malondialdehyde (MDA) levels significantly increased in R group and decreased significantly in M and MR groups after 4, 12, and 20 weeks, whereas catalase (CAT) and superoxide dismutase (SOD) activities decreased in the R group and increased in M and MR groups during the same time periods compared with the C group (p0.05) at 4 and 20 weeks except for inflammation and hair follicle atrophy, while there were significant effects at 12 weeks (pConclusion:Melatonin can be successfully used for the prevention and treatment of radiation-induced skin injury. We recommend the use of melatonin in optimal and safe doses. These doses should be administered over a long period of time for effective radioprotection and amelioration of skin damages as well as improving the therapeutic ratio of radiotherapy.

Radiotherapy is an important method for the treatment of malignant tumors. It can directly or indirectly lead to the formation of free radicals and DNA damage, resulting in a series of biological effects, including tumor cell death and normal tissue damage. These radiation effects are typically accompanied by the abnormal expression of sirtuin 1 (Sirt1), which deacetylates histones and non-histones. These Sirt1 substrates, including transcription factors and some catalytic enzymes, play a crucial role in anti-oxidative stress, DNA damage repair, autophagy regulation, anti-senescence, and apoptosis, which are closely related to triggering cell defense and survival in radiation-induced damage. In this article, we review the mechanisms underlying cellular responses to ionizing radiation and the role of Sirt1 in the process, with the aim of providing a theoretical basis for protection against radiation by Sirt1 as well as novel targets for developing radioprotective agents.

The risk of radiation damage has increased with the rapid development of nuclear technology and radiotherapy. Hence, research on radioprotective agents is of utmost importance. In the present study, a novel aminothiol compound 12, containing a linear alkylamino backbone and three terminal thiols, was synthesized. Owing to the appropriate capped groups in the chains, it has an improved permeability and oral bioavailability compared to other radioprotective agents. Oral administration of compound 12 improved the survival of mice that received lethal doses of γ-irradiation. Experimental results demonstrated that compound 12 not only mitigated total body irradiation-induced hematopoietic injury by increasing the frequencies of hematopoietic stem and progenitor cells but also prevented abdominal irradiation-induced intestinal injury by increasing the survival of Lgr5+ intestinal cells, lysozyme+ Paneth cells, and Ki67+ cells. In addition, compound 12 decreased oxidative stress by upregulating the expression of Nrf2 and NQO1 and downregulating the expression of NOX1. Further, compound 12 inhibited γ-irradiation-induced DNA damage and alleviated G2/M phase arrest. Moreover, compound 12 decreased the levels of p53 and Bax and increased the level of Bcl-2, demonstrating that it may suppress radiation-induced apoptosis via the p53 pathway. These results indicate that compound 12 has the possibility of preventing radiation injury and can be a potential radioprotector for clinical applications.

A novel bio-nanocomposite was developed by incorporating the extracted nanochitosan from shrimp wastes with Schiff base cobalt complex (Chit-Co complex). The phytosynthesis of Chit-Co complex/Ag bio-nanocomposite was designed utilizing Chit-Co complex at the presence of Ferulago angulate extraction and characterized by AFM, SEM, EDAX, TEM, FT-IR, and elemental analysis. The radioprotective application of this bio-nanocomposite on human lymphocyte cells was evaluated using micronucleus (MN) assay. Total antioxidant activities of it were evaluated using FRAP and DPPH assays. Chit-Co complex/Ag bio-nanocomposite significantly decreased the frequency of micronuclei in human lymphocytes exposed to ionization irradiation (IR). The highest protection was observed at 200 μg/ml. Also, maximum antioxidant activities of bio-nanocomposite were provided at the same dose. These data exhibit the radioprotective effect of a bio-nanocomposite based on wastes of living organisms can be an excellent radioprotective agent, which can protect the normal cells of human against the genetic damage by IR.

Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.

