Potential utility of peptides against damage induced by ionizing radiation.

Radioprotection is the process whereby biological systems are aided against undesirable radiation hazards. Primitive radioprotectors suffered from either having crucial side effects or low efficacy in clinical applications. Therefore, the search for less toxic but more capable radioprotectants has continued for decades. Peptides have been investigated as radioprotectants in a variety of preclinical models both in vitro and in vivo. Peptides exert their influence through scavenging free radicals, modifying cell signaling and inhibiting cell apoptosis. Demonstrating potential in vivo properties, peptide radiation countermeasures might find enough credit for use in humans in the future. This article reviews the potential therapeutic value of currently known radioprotective peptides and attempts to provide a comprehensive source for further scientific research in this area.

Radioprotective Agents: Strategies and Translational Advances.

Radioprotectors are agents required to protect biological system exposed to radiation, either naturally or through radiation leakage, and they protect normal cells from radiation injury in cancer patients undergoing radiotherapy. It is imperative to study radioprotectors and their mechanism of action comprehensively, looking at their potential therapeutic applications. This review intimately chronicles the rich intellectual, pharmacological story of natural and synthetic radioprotectors. A continuous effort is going on by researchers to develop clinically promising radioprotective agents. In this article, for the first time we have discussed the impact of radioprotectors on different signaling pathways in cells, which will create a basis for scientific community working in this area to develop novel molecules with better therapeutic efficacy. The bright future of exceptionally noncytotoxic derivatives of bisbenzimidazoles is also described as radiomodulators. Amifostine, an effective radioprotectant, has been approved by the FDA for limited clinical use. However, due to its adverse side effects, it is not routinely used clinically. Recently, CBLB502 and several analog of a peptide are under clinical trial and showed high success against radiotherapy in cancer. This article reviews the different types of radioprotective agents with emphasis on the strategies for the development of novel radioprotectors for drug development. In addition, direction for future strategies relevant to the development of radioprotectors is also addressed.

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

BACKGROUND: Chemoradiotherapy 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: As 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.

Repurposing of Various Current Medicines as Radioprotective Agents.

BACKGROUND: The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in radiotherapy for cancer treatment. These radiations can cause damage to the cell membrane, lipids, proteins, and DNA and generate free radicals. Evidence reports stated that radiotherapy accounts for 17-19% of secondary malignancies, labelling this treatment option a double-edged sword. OBJECTIVE: Radioprotective molecules are used for mitigating radiotherapy's side effects. These agents show free radical scavenging, antioxidant, collagen synthesis inhibition, protease inhibition, immune stimulation, increased cytokine production, electron transfer, and toxicity reduction properties. The most frequently used amifostine has an array of cancer applications, showing multitarget action as nephroprotective to cisplatin and reducing the chances of xerostomia. Many other agents, such as metformin, edaravone, mercaptopropionylglycine, in specific diseases, such as diabetes, cerebral infarction, cystinuria, have shown radioprotective action. This article will discuss potentially repurposed radioprotectors that can be used in the clinical setting, along with a brief discussion on specific synthetic agents like amifostine and PrC-210. METHODS: Rigorous literature search using various electronic databases, such as PubMed, ScienceDirect, Scopus, EMBASE, Bentham Science, Cochrane Library, etc., was made. Peer-review research and review papers were selected, studied, reviewed, and analysed. CONCLUSION: Safety and risk-free treatment can be guaranteed with the repurposed agents. Agents like metformin, captopril, nifedipine, simvastatin, and various others have shown potent radioprotective action in various studies. This review compiled repurposed synthetic radioprotective agents.

Mechanisms of radiation-induced endothelium damage: Emerging models and technologies.

Radiation-induced endothelial/vascular injury is a major complicating factor in radiotherapy and a leading cause of morbidity and mortality in nuclear or radiological catastrophes. Exposure of tissue to ionizing radiation (IR) leads to the release of oxygen radicals and proteases that result in loss of endothelial barrier function and leukocyte dysfunction leading to tissue injury and organ damage. Microvascular endothelial cells are particularly sensitive to IR and radiation-induced alterations in endothelial cell function are thought to be a critical factor in organ damage through endothelial cell activation, enhanced leukocyte-endothelial cell interactions, increased barrier permeability and initiation of apoptotic pathways. These radiation-induced inflammatory responses are important in early and late radiation pathologies in various organs. A better understanding of mechanisms of radiation-induced endothelium dysfunction is therefore vital, as radiobiological response of endothelium is of major importance for medical management and therapeutic development for radiation injuries. In this review, we summarize the current knowledge of cellular and molecular mechanisms of radiation-induced endothelium damage and their impact on early and late radiation injury. Furthermore, we review established and emerging in vivo and in vitro models that have been developed to study the mechanisms of radiation-induced endothelium damage and to design, develop and rapidly screen therapeutics for treatment of radiation-induced vascular damage. Currently there are no specific therapeutics available to protect against radiation-induced loss of endothelial barrier function, leukocyte dysfunction and resulting organ damage. Developing therapeutics to prevent endothelium dysfunction and normal tissue damage during radiotherapy can serve as the urgently needed medical countermeasures.

