Effective Radioprotective Agent Research Articles

Radioprotective activity of the liposomal composition of quercetin in acute radiation syndrome (experimental study)

Background. The targeted search for new effective radioprotective agents, especially among compounds with antioxidant properties, remains relevant. Among them, quercetin which has a high specific activity against oxidative stress (cited as a «universal antioxidant») deserves attention. The transport liposomal composition of quercetin, which significantly improves its bioavailability and is the basis of the licensed drug «Lipoflavon®» (LF), is known, but the radioprotective properties of this drug have not been studied. The purpose of the work is to position Lipoflavon as a radioprotector for the first time based on the study of radioprotective activity in an acute experiment with total irradiation of rats. Materials and methods. The rat model of acute radiation syndrome (ARS) was carried out by short-term bilateral total body irradiation (TBI) on a CLINAC (6 MeV) linear accelerator at doses of 5.5 and 7.0 Gy. The control rats were sham-irradiated. The test sample of LF was used for the studies. LF (1.5 mg/mL) was administered to rats 30 min before TBI through the tail vein. The control TBI rats were injected with physiological saline. Experimental rats were randomly assigned into groups as follows: group 1 – non-irradiated control (intact animals); group 2 – irradiated control at a dose of 5.5 Gy (TBI5.5); group 3 – irradiation at a dose of 5.5 Gy with administration of LF (LF + TBI5.5); group 4 – irradiated control at a dose of 7.0 Gy (TBI7.0); group 5 – irradiation at a dose of 7.0 Gy with administration of LF (LF + TBI7.0). Clinical characteristics of ARS, overall survival, and the mean survival time of the dead animals were determined. The profiles of lethality («peaks of death») were calculated as total rat lethality (%) in certain time periods of the ARS. In hematological studies, LF was administered 24 h prior to TBI and twice a week the next 4 weeks after TBI. The hematological parameters were monitored on days 3, 7, 14 and 21 after TBI. Results. It was established that prophylactic LF administered 30 min before TBI at doses of 5.5 and 7.0 Gy, which were LD20/30 and DL73.3/30, increased the 30-day survival rate of the irradiated rats to 90 and 40% respectively, compared to 80 and 26.7% in irradiated control, and changed the radiation lethality profile of the rats in the model of ARS. The radioprotective activity of LF manifested in the form of the absence of early and late peaks of death of the irradiated rats and the survival time of more than 30 days after the treatment in 40% of rats with LD73,3/30. Prophylactic and therapeutic administration of LF prevented development of severe leukopenia and thrombocytopenia and contributed to a more rapid and sustained recovery of erythrocytes during the period of ARS. The most efficient radioprotective therapeutic effect of LF was observed in rats with a dose of LD73.3/30. Conclusions. The results of the study substantiate the radioprotective activity of Lipoflavon in ARS and help develop the new approaches to using the licensed drug «Lipoflavon®» as an effective pharmacological therapeutic agent for radiation protection in acute radiation.

Radioprotective effect of polyvinylpyrrolidone modified selenium nanoparticles and its antioxidation mechanism in vitro and in vivo.

Polyvinylpyrrolidone (PVP) is a commonly used biomedical polymer material with good water solubility, biocompatibility, low immunogenicity, and low toxicity. The aim of this study is to investigate the antioxidant mechanism and clinical potential of PVP modified selenium nanoparticles (PVP-Se NPs) as a new radioprotective agent. A laser particle size analyzer and transmission electron microscope were used to characterize PVP-Se nanoparticles prepared by chemical reduction. Human umbilical vein endothelial cells (HUVECs) were used to evaluate the radiation protective effects of PVP-Se NPs. SD rats were employed as an in vivo model to identify the most effective concentration of PVP-Se NPs and assess their potential radioprotective properties. Western blot (WB) was used to detect the expression of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling proteins in human umbilical vein endothelial cells (HUVECs) and rat liver and kidney tissues. PVP-Se NPs could reduce the oxidative stress injury and inflammatory response caused by X-ray irradiation in HUVECs and rats, and inhibit cell apoptosis by modulating NF-κB and MAPK signaling pathways. PVP-Se NPs could increase HUVECs viability, reduce apoptosis, inhibit inflammatory factors IL-1β, IL-6 and TNF-α, improve the survival rate of rats, promote antioxidant enzyme activities in cells and rats, reduce malondialdehyde concentration in serum, and reduce the expression of inflammatory factors such as IL-1β, IL-6 and TNF-α in cell supernatant and liver and kidney tissues. PVP-Se NPs could significantly reduce the phosphorylation levels of NF-κB and MAPK pathway-associated proteins in HUVECs and rat liver and kidney tissues (p < 0.05). PVP-Se NPs can protect against radiation-induced oxidative damage by modulating NF-kB and MAPK pathways, providing a theoretical basis and experimental data for their use as an effective radioprotective agent.