Oxidative stress-induced off-target effects limit the therapeutic window of radiation therapy. Although many antioxidants have been evaluated as radioprotective agents, none of them are in widespread clinical use, owing to the side effects of the antioxidants themselves and the lack of apparent benefit. Aiming for a truly effective radioprotective agent in radiation cancer therapy, the performance of a self-assembling antioxidant nanoparticle (herein denoted as redox nanoparticle; RNP) is evaluated in the local irradiation of a subcutaneous tumor-bearing mouse model. Since RNP is covered with a biocompatible shell layer and possesses a core-shell type structure of several tens of nanometers in size, its lifetime in the systemic circulation is prolonged. Moreover, since 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), one of the most potent antioxidants, is covalently encapsulated in the core of RNP, it exerts intense antioxidant activity and induces fewer adverse effects by avoiding leakage of the TEMPO molecules. Preadministration of RNP to the mouse model effectively mitigates side effects in normal tissues and significantly extends the survival benefit of radiation cancer therapy. Moreover, RNP pretreatment noticeably increases the apoptosis/necrosis ratio of radiation-induced cell death, a highly desirable property to reduce the chronic side effects of ionizing irradiation.

Exposure to Ionizing radiation (IR) poses a severe threat to human health. Therefore, there is an urgent need to develop potent and safe radioprotective agents for radio-nuclear emergencies. Phosphatidylinositol-3-kinase (PI3K) mediates its cytoprotective signaling against IR by phosphorylating membrane phospholipids to phosphatidylinositol 3,4,5 triphosphate, PIP3, that serve as a docking site for AKT. Phosphatase and Tensin Homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating PIP3, thus suppressing PI3K/AKT signaling that could prevent IR induced cytotoxicity. The current study was undertaken to investigate the radioprotective potential of PTEN inhibitor (PTENi), bpV(HOpic). The cell cytotoxicity, proliferation index, and clonogenic survival assays were performed for assessing the radioprotective potential of bpV(HOpic). A safe dose of bpV(HOpic) was shown to be radioprotective in three radiosensitive tissue origin cells. Further, bpV(HOpic) significantly reduced the IR-induced apoptosis and associated pro-death signaling. A faster and better DNA repair kinetics was also observed in bpV(HOpic) pretreated cells exposed to IR. Additionally, bpV(HOpic) decreased the IR-induced oxidative stress and significantly enhanced the antioxidant defense mechanism in cells. The radioprotective effect of bpV(HOpic) was found to be AKT dependant and primarily regulated by the enhanced glycolysis and associated signaling. Furthermore, this in-vitro observation was verified in-vivo, where administration of bpV(HOpic) in C57BL/6 mice resulted in AKT activation and conferred survival advantage against IR-induced mortality. These results imply that bpV(HOpic) ameliorates IR-induced oxidative stress and cell death by inducing AKT signaling mediated antioxidant defense system and DNA repair pathways, thus strengthening its potential to be used as a radiation countermeasure.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

Unmodified hydrated С60 fullerene molecules (C60UHFM) were shown to reduce the formation ROS in water and 8-oxoguanine in DNA upon ionizing radiation impact. C60UHFM efficiently eliminate long-lived protein radicals arising after irradiation. In irradiated mice C60UHFM reduce the rate of single/double-strand DNA breaks and amount of chromosomal breaks. The radioprotective activity of C60UHFM was estimated by the survival rate of animals; the dose modification factor for animal survival was 1.3. Hematological tests showed that C60UHFM injection in mice prior to irradiation results in a decrement of irradiation-induced leucopenia and thrombocytopenia. Histological analysis testified that C60UHFM provide significant protection of small intestine tissues in mice against irradiation-induced damage. The obtained data assume that the radioprotective properties of C60UHFM are determined by their antioxidant, antiradical and DNA-protective qualities. Thus, it was demonstrated that C60UHFM are a novel antioxidant and radioprotective agent capable of substantial reduction of the harmful effects of ionizing radiation.