Radioprotectors: Nature's Boon.

BACKGROUND: Major approach in controlling as well as eradicating the cancerous growth is through radiotherapy, but this treatment leads to toxicity in the normal cells, leading to secondary malignancies, teratogenesis, and necrosis. More than 15,000 malignancies occur due to exposure to harmful radiations during computed tomography scans. Natural products are non-toxic; there have been reports that herbal products, when given along with radiation, have shown increased tumor control property. The discussed agents in this review have potential antioxidant, immunomodulatory, free radical scavenging, metal chelating, and anti-inflammatory properties. OBJECTIVE: To reduce the chances of toxicity, reduction in radiation dose or reducing the frequency of the therapy is made which usually leads to a therapeutically poor outcome. The most feasible method is to protect the normal cells by administration of radioprotective agents either before or after the exposure. These agents have been tested on animals and human cell models for evaluating their safety window and toxicity profile at the cellular level. The study aims to compile the effective natural radioprotective agents available, which can be further exploited by using certain QSAR studies to increase their potency. METHOD: Structured literature search from EMBASE, PubMed, Bentham Science, Scopus, and ScienceDirect was carried out and appropriate peer-reviewed review articles, as well as certain research articles, were included and compiled in this review paper. CONCLUSION: As various studies have indicated the harmful effects of ionizing radiations on normal cells, to reduce these effects, radioprotective agents are used before or after exposure to radiations. Compounds derived from natural sources are proved to have few side effects and they possess radioprotective property due to the presence of alkaloids, resins, volatile oils, tannins in their molecular structure. Various plants having such radioprotective constitutes have been identified for their radioprotective action and compiled in the present study.

Grape seed extract alleviates radiation-induced damages in human blood lymphocytes.

OBJECTIVE: Ionizing radiation induces deleterious effects in the biological systems by producing free radicals. Grape Seed Extract (GSE) as a free radical scavenger could protect the body against the damages. MATERIALS AND METHODS: In this study, 12 healthy male volunteers were divided into Groups 1, 2, 3 and 4 and received 100, 300, 600 and 1000 mg GSE, respectively. Peripheral blood samples were collected from each volunteer 15 min before, and 1, 2, and 5 hr after GSE oral administration. Blood samples were then irradiated with 150 cGy of 100 kvp X-ray (Irradiated control group, was treated with only 1.5 Gy of X-rays). Cytogenic damages were detected by micronucleus assay. RESULTS: Results showed that irradiation significantly increased the incidence of micronuclei (p<0. 001). In group 1, the mean reduction of micronucleus rate was 26.53%, 34.92%, and 31.38%, 1, 2, and 5 hr after GSE ingestion (p<0.001), respectively; this variable in group 2 was 17.38, 38.33, and 31.38 (p<0. 001), in group 3, was 35.65%, 46%, and 37.15% (p<0.001), respectively and in group 4, was 41.35%, 51.73%, and 50.55% (p<0.0001), respectively. The samples collected 1, 2, and 5 hr after ingestion of GSE exhibited a significant decrease in the incidence of micronuclei compared with the radiation control group. The maximum protection and reduction in frequency of micronuclei (51.73%) was observed 2 hr after ingestion of 1000 mg GSE. CONCLUSION: Consumption of GSE before undergoing radiation protects human lymphocytes against X-rays by reducing radiation-induced genotoxicity.

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents.

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

The roles of radio-functional natural chemicals for the development of cancer radiation therapy.

Ionizing radiation (IR) targeted at killing cancer cells also damages normal human cells and tissues through oxidative stress. Thus, the practical treatment of cancer using radiation therapy (RT) is sometimes limited because of the acute side effects in individual patients. In addition, some radioresistant cancers are difficult to treat with limited doses of IR, which leads to treatment failure. Natural chemicals that have unique physiological functions and low toxicity offer significant advantages for the development of new radiation therapies. Natural chemicals can counteract the oxidative damage caused by IR during RT because of their strong antioxidant ability. Certain natural chemicals can also serve as radiosensitizers that can enhance the cancer-killing effects. This review article discusses the main roles of radio-functional natural chemicals in the development of cancer RT.

Target/signalling pathways of natural plant-derived radioprotective agents from treatment to potential candidates: A reverse thought on anti-tumour drugs.

