Alpha-2-macroglobulin as a radioprotective agent: a review

Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin（α2M） possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a nonselective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailovi？ et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, antifibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.

Radioprotective effects of cimetidine on rats irradiated by long-term, low-dose-rate neutrons and ^(60)Coγ-rays

Background: Cimetidine, an antagonist of histamine type II receptors, has shown protective effects against γ-rays or neutrons. However, there have been no reports on the effects of cimetidine against neutrons combined with γ-rays. This study was carried out to evaluate the protective effects of cimetidine on rats exposed to long-term, low-dose-rate neutron and γ-ray combined irradiation(n-γ LDR).Methods: Fifty male Sprague-Dawley(SD) rats were randomly divided into 5 groups: the normal control group, radiation model group, 20mg/(kg·d) cimetidine group, 80mg/(kg·d) cimetidine group and 160mg/(kg·d) cimetidine group(10 rats per group). Except for the normal control group, 40 rats were simultaneously exposed to fission neutrons(^(252)Cf, 0.085 m Gy/h) for 22 h every day and γ-rays(^(60)Co, 0.097Gy/h) for 1.03 h once every three days, and the cimetidine groups were administered intragastrically with cimetidine at doses of 20, 80 and 160mg/kg each day. Peripheral blood WBC of the rats was counted the day following exposure to γ-rays. The rats were anesthetized and sacrificed on the day following exposure to ^(252)Cf for 28 days. The spleen, thymus, testicle, liver and intestinal tract indexes were evaluated. The DNA content of bone marrow cells and concanavalin A(Con A)-induced lymphocyte proliferation were measured. The frequency of micronuclei in polychromatic erythrocytes(f MNPCEs), superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione peroxidase(GSH-Px) in the serum and liver tissues were detected.Results: The peripheral blood WBC in the cimetidine groups was increased significantly on the 8th day and the 26 th day compared with those in the radiation model group. The spleen, thymus and testicle indexes of the cimetidine groups were higher than those of the radiation model group. The DNA content of bone marrow cells and lymphocyte proliferation in the cimetidine groups were increased significantly, and fMNPCE was reduced 1.41-1.77 fold in cimetidine treated groups. The activities of SOD and GSH-Px in the cimetidine groups were increased significantly, and the content of MDA in the cimetidine groups was decreased significantly.Conclusions: The results suggested that cimetidine alleviated damage induced by long-term, low-dose-rate neutron and γ combined irradiation via antioxidation and immunomodulation. Cimetidine might be useful as a potent radioprotector for radiotherapy patients as well as for occupational exposure workers.

Research progress in the radioprotective effect of the canonical Wnt pathway

Irradiation from diverse sources is ubiquitous and closely associated with human activities. Radiation therapy (RT), an important component of multiple radiation origins, is a common therapeutic modality for cancer. More importantly, RT provides significant contribution to oncotherapy by killing tumor cells. However, during the course of therapy, irradiation of normal tissues can result in a wide range of side effects, including self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Although numerous promising radioprotective agents have emerged, only a few have successfully entered the market because of various limitations. At present, the widely accepted hypothesis for protection against radiation-caused injury involves the Wnt canonical pathway. Activating the Wnt/β-catenin signaling pathway may protect the salivary gland, oral mucosa, and gastrointestinal epithelium from radiation damage. The underlying mechanisms include inhibiting apoptosis and preserving normal tissue functions. However, aberrant Wnt signaling underlies a wide range of pathologies in humans, and its various components contribute to cancer. Moreover, studies have suggested that Wnt/ β-catenin signaling may lead to radioresistance of cancer stem cell. These facts markedly complicate any definition of the exact function of the Wnt pathway.