Radiation-induced lung injury is characterized by an acute pneumonia phase followed by a fibrotic phase. At the time of irradiation, a rapid, short-lived burst of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) occurs, but chronic radiation-induced lung injury may occur due to excess ROS such as H2O2, O2•−, ONOO−, and •OH. Molecular hydrogen (H2) is an efficient antioxidant that quickly diffuses cell membranes, reduces ROS such as •OH and ONOO−, and suppresses damage caused by oxidative stress in various organs. In 2011, through the evaluation of electron-spin resonance and fluorescent indicator signals, we had reported that H2 can eliminate •OH and can protect against oxidative stress-related apoptotic damage induced by irradiation of cultured lung epithelial cells. We had explored for the first time the radioprotective effects of H2 treatment on acute and chronic radiation-induced lung damage in mice by inhaled H2 gas (for acute) and imbibed H2-enriched water (for chronic). Thus, we had proposed that H2 be considered a potential radioprotective agent. Recent publications have shown that H2 directly neutralizes highly reactive oxidants and indirectly reduces oxidative stress by regulating the expression of various genes. By regulating gene expression, H2 functions as an anti-inflammatory and anti-apoptotic molecule and promotes energy metabolism. The increased evidence obtained from cultured cells or animal experiments reveal a putative place for H2 treatment and its radioprotective effect clinically. This review focuses on major scientific advances in the treatment of H2 as a new class of radioprotective agents.

In recent years, many studies have shown that hydrogen has therapeutic and preventive effects on various diseases. Its selective antioxidant properties were well noticed. Most of the ionizing radiation-induced damage is caused by hydroxyl radicals (·OH) from radiolysis of H2O. Since hydrogen can mitigate such damage through multiple mechanisms, it presents noteworthy potential as a novel radio-protective agent. This review analyses possible mechanisms for hydrogen’s radioprotective properties and effective delivery methods. We also look into details of vitro and vivo studies for hydrogen’s radioprotective effects, and clinical practices. We conclude that hydrogen has good potential in radio-protection, with evidence that warrants greater research efforts in this field.

Duodenal injury caused by radiotherapy of upper tumor is a serious and inescapable complication due to the special anatomical structure and complex intestinal microenvironment of duodenum. However, the prevention and treatment of radiation-induced damage of duodenum are still a challenge in clinic. In this study, fullerenol@nano-montmorillonite (FNMT) nanocomposite was obtained by mechanical synthesis which processes good chemical stability, long retention time in duodenum and high free radical scavenging activity. And for the first time we explore its role in protecting duodenum damage caused by X-ray irradiation. On the one hand, fullerenol, with good water solubility, chemical stability, and extensive free radical scavenging ability, can effectively alleviate mitochondrial and DNA damage caused by radiation-generated reactive oxygen species (ROS). On the other hand, nano-montmorillonite (NMMT) is used as a drug carrier, which enables the long residence time of fullerenol in duodenum because of its strong intestinal adhesion ability. By taking advantage of both fullerenol and NMMT, the FNMT nanocomposite significantly reduces radiation-induced diarrhea, weight loss, and duodenum tissue pathological damage of mice. This study not only establishes a new platform for duodenal radioprotective agent based on nanomaterials but also has a potential for clinical transformation.

In this study, three novel flavonoid composite materials, created by combining an aglycone [quercetin (QUE), hesperetin (HES) or naringenin (NAR)] with monoglucosyl rutin (MGR), were designed to test for improved radioprotectivity compared with that provided by administration of MGR alone. Aglycone in the MGR-composite state was highly soluble in water, compared with aglycone alone dissolved in dimethyl sulfoxide or distilled water. The antioxidant activity of the three flavonoid composites was as high as that of MGR only. Next, the cytotoxicity test after 30 min treatment of an MGR composite showed a clear reduction in cell viability and suggested that a rapid introduction of aglycone into cells had taken place. In addition, QUE/MGR and HES/MGR composites strongly scavenged intracellular reactive oxygen species (ROS) induced by X-ray irradiation as well as MGR alone did. However, in the colony-formation assay using irradiated Chinese hamster ovary (CHO) cells, the HES/MGR composite showed a stronger radioprotective effect than MGR alone did, but the QUE/MGR composite showed no additional protective effect compared with the control. Furthermore, it was revealed that QUE and QUE/MGR composite treatment had the effect of reducing the glutathione (GSH) content in cells, and that QUE showed a stronger inhibition of PARP activity compared that of HES and NAR. Our data demonstrated that when designing a flavonoid composite as a radioprotective agent, it was necessary to select an appropriate aglycone, considering not only its antioxidant ability but also its inhibitory effect on cell recovery or DNA repair after radiation injury.