Radiation damage can occur in nuclear power plant workers when physical protections fail, which results in nuclear leakage through the protective layers. Alternatively, workers may be unable to use physical protection in time (in the case of a sudden nuclear weapons attack). In addition, patients who receive local radiotherapy and are not allowed to adopt local physical protection may experience radiation damage. Thus, protection against chemical radiation has become indispensable. In view of the side effects caused by synthetic radioprotective agents (such as amisfostine), searching for radioprotective agents from plant sources is an alternative strategy. Radiation damage can cause multiple signalling pathway disturbances, leading to multiple organ injuries. Changes in these signalling pathways can lead to apoptosis, necrosis, and autophagy, as well as organ fibrosis, atrophy, and inflammation. Through literature searches, we determined that most targets for treating radiation injury are mechanistically opposite those of anti-tumour agents. This is likely attributable to the idea that anti-tumour agents promote cell necrosis or apoptosis, whereas the goal of anti-radiation agents is to promote cell survival or autophagy. This observation has important theoretical and practical significance when searching and developing new radioprotective agents derived from plant extracts. Further, it has important guiding value for meeting military needs and serving the public.

Radioprotective effects of lentil sprouts against X-ray radiation.

The present study investigated the radioprotective efficacy of lentil (Lens culinaris) sprouts against X-ray radiation-induced cellular damage. Lentil seeds were dark germinated at low temperature and the sprout extract was prepared in PBS. Free radical scavenging of extract was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and then the radioprotective potency of extract (0 to 1000 µg/mL) on the lymphocyte cells was determined by lactate dehydrogenases assay. Moreover, micronuclei assay was assessed using the cytokinesis-block technique. The irradiations were performed using 6 MV X-ray beam. The value of IC50 for DPPH assay was 250 µg/mL. The median lethal dose for radiation was determinate at 5.37 Gy. Pretreatment with lentil sprout extract at 1000 µg/mL reduced cytotoxicity at 6 Gy total concentration from 70% to 50%. The results of micronuclei assay indicated that cells were resistant to radiation at concentrations of 500-1000 µg/mL of exogenous lentil sprout extract. The value of median effective concentration for micronuclei assay was 500 µg/mL. The results indicated that lentil sprout extract showed actually somewhat radioprotective effect on lymphocyte cell. In addition, the obtained results suggest that extract of total lentil sprout have more antioxidant activity than radicle part.

Radioprotective activity of curcumin-encapsulated liposomes against genotoxicity caused by Gamma Cobalt-60 irradiation in human blood cells.

PURPOSE: While the radioprotective activity of curcumin against genotoxicity has been well established, its poor oral bioavailability has limited its successful clinical applications. Nanoscale formulations, including liposomes, have been demonstrated to improve curcumin bioavailability. The objective of the present work was (1) to prepare and characterize curcumin-encapsulated liposomes (i.e. size, colloidal stability, encapsulation efficiency, and payload), and (2) subsequently to evaluate their radioprotective activity against genotoxicity in human blood cells caused by Gamma Cobalt-60 irradiation. MATERIALS AND METHODS: The curcumin-encapsulated liposomes were prepared by lipid-film hydration method using commercial phosphatidylcholine (i.e. Phospholipon® 90G). The blood cells were obtained from healthy male donors (n = 3) under an approved ethics protocol. The cell uptake and the radioprotective activity of the curcumin-encapsulated liposomes were characterized by fluorescence microscopy and micronucleus assay, respectively. RESULTS: Nanoscale curcumin-encapsulated liposomes exhibiting good physical characteristics and successful uptake by the human blood cells were successfully prepared. The radioprotective activity of the curcumin-encapsulated liposomes was found to be dependent on the curcumin concentration, where an optimal concentration existed (i.e. 30 µg/mL) independent of the irradiation dose, above which the radioprotective activity had become stagnant (i.e. no more reduction in the micronuclei frequency). CONCLUSIONS: The present results established for the first time the radioprotective activity of curcumin-encapsulated liposomes in human blood cells, which coupled by its well-established bioavailability, boded well for its potential application as a nanoscale delivery system of other radioprotective phytochemicals.

Radioprotective effect of Zamzam (alkaline) water: A cytogenetic study.

BACKGROUND: Radioprotectors are useful compounds to reduce radiation toxicity of normal cells. Many natural radioprotectors have antioxidant power and display fewer toxicity and side effects than the chemical ones. Alkaline waters such as Zamzam have antioxidant power potentially. This study aimed to investigate the radioprotective effect of Zamzam water in mice bone marrow exposed to gamma radiation by micronuclei test. METHOD: Five study groups including control group which was fed by ordinary water, the second group was fed by Zamzam water, and radiation groups were received 2Gy gamma with ordinary and Zamzam water for 10 days and another for 20 days. The frequency of micronuclei and polychromatic erythrocytes to normochromatic erythrocytes ratio were calculated by micronuclei test. RESULT: In the absence of radiation, no significant difference was found between Zamzam group and control in the number of micronuclei in normochromatic erythrocytes, micronuclei in polychromatic erythrocytes, and the polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte ratio. But all of these indices were significantly different between irradiated and non-irradiated groups. The frequency of micronuclei in polychromatic erythrocytes was not significantly different between 10 and 20 days Zamzam irradiated groups, but the reduction in micronuclei in normochromatic erythrocytes and an increase in the polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte ratio compared to ordinary water were seen in 20 days Zamzam group. Dose reduction factor was 1.36 and 2 for Zamzam water groups of 10 days and 20 days, respectively. CONCLUSION: The results demonstrated that Zamzam alkaline water could reduce clastogenic and cytotoxic effects of gamma irradiation.