Mitochondria-Targeted Nitronyl Nitroxide Radical Nanoparticles for Protection against Radiation-Induced Damage with Antioxidant Effects.

Radiotherapy is a non-invasive method that is widely applied to treat and alleviate cancers. However, radiation-induced effects in the immune system are associated with several side effects via an increase in oxidative stress and the inflammatory response. Therefore, it is imperative to develop effective clinical radiological protection strategies for the radiological protection of the normal organs and immune system in these patients. To explore more effective radioprotective agents with minimal toxicity, a mitochondria-targeted nitronyl nitroxide radical with a triphenylphosphine ion (TPP-NIT) was synthesized and its nanoparticles (NPs-TPP-NIT) were prepared and characterized. The TPP-NIT nanoparticles (NPs-TPP-NIT) were narrow in their size distribution and uniformly distributed; they showed good drug encapsulation efficiency and a low hemolysis rate (<3%). The protective effect of NPs-TPP-NIT against X-ray irradiation-induced oxidative damage was measured in vitro and in vivo. The results show that NPs-TPP-NIT were associated with no obvious cytotoxicity to L-02 cells when the concentration was below 1.5 × 10-2 mmol. NPs-TPP-NIT enhanced the survival rate of L-02 cells significantly under 2, 4, 6, and 8 Gy X-ray radiation exposure; the survival rate of mice was highest after 6 Gy X-ray irradiation. The results also show that NPs-TPP-NIT could increase superoxide dismutase (SOD) activity and decrease malondialdehyde (MDA) levels after the L-02 cells were exposed to 6.0 Gy of X-ray radiation. Moreover, NPs-TPP-NIT could significantly inhibit cell apoptosis. NPs-TPP-NIT significantly increased the mouse survival rate after irradiation. NPs-TPP-NIT displayed a marked ability to reduce the irradiation-induced depletion of red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). These results demonstrate the feasibility of using NPs-TPP-NIT to provide protection from radiation-induced damage. In conclusion, this study revealed that NPs-TPP-NIT may be promising radioprotectors and could therefore be applied to protect healthy tissues and organs from radiation during the treatment of cancer with radiotherapy.

Astragalus polysaccharide promotes the regeneration of intestinal stem cells through HIF-1 signalling pathway.

Ionizing radiation (IR)-induced intestinal injury is usually accompanied by high lethality. Intestinal stem cells (ISCs) are critical and responsible for the regeneration of the damaged intestine. Astragalus polysaccharide (APS), one of the main active ingredients of Astragalus membranaceus (AM), has a variety of biological functions. This study was aimed to investigate the potential effects of APS on IR-induced intestine injury via promoting the regeneration of ISCs. We have established models of IR-induced intestinal injury and our results showed that APS played great radioprotective effects on the intestine. APS improved the survival rate of irradiated mice, reversed the radiation damage of intestinal tissue, increased the survival rate of intestinal crypts, the number of ISCs and the expression of intestinal tight junction-related proteins after IR. Moreover, APS promoted the cell viability while inhibited the apoptosis of MODE-K. Through organoid experiments, we found that APS promoted the regeneration of ISCs. Remarkably, the results of network pharmacology, RNA sequencing and RT-PCR assays showed that APS significantly upregulated the HIF-1 signalling pathway, and HIF-1 inhibitor destroyed the radioprotection of APS. Our findings suggested that APS promotes the regeneration of ISCs through HIF-1 signalling pathway, and it may be an effective radioprotective agent for IR-induced intestinal injury.