Soluble factors secreted by human Wharton’s jelly mesenchymal stromal/stem cells exhibit therapeutic radioprotection: A mechanistic study with integrating network biology

BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims。

Radiation effects and radioprotection by Thai medicinal plants in mouse macrophage cell line

Objective:To investigate the effects of radiation on growth-arrested(GA) and micronucleus-production(MP) rates,and the radioprotective properties of Thai medicinal plants in mouse macrophage cell line RAW264.7 in vitro.Methods:Mouse macrophage cell line(RAW264.7) was cultured in vitro.Various radiation exposures, growth-arrested rate assay,micronucleus production assay,and radioprotection by Thai medicinal plants were performed.Results:The results showed that GA and MP rates forγ-rays and UV were dose-dependent. The 50%-affected dose ofγand UV radiation for the GA rate was 10 Gy and 159 microwatt/cm for 0.5 seconds, respectively.After X-ray exposure,there was no apparent effect on RAW264.7 cells,even with a fortyfold human diagnostic dose.Two exposures toγradiation at 20 Gy resulted in a significantly higher MP rate than 20 Gy single exposure or control(P【0.05).The Thai medicinal plants(Kamin-chun capsules,Curcuma longa Linn;Hed lingeu,Ganoderma lucidum;Ya Pakking capsule,Murdannia loriformis) could not prevent cell damage,but epigallocatechin gallate and L-cysteine could provide protection from 2 Gyγ-ray exposure. Conclusion:γradiation caused chromosomal damage during cell division and UV caused cell death, while X-ray radiation was safe.The radioprotective effects of Thai medicinal plants,Kamin-chun,Hed lingeu, and Ya Pakking,could not prevent cell damage in this study.

Cation-anionicpalladium Complexes—New Types of Antitumor, Immune Response-modulating and Radioprotective Agents

Here we report results of our investigations of new class of bioactive palladium compounds (AH n ) m [PdCl 4 ], which were discovered as a result of systematic study of correlations between composition, structure and bioactivity of different types of platinum metals coordination compounds. For the first time we demonstrated in vivoa possibility of development of palladium compounds, which exceed cisplatin in antitumor activity and do not show immunosuppressive effects, and palladium compounds with immunostimulating and radioprotective activities. Combinations of cytostatic agents or radiation with palladium complexes lead to significant synergism of their activities and high therapeutic efficiency exceeded an efficiency of their separated use.

Comparative studies on radioprotection of recombinant human interleukin－1 in C_3H and BALB／c mice

There is a strain difference in radioprotection of interleukin-l(lL-1) between C3H and BALB/c mice.The dose producing effective radioprotection in C3H mice was much higher than that in BALB/c mice.Our studies also showed that the number of CFU-S12 in BALB

Evaluation of the Knowledge of CT Scan Prescribers on Patients’ Radioprotection in Senegal

Medical imaging has enabled major improvements in the medical care of the patient. However, some of these tests have the disadvantage of using ionizing radiation at low doses. Although the CT scan is a powerful diagnostic tool, it remains a highly radiant imaging modality. In addition, the risk of radiation-induced cancer associated with low X-ray doses is established by the American Phase 2 study BEIR VII, and preventive measures require a good level of knowledge on radioprotection by imaging test prescribers. In our study, we evaluated the knowledge of CT scan prescribers in Senegal regarding patient radioprotection. These prescribers consisted of physicians and surgeons without distinction of specialty. Our objective was to have the required data for optimizing CT prescriptions in compliance with the principles of radioprotection. Our work focused on a descriptive analytical study of 107 doctors who prescribed CT scan in public health institutions in Senegal. Our results revealed poor knowledge of doctors prescribing CT scan on induced radio risks, even though the majority of them stated that they took those risks into account. Our data were not isolated, they were applicable to similar studies conducted outside Senegal. In summary, our study led on the one hand to recommendations on initial and continuing training and on the other hand on organizational and regulatory considerations.