In this work, a series of novel benzyl naphthyl sulfoxides (sulfones) derived from Ex-RAD were designed and synthesized as potential radioprotective agents. Some of the compounds considerably protected HUVECs against 60Co γ-irradiation, accompanied by the absence of cytotoxicity. Compared to Ex-RAD, compound 8n not only exhibited a significant protective effect on cell survival and radiation-induced DNA damage, but also remarkably enhanced the survival (100%) of mice in 30 days after being exposed to irradiation. The results suggested that some target compounds are valuable for further research as promising radioprotectors.

Free radicals and reactive oxygen species (ROS) are generated using various endogenous systems or from external sources such as exposure to different physiochemicals. Ionizing radiation damage to the cell can be caused by the direct or indirect effects of radiotherapy processes. Silymarin (SM), a flavanolignan compound, has been identified as a natural potent antioxidant with cytoprotection activities due to scavenging free radicals. The aim of the present study was to evaluate the radioprotective effect of SM on sperm parameters of mice induced by γ-rays. A total number of 40 adult, male NMRI mice were randomly divided into four equal groups. The control group was neither treated with SM nor irradiated by γ-rays. The second group was only irradiated with 2Gy of γ-rays. The third group was firstly treated with 50mg/kg of SM for 7 consecutive days, and one day later, last injections were irradiated by 2Gy of γ-rays. The fourth groups received only 50mg/kg of SM for 7 consecutive days. All the animals were treated intraperitoneally. Histopathological and morphometrical examinations were performed. The data were analyzed using ANOVA and Tukey post hoc test. A value of p

It is commonly known that radiotherapy is still a key modality for treatment of cancer. Though this effect is desirable during radiotherapy, it leads to radiotoxicity on normal healthy cells. In the present research, we designed, synthesized and analyzed a series of nitronyl nitroxide radical (NITR) spin-labeled resveratrol (RES) derivatives. The cytotoxicity of the newly synthesized substances was tested on Jurkat T cells. The derivatives were studied as reactive oxygen species (ROS) scavenger to protect ionizing radiation of Jurkat T cells upon 6 Gy X-irradiation. The experimental results revealed that compound 2 and 3 could significantly alleviate the damage of Jurkat T cells, as evidenced by decreasing ROS production and restoring the cell apoptosis. Further mechanism investigations indicated that the radioprotective effects of the novel derivatives were largely associated with modulating the expression of apoptotic proteins including cIAP-1, cIAP-2, cytochrome c, caspase-3 and caspase-9. Based on the experimental result, we disclosed that the novel NITR spin-labeled RES derivatives exhibit the potential to be used as the novel radioprotective candidates to ameliorate the injury induced by ionizing radiation.

When ionizing radiations are exposed to humans, numerous deleterious health effects including cancer may occur. Recently, radioprotective agents with a novel mode of action have drawn strong interest. Radioprotective agents are able to palliate, to prevent, or to handle radio-induced side-effects. In this study, in the parliamentary procedure to investigate the radioprotective effects of some pharmacological compounds, we have estimated the effective atomic number (Z eff ) and electron density (N e ) of six analgesic and anti-inflammatory drugs for total photon interaction in the energy range of 1 keV–100 MeV using WinXCom. In addition, and by Geometric-Progression (G-P) method, the energy absorption (EABF) and exposure buildup factors (EBF) for incident photon energy 0.015 MeV to 15 MeV up to penetration depths of 40 mean free paths (mfp) were estimated. It has been observed that EABF and EBF posses maximum values in the intermediate energy region, where Compton scattering is the dominant photon interaction process. Among the selected compounds, Etodolac (ET) has the largest EABF and EBF, while the minimal values of EABF and EBF were recorded for Meloxicam (ME). The present work could be useful to develop novel pharmacological compounds used in radioprotection, medical diagnostics, and radiation therapy.

The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.