Exploring Natural Products as Radioprotective Agents for Cancer Therapy: Mechanisms, Challenges, and Opportunities.

Radiotherapy is an important cancer treatment. However, in addition to killing tumor cells, radiotherapy causes damage to the surrounding cells and is toxic to normal tissues. Therefore, an effective radioprotective agent that prevents the deleterious effects of ionizing radiation is required. Numerous synthetic substances have been shown to have clear radioprotective effects. However, most of these have not been translated for use in clinical applications due to their high toxicity and side effects. Many medicinal plants have been shown to exhibit various biological activities, including antioxidant, anti-inflammatory, and anticancer activities. In recent years, new agents obtained from natural products have been investigated by radioprotection researchers, due to their abundance of sources, high efficiency, and low toxicity. In this review, we summarize the mechanisms underlying the radioprotective effects of natural products, including ROS scavenging, promotion of DNA damage repair, anti-inflammatory effects, and the inhibition of cell death signaling pathways. In addition, we systematically review natural products with radioprotective properties, including polyphenols, polysaccharides, alkaloids, and saponins. Specifically, we discuss the polyphenols apigenin, genistein, epigallocatechin gallate, quercetin, resveratrol, and curcumin; the polysaccharides astragalus, schisandra, and Hohenbuehelia serotina; the saponins ginsenosides and acanthopanax senticosus; and the alkaloids matrine, ligustrazine, and β-carboline. However, further optimization through structural modification, improved extraction and purification methods, and clinical trials are needed before clinical translation. With a deeper understanding of the radioprotective mechanisms involved and the development of high-throughput screening methods, natural products could become promising novel radioprotective agents.

Effectiveness of oral famotidine in reducing the hematologic complications of radiotherapy in patients with esophageal and cardia cancers: a randomized controlled trial

BackgroundChemoradiotherapy complications has always been of great concern to both clinicians and patients during the course of treatment. The purpose of the present study was to examine the effectiveness of oral famotidine on the reduction of hematologic complications of patients with esophageal and gastric cardia cancers undergoing radiotherapy.MethodsA single-blind controlled trial was conducted on 60 patients with esophageal and cardia cancers, who were undergoing chemoradiotherapy. Patients were randomly assigned to 2 groups with 30 patients to receive either 40 mg of oral famotidine (daily and 4 h before each session) or placebo. Complete blood count with differential, platelet counts, and hemoglobin levels were obtained weekly during treatment. The main outcome variables were lymphocytopenia, granulocytopenia, thrombocytopenia, and anemia.ResultsThe findings indicated a significant effect of famotidine on reduction of thrombocytopenia among intervention group compared to control group (P < 0.0001). Even so, the effect of intervention was not significant for other outcome variables (All, P ≥ 0.05). The lymphocyte (P = 0.007) and platelet (P = 0.004) counts were also significantly greater in famotidine group in comparison with placebo group at the end of the study.ConclusionAs evidenced by the findings of the current study, famotidine might be recommended as an effective radioprotective agent among patients with esophageal and gastric cardia cancers to prevent Leukocyte and platelet reduction to some extent.Trial registration This study was prospectively registered at irct.ir (Iranian Registry of Clinical Trials) with the code IRCT20170728035349N1, 2020-08-19.