Radioprotective Effect of Laser Radiation With a Wavelength of 532 nm on Fibroblast Cells

Studies have been carried out to test the assumption that the primary photoreceptors for the radioprotective action of 633 nm laser radiation are the cytochrome-c-oxidases.To do this,the device was created for radiation protection of biological objects based on laser module with a wavelength of 532 nm.Experiments conducted on murine fibroblast cells showed that the radioprotection effect of laser irradiation was observed in the dose interval about 0.4-0.85 mJ/cm2.Maximum radioprotection effect is observed at laser radiation energy density^0.56 mJ/cm2.The determination of the cell survival with the automatic counterСТ20 after the action of the ionizing and combined irradiation showed that radioprotective action of the laser radiation with the wavelength of 533 nm,as well as the radiation with the wavelength of 633 nm,is transferred by the mechanism of the“bystander effect”.In addition,it was found that radioprotection effect of laser irradiation observed on the criterion of number of surviving single cells,compared with cells exposed to?-radiation Laser irradiation,produces effective radioprotecting action also on the criterion of grown cell colonies.The value of the dose modification factor(DMF)calculated on 50%cell survival(LD50)is equal to 1.4.The results suggest that in the case of radioprotective action of small doses of laser radiation with a wavelength of 633 nm,as well as 532 nm primary photoreceptors is the cytochrome-c-oxidases.

On the immunological limitations of hibernation and synthetic torpor as a supporting technique for astronauts’ radioprotection in deep space missions

Although human hibernation has been introduced as an effective technique in space exploration,there are concerns regarding the intrinsic risks of the approach(i.e.,synthetic torpor)and other factors involved in this procedure.Besides concerns about the brain changes and the state of consciousness during hibernation,an"Achilles heel"of the hibernation is the negative impact of torpor on factors such as the number of circulating leukocytes,complement levels,response to lipopolysaccharides,phagocytotic capacity,cytokine production,lymphocyte proliferation,and antibody production.Moreover,increased virulence of bacteria in deep space can significantly increase the risk of infection.The increased infection risk during long-term space missions with the combined effects of radiation and microgravity affect the astronauts’immune system.With these additional immune system stressors,torpor-induced extraimmunosuppression can be potentially life threatening for astronauts.

Radioprotective effects of the expression of FLT3 ligand regulated by Egr-1 regulated element on radiation injury of SCID mice

Objective: In order to explore the radioprotective effects of the expression of hematopoietic growth factors regulated by radio-inducible promoter on radiation injury. Methods:The human FL (Flt3 ligand) cDNA and EGFP (enhanced green fluorescent protein) cDNA were linked together with IRES and then inserted into the eukaryotic expression vector pCI-Egr, which was constructed by substituting CMV promoter in pCIneo with the Egr-1 promoter (Egr-EF). The vector was transferred into human bone marrow stromal ...

H_(2)S-releasing adhesive hydrogel as oral radioprotectant for gastrointestinal tract radioprotection

Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radioprotectant Gel@GYY that integrates a porous gelatin-based(Gel)hydrogel and a pH-responsive hydrogen sulfide(H2S)donor GYY4137(morpholin-4-ium 4 methoxyphenyl(morpholino)phosphinodithioate).Gel@GYY has a remarkable adhesion ability and long retention time,which not only enables responsive release of low-dose H2S in stomach and subsequently sustained release of H2S in the whole intestinal tract especially in the colon,but also ensures a close contact between H2S and GI tract.The released H2S can effectively scavenge free radicals induced by X-ray radiation,reduce lipid peroxidation level,repair DNA damage and recover vital superoxide dismutase and glutathione peroxidase activities.Meanwhile,the released H2S inhibits radiation-induced activation of nuclear factorκB(NF-κB),thus reducing inflammatory cytokines levels in GI tract.After treatment,Gel@GYY displays efficient excretion from mice body due to its biodegradability.This work provides a new insight for therapeutic application of intelligent H2S-releasing oral delivery system and potential alternative to clinical GI physical damage protectant.

The simulation of GCRs at near earth interplanetary locations for radioprotection

The interplanetary radiation environment is detrimental to space missions,giving rise to cumulative damage to both astronauts and payloads and enhanced background levels in detectors.Therefore,there is a pressing need for a reliable simulation of these harmful effects for risk assessment and shielding optimization in manned space missions.We have modeled the interaction processes of the two most abundant galactic cosmic ray particle fluxes(protons and helium nuclei) using the Geant4 toolkit for a given space vehicle model.The total energy deposited due to protons and helium nuclei is calculated in this work,and the energy deposited due to the secondary particles generated by this radiation is also estimated.