Protection of normal tissues against ionizing radiation-induced damages is a critical issue in clinical and environmental radiobiology. One of the ways of accomplishing radiation protection is through the use of radioprotectors. In the search for the most effective radioprotective agent, factors such as toxicity, effect on tumors, number of tissues protected, ease of administration, long-term stability, and compatibility with other drugs need to be assessed. Thus, in the present study, we systematically review existing studies on a chemical radioprotector, Ex-RAD, with the aim of examining its efficacy of radiation protection as well as underlying mechanisms. To this end, a systematic search of the electronic databases including Pubmed, Scopus, Embase, and Google Scholar was conducted to retrieve articles investigating the radioprotective effect of Ex-RAD. From an initial search of 268 articles, and after removal of duplicates as well as applying the predetermined inclusion and exclusion criteria, 10 articles were finally included for this systematic review. Findings from the reviewed studies indicated that Ex-RAD showed potentials for effective radioprotection of the studied organs with no side effect. Furthermore, the inhibition of apoptosis through p53 signaling pathway was the main mechanism of radioprotection by Ex-RAD. However, its radioprotective effect would need to be investigated for more organs in future studies.

Background and objectives: Ionizing radiation (IR) has been of immense benefit to man, especially for medical purposes (diagnostic imaging and radiotherapy). However, the risks of toxicity in healthy normal cells, leading to cellular damage as well as early and late side effects, have been major drawbacks. The aim of this study was to evaluate the radioprotective effect of hesperidin against IR-induced damage. Materials and Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were applied in reporting this study. A search was conducted using the electronic databases PubMed, Scopus, Embase, Google Scholar, and www.ClinicalTrials.gov for information about completed or ongoing clinical trials. Results: From our search results, 24 studies involving rats, mice, and cultured human and animal cells were included. An experimental case—control design was used in all studies. The studies showed that the administration of hesperidin reduced oxidative stress and inflammation in all investigated tissues. Furthermore, it increased 30-day and 60-day survival rates and protected against DNA damage. The best radioprotection was obtained when hesperidin was administered before irradiation. Conclusions: The results of the included studies support the antioxidant, anti-inflammatory, and antiapoptotic abilities of hesperidin as a potential radioprotective agent against IR-induced damage. We recommend future clinical trials for more insights.

The goal of this study was to develop novel radioprotective agents targeting the intrinsic apoptotic pathway and thus decreasing the radiation-induced damage. For that purpose, we designed, synthesized and analyzed ten new compounds based on the 1-(4-(2-hydroxyethyl)piperazin-1-yl)-3-phenoxypropan-2-ol leading structure. The cytotoxicity of the newly synthesized substances was tested in vitro on cell lines derived from different progenitor cells by WST-1 proliferation assay. MTT test was utilized to assess half-maximal inhibitory concentrations and maximum tolerated concentrations of novel compounds in A-549 cells. Screening for radioprotective properties was performed using flow-cytometry in MOLT-4 cells exposed to 60Co ionizing gamma radiation. Selected candidates underwent in vivo testing in C57Bl/6 J mice having a positive impact on their immunological status. In summary, we report here promising compounds with radioprotective effect in vivo.

The purpose of this study was to test the radioprotective effect of selenium in the bone microarchitecture of irradiated rats mandibles. Forty rats were separated into 4 groups with 10 animals: control group (CG), irradiated group (IG), sodium selenite group (SSG) and sodium selenite irradiated group (SSIG). A single dose of 0.8 mg/kg sodium selenite was administered intraperitoneally in the SSG and SSIG groups. One hour later, animals of IG and SSIG groups were irradiated with 15 Gy of x-rays. Forty days after radiation a bilateral extraction of the mandibular first molars was performed. After the extraction procedure, five rats were killed after fifteen days and others five after thirty days. Micro- computed tomography was used to evaluate cortical and trabecular bone of each rat. The mean and standard deviation of each bone microarchitecture parameter were analyzed using the statistical test of two-way Analysis of Variance (ANOVA). At 15 days, the bone volume presented higher values in the CG and SSG groups (p=0.001). The same groups presented statistically significant higher values when bone volume fraction (p