Radioprotective effect of Malva sylvestris L. against radiation-induced liver, kidney and intestine damages in rat: A histopathological study

BackgroundIonizing radiation (IR) is widely used in the treatment of cancer in radiotherapy. One of the main concerns of patients with gastrointestinal cancers undergoing radiotherapy is the harmful side effects of IR on normal tissues. The liver, kidney, and duodenum are usually exposed to high doses of radiation in the treatment of some cancers in abdominal region radiotherapy. We aimed to assess the radioprotective effects of Malva sylvestris L. against IR damages to the abdominal region. Materials and methodsThis current study was conducted on 45 rats divided randomly into nine groups of five: A) negative control group, B) sham group, C) irradiation group, D) mallow treatment-1(200gr/kg), E) mallow treatment-2(400gr/kg), F) mallow treatment-3(600gr/kg), G) mallow treatment-4(200gr/kg) plus irradiation, H) mallow treatment-5(400gr/kg) plus irradiation, I) mallow treatment-6(600gr/kg) plus irradiation. Irradiation was performed with a 6Gy x-ray. Histopathological evaluations were performed 10 days after irradiation. ResultsThe histopathological examination results confirmed that preventive therapy with the effective dose of mallow reduced the liver, kidney, and intestine damage induced by radiation. The dose of 400 mg/kg was more effective than other selected dose in improving the damage caused by irradiation in the studied tissues. ConclusionThis study concludes that Malva sylvestris L. contributed to significant improvements in radiation-induced histological parameters of the liver and kidney and, to a lesser extent, in the intestine. These results collectively indicate that mallow is an effective radioprotective agent.

Herbal Radioprotectors: A mini-review of the Current Status

Because of our increased dependency on the use of radiation in areas such as the food industry, agriculture, space exploration, diagnostics and treatment of various diseases including cancer, the possibilities of unnecessary exposure to ionizing radiation have considerably increased. Hence, there is a need to develop an effective radioprotective agent that can protect against the deleterious effects of ionizing radiation. So far, many synthetic and natural substances studied for use as radioprotectors have failed to reach clinics. Natural compounds are becoming more popular in radiation research due to their low toxicity, higher efficacy and cost-effectiveness. Plants and herbs contain a plethora of bioactive compounds having antioxidants, anti-inflammatory and immunostimulant properties which can act either in isolation or in combination to protect against the harmful effects of ionizing radiation This review mainly focuses on the radioprotective potential of various herbs and plants. The results obtained from various herbal extracts have shown protection against radiation-induced injuries in preclinical studies. This evaluation may help develop a potent radioprotector of desired efficacy.

Antioxidant Nanomedicine Significantly Enhances the Survival Benefit of Radiation Cancer Therapy by Mitigating Oxidative Stress-Induced Side Effects.

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.

Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.

Radiation protection by Ex-RAD: a systematic review.

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.

Protective Effect of Asiaticoside on Radiation-induced Proliferation Inhibition and DNA Damage of Fibroblasts and Mice Death.

BackgroundRadiation-induced injuries (RII) mainly result from reactive oxygen species (ROS), which are harmful compounds that can damage DNA. Asiaticoside (AC), one of the main functional components extracted from Centella asiatica, has potent pharmacological effects such as anti-inflammatory and anti-oxidant activity. However, its role in RII remains unclear.PurposeThe purpose of the current study is to investigate whether AC can mitigate RII in vitro and in vivo.Material and MethodsCell model of RII was successfully established by 5J/m2 radiation in vitro. For the in vivo RII model, mice were irradiated with 5 Gy to the thorax. The degree of damage to cells or mouse tissue was determined by measuring the numbers of DNA double-strand breaks (DSBs), oxidative stress, and mouse survival rates.ResultsIn the in vitro assay, AC administration significantly reduced radiation-induced growth inhibition of Escherichia coli and fibroblasts, DSBs and apoptosis of fibroblasts; in the in vivo study, AC could decrease antioxidant capacity (T-AOC) of plasma and protect mice from RII, thereby improving the survival rates of mice after radiation.ConclusionsThese novel data indicate that AC is able to prevent radiation-initiated genotoxicity by mitigating DNA damage, and might serve as a safe and effective radio-protective agent.

INVESTIGATION OF THE RADIOPROTECTIVE EFFECT OF ORTHOVANADATE IN MICE AFTER TOTAL BODY IRRADIATION.