Prevention of γ-Radiation-Induced DNA Damage in Human Lymphocytes Using a Serine-Magnesium Sulfate Mixture.

OBJECTIVES: Ionising radiation has deleterious effects on human cells. N-acetylcysteine (NAC) and cysteine, the active metabolite of NAC, are well-known radioprotective agents. Recently, a serine-magnesium sulfate combination was proposed as an antidote for organophosphate toxicity. This study aimed to investigate the use of a serine-magnesium sulfate mixture in the prevention of γ-radiation-induced DNA damage in human lymphocytes as compared to NAC and cysteine. METHODS: This study was carried out at the Iran University of Medical Sciences, Tehran, Iran, between April and September 2016. Citrated blood samples of 7 mL each were taken from 22 healthy subjects. Each sample was divided into 1 mL aliquots, with the first aliquot acting as the control while the second was exposed to 2 Gy of γ-radiation at a dose rate of 102.7 cGy/minute. The remaining aliquots were separately incubated with 600 µM concentrations each of serine, magnesium sulfate, serine-magnesium sulfate, NAC and cysteine before being exposed to 2 Gy of γ-radiation. Lymphocytes were isolated using a separation medium and methyl-thiazole-tetrazolium and comet assays were used to evaluate cell viability and DNA damage, respectively. RESULTS: The serine-magnesium sulfate mixture significantly increased lymphocyte viability and reduced DNA damage in comparison to serine, magnesium sulfate, NAC or cysteine alone (P <0.01 each). CONCLUSION: The findings of the present study support the use of a serine-magnesium sulfate mixture as a new, non-toxic, potent and efficient radioprotective agent.

Prospects in the development of natural radioprotective therapeutics with anti-cancer properties from the plants of Uttarakhand region of India.

Radioprotective agents are substances those reduce the effects of radiation in healthy tissues while maintaining the sensitivity to radiation damage in tumor cells. Due to increased awareness about radioactive substances and their fatal effects on human health, radioprotective agents are now the topic of vivid research. Scavenging of free radicals is the most common mechanism in oncogenesis that plays an important role in protecting tissues from lethal effect of radiation exposure therefore radioprotectors are also good anti-cancer agents. There are numerous studies indicating plant-based therapeutics against cancer and radioprotection. Such plants could be further explored for developing them as promising natural radioprotectors with anti-cancer properties. This review systematically presents information on plants having radioprotective and anti-cancer properties.

Origanum vulgare leaf extract protects mice bone marrow cells against ionizing radiation.

OBJECTIVE: Ionizing radiation produces free radicals which induce DNA damage and cell death. Origanum vulgare leaf extract (OVLE) is a natural compound and its capability of scavenging free radicals and its antioxidant activity have been demonstrated by many researchers. In this study, using micronucleus assay, radioprotective effect of OVLE against clastogenic and cytotoxic effect of gamma irradiation has been investigated in mice bone marrow cells. MATERIALS AND METHODS: OVLE was injected intraperitoneally to the BALB/c mice 1hr prior to gamma irradiation (3Gy) at the doses of 100 and 200 mg/kg. Twenty four hours after irradiation or treatment, animals were killed and smears were prepared from the bone marrow cells. The slides were stained with May Grunwald-Giemsa method and analyzed microscopically. The frequency of micronucleated polychromatic erythrocytes (MnPCEs), micronucleated normochromatic erythrocyte (MnNCEs) and cell proliferation ratio PCE/PCE+NCE (polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte) were calculated. RESULTS: The results showed that gamma irradiation (3Gy) increased the frequency of MnPCEs, MnNCEs and reduced the PCE/PCE+NCE ratio in mice bone marrow compared to the non-irradiated control group (p<0.0001). Injection of OVLE significantly reduced the frequency of MnPCEs (p<0.0001) and MnNCEs (p<0.05) and increased the PCE/PCE+NCE ratio as compared to the irradiated control group (p<0.05). CONCLUSION: It seems that OVLE with its antioxidant properties and its capability of scavenging free radicals and reactive oxygen species can reduce the cytotoxic effects of gamma irradiation in mice bone marrow cells.