Although radiation therapy (RT) is a feasible treatment approach for early colorectal cancer, RT is considerably toxic to normal tissues due to the increased reactive oxygen species production, which can induce tissue damage. Ginseng, a natural antioxidant agent, exhibits the protective effects against ionizing radiation (IR)-induced damage in in vitro and in vivo models. The explosive puffing of ginseng has been investigated as a process to improve the efficacy of ginseng due to the resulting physicochemical changes in its functional components. In this study, we provided the evidence for promotion in the beneficial role of puffed ginseng extract (PGE) and associated mechanisms of action, in comparison with white ginseng extract (WGE), against IR-induced colorectal injury, using in vivo study on a mouse model. To study the role of PGE in preventing IR-induced damage, we examined colorectal injury and apoptotic changes in mice exposed to 137Cs at 8 Gy. High-performance liquid chromatography analysis showed that PGE had an increased total ginsenoside concentration with new generation of Rg3, Rg5, and Rk1, compared with the concentrations in WGE. Administering PGE, but not WGE, significantly ameliorated IR-induced colorectal cell death through negative regulation of apoptotic signaling pathways. These antiapoptotic effects of PGE were linked to the capacity to suppress the p53-mediated DNA damage response and NF-κB-mediated apoptotic signaling. Moreover, IR-induced oxidative stress in the colorectal epithelium was markedly reduced by PGE administration. Collectively, this study establishes a mechanism of action by which PGE counteracts IR-induced colorectal injury as a novel radioprotective agent.

Novel glucosyl flavonoids are developed by the addition of glucose to naturally occurring flavonoids. Flavonoids are known antioxidants that possess radioprotective properties. In order to investigate the radioprotective properties of novel glucosyl flavonoids, in vitro DNA double-strand breaks (DSBs) analysis was carried out. In the present study, Quercetin, Naringenin, and Hesperetin groups of flavonoids included in the natural and novel glucosyl 13 flavonoids were investigated. Flavonoids were mixed with Lambda DNA, and subsequently exposed to gamma‑rays. Furthermore, DNA DSB yields were visualized by gel electrophoresis. Quercetin derivatives displayed reduced DNA DSB formation at 10 µM. At a high concentration, the majority of flavonoids displayed radioprotective properties as a reduction of DSB yields. Suppression of DSB formation was confirmed via the molecular combing assay for Quercetin, and three monoglucosyl flavonoids. Glucosylation showed positive effects for radioprotection and monoglucosyl-Rutin showed superior radioprotective properties when compared to monoglucosyl-Naringin and Hesperidin. In addition, Quercetin derivatives had greater total antioxidant capacities and DPPH radical scavenging ability than other flavonoid groups. Since Quercetin, Isoquercetin, and Rutin display poor water solubility, monoglucosyl-Rutin, maltooligosyl-Isoquercetin, and maltooligosyl-Rutin may be better radioprotective agents and easily bioavailable with increased water solubility.

Providing protection from radiation damage is a great medical challenge. Metal-organic frameworks (MOFs) have high drug-loading capacities and excellent biocompatibility and are thus useful as drug-delivery systems. We fabricated a new drug carrier based on nanoscale MIL-101(Fe) to co-deliver two radioprotective agents by encapsulating WR-1065 (the active metabolite of amifostine) and glutathione (GSH). Consequently, the drug loading amounts of our drug carrier were 35.6 wt% and 6.5 wt% for WR-1065 and GSH, respectively. Moreover, radioprotective efficacy improved after PEGylation, which increased permeability and stability of these nanoparticles. In vitro studies showed that the MOF-based radioprotector had lower cytotoxicity compared with free WR-1065, and it increased cell viability by scavenging the accumulated reactive oxygen species and resisting DNA damage after irradiation. The MOF-based radioprotector—administered orally to mice—demonstrated efficacy at mitigating acute radiation syndrome; and its 30-d survival rate after lethal total body irradiation (TBI, 8 Gy) was 80%. The MOF-based radiation countermeasures led to significant improvements in peripheral blood cell count, hematopoietic stem and progenitor cells (HSPCs) frequency, and clonogenic function of hematopoietic progenitor cell. The ameliorated hematopoietic system injury in HSPCs is probably attributable to downregulation of BAX and BAK expression and upregulation of BCL-CL expression through the inhibition hematopoietic cell apoptosis. Therefore, the MOF-based radioprotectant has the potential to be used as a promising therapeutic candidate to attenuate TBI-induced hematopoietic injury.