The increasing risk of acute large-scale exposure of ionising irradiation on the population underlines the necessity of developing effective radioprotective and mitigating agents. The aim of this work was to investigate the effect of sodium orthovanadate pre-treatment on mice exposed to high doses of gamma rays (from 5 to 13Gy). The determination of median lethal dose within 30days confirmed that orthovanadate applied to total-body-irradiated mice intra-peritoneally has a radioprotective but not a mitigating effect. With orthovanadate pre-treatment, the composition of cellularity in the bone marrow improved substantially and the main lymphocyte populations restored during the first month after irradiation. These findings contribute to 'gap-filling' in radioprotective effects and demonstrate the importance of haematological parameters in radiation-response prediction.

Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: Emphasis on TGF-β/MAPKs signaling pathway

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-β protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-β/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.

Ferulic acid protects against radiation-induced testicular damage in male rats: impact on SIRT1 and PARP1.

Ionizing radiation is a major contributor to male infertility by destroying spermatogenesis. Therefore, the need for an effective radio-protective agent is evident. The objective of the present study was to investigate the potential radio-protective effect of ferulic acid (FA) on radiation-induced testicular damage. Mature male Sprague-Dawley rats were either exposed to a single-dose gamma radiation (5Gy) and/or treated with FA (50mg/kg), daily for 7days before irradiation. Sirtuin1 (SIRT1), poly (ADP-ribose) polymerase 1 (PARP1), cytosolic calcium content, and the male reproductive functions (sperm head abnormality) as well as oxidative stress markers were assessed 7days after irradiation. FA significantly maintained active spermatogenesis. Moreover, it reversed the oxidative stress effects of irradiation. The irradiated group showed marked elevation in both PARP1 expression and activity as well as in cytosolic calcium concentration, whereas SIRT1 activity and expression markedly decreased; in contrast, FA treatment prevented these alterations. Results of histopathological examination of testicular tissues indicated coincidence with those recorded by biochemical analyses. Our data show for the first time that FA had radio-protective effect against radiation-induced testicular damage. It improved spermatogenesis through increasing testicular SIRT1 and testosterone levels and decreasing oxidative stress, PARP1, and cytosolic calcium.

A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice.

Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application.

Novel regenerative peptide TP508 mitigates radiation-induced gastrointestinal damage by activating stem cells and preserving crypt integrity

In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin) 24 h after lethal radiation exposure (9 Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post exposure prevents the disintegration of GI crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also upregulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24 h post exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment.

Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis.

Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.

Flavonoids of Rosa roxburghii Tratt act as radioprotectors.

To study the radioprotective effects of flavonoids from Rosa roxburghii Tratt (FRT). The radioprotective effects of FRT were investigated by examining cell viability, 30-day survival of mice and the number of colony-forming units in spleen (CFU-S) after total-body 60Co irradiation. The survival rates of irradiated cells gradually increased with increasing concentrations of FRT. The survival rate was the highest at 87% with a concentration of 30 μg/mL. Pretreatment with FRT was needed to realize its radioprotective activity in mice at the dose of 60 mg/kg. With the increasing doses of 30 mg/kg, 60 mg/kg and 120 mg/kg, the numbers of CFU-S increased, and were significantly different compared with the control group. Pretreatment with FRT prior to irradiation resulted in significantly higher cell survival at 24 h after 5 Gy radiation, increased 30-day survival in mice after exposure to a potentially lethal dose of 8 Gy, and resulted in a higher number of CFU-S in mice after exposure to a dose of 6 Gy. These results collectively indicate that FRT is an effective radioprotective agent.

Amentoflavone acts as a radioprotector for irradiated v79 cells by regulating reactive oxygen species (ROS), cell cycle and mitochondrial mass.

Radioprotective effects of amentoflavone were investigated by examining cell viability, apoptosis, cell cycling concentrations of intracellular ROS (reactive oxygen species), and relative mitochondrial mass by flow cytometry after 60Co irradiation. Pretreatment with amentoflavone 24 hours prior to 8 Gy 60Co γ-ray irradiation significantly inhibited apoptosis, promoted the G2 phase, decreased the concentration of ROS and mitochondrial mass. These results collectively indicate that amentoflavone is an effective radioprotective agent.