General principles of developing novel radioprotective agents for nuclear emergency

With the rapid application of nuclear energy and radiological technology in national economy and military field,the risk of nuclear accidents increases as well.Exposure to irradiation causes severe damages to the human body,and radioprotective agents are required for medical protection.To find the safe and effective radioprotective agents is the key for nuclear emergency.Recently,Toll like receptors(TLRs)and PHD-HIF oxygen sensing signal pathway have been extensively studied for radioprotection.Great progress has been made in this field and a number of radioprotective agents have been found.In this review,we have summarized recent findings of radioprotective roles of TLRs signaling pathway and PHD-HIF signaling pathway and discussed the general principles of developing novel radioprotective agents.These findings will provide opportunities for developing new strategies to prevent IR-induced injuries in public health events.

Personalized radioprotection in tumor patients after^(125)I seed brachytherapy

Objective:To investigate patient-specific radioprotection mathods for people in close contact with cancer patientstreated by 12I-seed implantation.Methods:The initial dose rates(D_(0))at distances of 30 and 100 cm from 80 patients who had undergone ^(125)I-seed implantation were measured within 24 h of the procedure.The dose rate at t(D_(t))and effective dose(E)were calculated according to the measurad vales of D.The appropriate precaution times for general adult family members,spouses,coworkers,and children or pregnant women were determined,and the relationships between and precaution time for different close-contact groups were derived by curve-fitting the corresponding data.Results:The mean D vahes of 80 patients at distanes of 30 and 100cm were(15.24±11.25)μSv/h and(1.96±2.63)μSv/h,respectively(P<0.05).The mean values and range of precaution time for general adult familymembers,spouses,coworkers,and children or pregnant women were(4.17±16.55),(102.93±49.22),(51.00±61.29),and(34.27±56.90)d(0-90.61),(0-234.01),(0-247.81),and(0-224.69)d,respectively.Furthemore,a logarithmic relationship betwen D and precaution time(Y)was observed for the different groujps.The equations of these relationships were detemined to be Y=-131.569+83.256 lnD_(0) for general adult family mambers,Y=—108.532+83.318 lnD_(0) for spouses,Y=25.470+83.318 lnD,for coworkers,and Y=2.585+83.229 lnD_(0) for children or pregnant women.Conchusions:Some cancer patients treated by ^(125)I-seed brachytherapy emitover-dose levels of γ-rays,necessitatingradiation protection for their close contacts.However,appropriate patient-specific radiation protection fordifferent close contacts can be determined based on the precaution time calculated using the D_(0) value.

Lymphoid-biased hematopoietic stem cells and myeloid-biased hematopoietic progenitor cells have radioprotection activity

Radioprotection was previously considered as a function of hematopoietic stem cells(HSCs).However,recent studies have reported its activity in hematopoietic progenitor cells(HPCs).To address this issue,we compared the radioprotection activity in 2 subsets of HSCs(nHSC1 and 2 populations)and 4 subsets of HPCs(nHPC1–4 populations)of the mouse bone marrow,in relation to their in vitro and in vivo colony-forming activity.Significant radioprotection activity was detected in the nHSC2 population enriched in lymphoid-biased HSCs.Moderate radioprotection activity was detected in nHPC1 and 2 populations enriched in myeloid-biased HPCs.Low radioprotection activity was detected in the nHSC1 enriched in myeloid-biased HSCs.No radioprotection activity was detected in the nHPC3 and 4 populations that included MPP4(LMPP).Single-cell colony assay combined with flow cytometry analysis showed that the nHSC1,nHSC2,nHPC1,and nHPC2 populations had the neutrophils/macrophages/erythroblasts/megakaryocytes(nmEMk)differentiation potential whereas the nHPC3 and 4 populations had only the nm differentiation potential.Varying day 12 spleen colony-forming units(day 12 CFU-S)were detected in the nHSC1,nHSC2,and nHPC1–3 populations,but very few in the nHPC4 population.These data suggested that nmEMk differentiation potential and day 12 CFU-S activity are partially associated with radioprotection activity.Reconstitution analysis showed that sufficient myeloid reconstitution around 12 to 14 days after transplantation was critical for radioprotection.This study implied that radioprotection is specific to neither HSC nor HPC populations,and that lymphoid-biased HSCs and myeloid-biased HPCs as populations play a major role in radioprotection.