microRNAs (miRNAs) constitute a large class of post-transcriptional regulators of gene expression. It has been estimated that miRNAs regulate up to 30% of the protein-coding genes in humans. They are implicated in many physiological and pathological processes, including those involved in radiation-induced heart damage. Biomedical studies indicate that molecular hydrogen has potential as a radioprotective agent due to its antioxidant, anti-inflammatory, and signal-modulating effects. However, the impact of molecular hydrogen on the expression of miRNAs in the heart after irradiation has not been investigated. This study aimed to explore the involvement of miRNA-1, -15b, and -21 in the protective action of molecular hydrogen on rat myocardium damaged by irradiation. The results showed that the levels of malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) increased in the rat myocardium after irradiation. Treatment with molecular hydrogen-rich water (HRW) reduced these values to the level of non-irradiated controls. miRNA-1 is known to be involved in cardiac hypertrophy, and was significantly decreased in the rat myocardium after irradiation. Application of HRW attenuated this decrease in all evaluated time periods. miRNA-15b is considered to be anti-fibrotic, anti-hypertrophic, and anti-oxidative. Irradiation downregulated miRNA-15b, whereas administration of HRW restored these values. miRNA-21 is connected with cardiac fibrosis. We observed significant increase in miRNA-21 expression in the irradiated rat hearts. Molecular hydrogen lowered myocardial miRNA-21 levels after irradiation. This study revealed for the first time that the protective effects of molecular hydrogen on irradiation-induced heart damage may be mediated by regulating miRNA-1, -15b, and -21.

Monoterpenes are major active components of lavender, thyme, and mint. The X-ray radioprotective activity of pure monoterpenes is attributed to their scavenging ability against active species, but so far no firm evidence has been demonstrated. The objective of this study is to quantitatively determine antioxidant abilities of monoterpenes and collate it with radioprotective activity. Using multiple free-radical scavenging (MULTIS) method, we have determined the scavenging abilities of monoterpenes (linalool, thymol, and menthol) against six active species. A previous study has shown that the monoterpene linalool is a radioprotector for cellular systems, therefore, its scavenging ability was compared with known radioprotective agents such as cysteamine and amifostine. Results indicated that the monoterpene menthol but not linalool is a potent scavenger of reactive oxygen species and its scavenging magnitude is comparable to cysteamine and amifostine. This paper is first to show a correlation between ROS scavenging ability and radioprotective action.

3,3′ Diseleno dipropionic acid (DSePA), a synthetic compound has been shown to have radioprotective activity, especially as a lung radioprotector. In this study, the pharmacokinetics and biodistribution of DSePA in MX-1 tumour bearing SCID mice were evaluated. Twenty SCID mice were administered DSePA (50 mg/kg bodyweight) by oral gavage following which four animals each were sacrificed at 15, 30 min, 1, 2 and 4 h. Blood and tissue samples were collected for determination of DSePA concentration by graphite furnace atomic absorption spectrometry (GFAAS) method. The control group (n = 4) was administered sterile water and sacrificed at 4 h. Peak plasma concentration (C max) of 2.7 µg/ml was observed at 15 min which returned to near baseline (baseline = 0.6 µg/ml) at 1 h following drug administration. Biphasic pharmacokinetics characterized by rapid distribution phase and a slower elimination phase were observed. Highest maximal concentration (C max) of the drug was observed in lung (19.2 µg/g at 30 min) followed by intestine (14.64 µg/g at 15 min) and kidney (12.96 µg/g at 15 min). There was negligible uptake in tumor tissue and no uptake in brain. DSePA has a favorable pharmacokinetic profile which makes it a potentially good candidate for further development as a radioprotective agent.