Radioprotective thermally generated free-radical dextrins

Effect of doses of the X-ray radiation from 0 to 400 Gy upon granular cornstarch and dextrins (British gums, BG) thermally generated from it at 230-300℃ was recognized with quantitative EPR and IR ab-sorption spectroscopy, molecular mass distribution in the depolymerization products, Scanning Elec-tron Microscopy, and X-ray diffractometry. Fractal analysis of the profiles of molecular mass distribu-tion showed that the depolymerization involved debranching of amylopectin. Roasting of cornstarch produced BG which differed in concentration and EPR parameters of stable free radicals from BG generated by X-ray radiation. Two types of stable free radicals, with Gaussian and Lorentzian shapes of EPR signals, were recognized. The shapes of the signals and temperature dependence on free radical intensity indicated exchanging interactions of the antiferromagnetic type, causing partial quenching of the spins at-196℃ (77K). Upon X-ray irradiation, new radicals were generated, the number and stability of which strongly depended on the types of radicals present before irradiation. These radicals slowly ceased because of a repolymerization of BG on storage.

大型综合医院辐射安全管理的探索与实践

通过梳理分析大型综合医院辐射安全管理工作中的难点,从管理体系、放射诊疗设备和场所的全生命周期管理、人员管理、信息管理、文化建设五个维度来推进辐射安全管理工作。建立科学的安全管理体系,以全生命周期管理模式为参考,结合医院实际情况,制定管理制度,明晰权责划分,加强人员管理,积极信息化建设和文化宣贯工作,将管理工作规范化、常态化、标准化。充分认识辐射安全的重要性,确保辐射安全管理工作科学发展,降低潜在的人员健康和环境安全风险。

丙二醇联合肝细胞生长因子修饰牙髓干细胞外泌体保护人表皮细胞的放射损伤

背景:肿瘤放疗以及核事故等原因引起的放射性皮肤损伤救治仍旧是一个严重的医学问题,单一的防治手段均难以达到有效的治疗结果,寻找新的综合治疗手段是重要的研究方向。目的:观察丙二醇联合肝细胞生长因子修饰牙髓干细胞来源外泌体对于人表皮放射性损伤细胞模型的保护作用及相关作用机制。方法:①使用携带人肝细胞生长因子基因的重组腺病毒感染人牙髓干细胞,超速离心法分离制备外泌体,即Ad.HGF DPSC-Exo。②通过X射线照射诱导人表皮细胞HaCaT放射损伤,细胞分别于照射前用丙二醇预处理,照射后用Ad.HGF DPSC-Exo处理。通过CCK-8法测定细胞增殖活力,流式细胞术检测细胞凋亡情况,细胞划痕实验检测细胞迁移情况,PCR检测P21和P53的表达水平。结果与结论:丙二醇、Ad.HGF.DPSC-Exo、Ad.HGF.DPSC-Exo+丙二醇均可显著改善HaCaT细胞的生长抑制、减少细胞凋亡、提高细胞增殖和迁移能力,显示出较好的辐射防护效果,且Ad.HGF.DPSC-Exo+丙二醇联合作用效果更好。此外,Ad.HGF.DPSC-Exo+丙二醇能够减轻细胞G2/M期阻滞,降低细胞周期调控基因P53和P21的表达。综上所述,丙二醇预处理联合Ad.HGF.DPSC-Exo能够有效保护放射诱导的HaCaT细胞损伤,为辐射性皮肤损伤的防治提供了新的思路和有效方法。