Radioprotective action of gossypetin (GTIN) against gamma (γ)-radiation-induced oxidative stress in liver was explored in the present article. Our main aim was to evaluate the protective efficacy of GTIN against radiation-induced alteration of liver in murine system. To evaluate the effect of GTIN, it was orally administered to mice at a dose of 30 mg/kg body weight for three consecutive days prior to γ-radiation at a dose of 5 Gy. Radioprotective efficacy of GTIN were evaluated at physiological, cellular, and molecular level using biochemical analysis, comet assay, flow cytometry, histopathology, immunofluorescence, and immunoblotting techniques. Ionizing radiation was responsible for augmentation of hepatic oxidative stress in terms of lipid peroxidation and depletion of endogenous antioxidant enzymes. Immunoblotting and immunofluorescence studies showed that irradiation enhanced the nuclear translocation of nuclear factor kappa B (NF-κB) level, which leads to hepatic inflammation. To investigate further, we found that radiation induced the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK)-mediated apoptotic pathway and deactivation of the NF-E2-related factor 2 (Nrf2)-mediated redox signaling pathway, whereas GTIN pretreatment ameliorated these radiation-mediated effects. This is the novel report where GTIN rationally validated the molecular mechanism in terms of the modulation of cellular signaling system’ instead of ‘ This is the novel report where GTIN is rationally validated in molecular terms to establish it as promising radioprotective agents. This might be fruitful especially for nuclear workers and defense personnel assuming the possibility of radiation exposure.

The immune system is specifically sensitive to oxidative stress induced by ionizing radiation because of its rapid proliferative activity. For this reason, an instructive immune system is one of the best ways to minimize side effects, such immunodeficiency, of gamma radiation. Over the past few decades, several natural plants with antioxidant and immunomodulatory properties have been identified as adjuncts for nontoxic and successful radiotherapy. Hizikia fusiforme extract (HFE) containing plentiful dietary fiber and fucoidan is known for its instructive antioxidant capacity, immunomodulation abilities, and immune activation. In this study, we determined whether HFE protects radiosensitive immune cells from gamma radiation-induced damage. C57BL/6 mice were irradiated with gamma-ray. The effect of HFE on the ionizing radiation damage of immune cells was then evaluated with an MTT assay, 3H-thymidine incorporation assay, and PI staining. We found that HFE stimulated the proliferation of gamma-ray irradiated immune cells without cytotoxic effects. We also observed that HFE not only decreased DNA damage but also reduced gamma radiation-induced apoptosis of the immune cells. Our results suggest that HFE can protect immune cells from gamma-ray damage and may serve as an effective, non-toxic radioprotective agent.

Cytoprotective compounds such as amifostine play an important role in chemo- and radiotherapy due to their ability to reduce the side effects of these treatments. Our work was initiated with the intention to design, synthesise and test a new class of heterocyclic compounds that would have an antioxidative profile with the potential to be further developed as cytoprotective agents. The design was based on the privileged tetrahydrobenzazepine scaffold found in many natural products with a wide range of biological properties. This structure was further functionalised with moieties known to possess antioxidative features such as tertiary amine and styrene double bond. A series of eight tetrahydrobenzazepine derivatives of isoquinoline, 3,4-dihydro-β-carboline and pyridine were synthesised employing the Heck reaction as a key transformation. Some of the prepared compounds were tested for their in vitro effects on chromosome aberrations in peripheral human lymphocytes using the cytochalasin-B blocked micronucleus (MN) assay. Three tetrahydrobenzoazepine derivatives showed significant cytoprotective properties, comparable or even better to those of the radioprotective agent amifostine.

Medical imaging has become a central component of patient care to ensure early and accurate diagnosis. Unfortunately, many imaging modalities use ionizing radiation to generate images. Ionizing radiation even in low doses can cause direct DNA damage and generate reactive oxygen species and free radicals, leading to DNA, protein, and lipid membrane damage. This cell damage can lead to apoptosis, necrosis, teratogenesis, or carcinogenesis. As many as 2% of cancers (and an associated 15,000 deaths annually) can be linked to computed tomography exposure alone. Radioprotective agents have been investigated using various models including cells, animals, and recently humans. The data suggest that radioprotective agents working through a variety of mechanisms have the potential to decrease free radical damage produced by ionizing radiation. Radioprotective agents may be useful as an adjunct to medical imaging to reduced patient morbidity and mortality due to ionizing radiation exposure. Some radioprotective agents can be found in high quantities in antioxidant rich foods, suggesting that a specific diet recommendation could be beneficial in radioprotection.