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.

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.

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 ...

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.

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.

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.

Jamun (<i>Syzygium cumini </i>(L.)): A Review of Its Food and Medicinal Uses

Eugenia jambolana Lam., commonly known as black plum or “jamun” is an important medicinal plant in various traditional systems of medicine. It is effective in the treatment of diabetes mellitus, inflammation, ulcers and diarrhea and preclinical studies have also shown it to possess chemopreventive, radioprotective and antineoplastic properties. The plant is rich in compounds containing anthocyanins, glucoside, ellagic acid, isoquercetin, kaemferol and myrecetin. The seeds are claimed to contain alkaloid, jambosine, and glycoside jambolin or antimellin, which halts the diastatic conversion of starch into sugar. The present review has been primed to describe the existing data on the information on traditional and medicinal use.

Radio-protective effect of vitamin E on spermatogenesis in mice exposed to γ-irradiation: a flow cytometric study

Aim: To investigate the effect of vitamin E on the radioprotection of spermatogenesis and chromatin condensation of spermatozoa during passage through the epididymis in mice exposed to irradiation. Methods: Adult outbred male ICR mice were orally administered natural vitamin E (VE, D-α-tocopheryl acetate) at 400 IU/kg for 7 days before exposure to 1 Gy of γ-irradiation. The animals were sacrificed at day 1, 7, 14, 21, 28, 35 and 70 post-irradiation (IR) and the percentage of testicular germ cells and epididymal sperm chromatin condensation was analyzed using flow cytometry. Results: Serum D-α-tocopheryl acetate levels were 47.4 ± 3.2 μg/dL in the treated group, yet it could not be detected in the control group. The testicular weight of irradiated mice pretreated with VE+IR was significantly (P<0.05) higher than that of those without VE treatment (IR) at day 14 and 21 post-irradiation. The percentage of primary spermatocytes (4C) in the VE+IR group was comparable to the controls but significantly (P<0.05) higher than those in the IR group from day 7 to 35 post-irradiation. The percentage of round spermatids (1C) in the VE+IR group was also significantly (P<0.05) higher than those in the IR group at day 28 post-irradiation. The primary spermatocytes : spermatogonia ratio in the IR group was significantly (P<0.05) declined at day 7 to 35 post-irradiation when compared to the VE+IR and control groups. The round spermatid : spermatogonia ratio in the VE+IR group was significantly (P<0.05) higher than that of the IR group at day 14 and 28 post-irradiation. The chromatin condensation of epididymal spermatozoa measured by propidium iodide uptake was not affected by 1 Gy of γ-irradiation. Conclusion: The administration of VE prior to irradiation protects spermatogenic cells from radiation.

Relationship and interactions of curcumin with radiation therapy

Curcumin is widely reported to have remarkable medicinal- and antineoplastic- properties. This review details curcumin's relationship with radiotherapy(RT), principally as a radiosensitizer for various malignancies and a radioprotector for normal tissues. First, examples of radiosensitization are provided for various cancers:Pediatric, lymphoma, sarcoma, prostate, gynecologic, pancreas, liver, colorectal, breast, lung, head/neck, and glioma. It is not the purpose of this article to comprehensively review all radiosensitization data; however, high-quality studies are discussed in relationship to currently-controversial RT questions for many cancers, and thus the importance of developing a natural radiosensitizer. Attention is then shifted to radioprotection, for which supporting research is discussed for the following RT toxicities: Dermatitis, pneumonitis, cataractogenesis, neurocognition, myelosuppression, secondary malignancies, and mucositis/enteritis. Though there is fewer data for radioprotection, the overall quality of clinical evidence is higher, and small clinical trials implicating the efficacy of curcumin for RT toxicities(vs placebo/current therapies) are also detailed. Though the overall level of evidence for curcumin as a radiosensitizer and radioprotector is low, it must be recognized that risks of adverse effects are exceedingly low, and clinicians may need to judge the yet-unproven rewards with low toxicity risks.

Neuroprotective agents effective against radiation damage of central nervous system

Ionizing radiation caused by medical treatments,nuclear events or even space flights can irreversibly damage structure and function of brain cells.That can result in serious brain damage,with memory and behavior disorders,or even fatal oncologic or neurodegenerative illnesses.Currently used treatments and drugs are mostly targeting biochemical processes of cell apoptosis,radiation toxicity,neuroinflammation,and conditions such as cognitive-behavioral disturbances or others that result from the radiation insult.With most drugs,the side effects and potential toxicity are also to be considered.Therefore,many agents have not been approved for clinical use yet.In this review,we focus on the latest and most effective agents that have been used in animal and also in the human research,and clinical treatments.They could have the potential therapeutical use in cases of radiation damage of central nervous system,and also in prevention considering their radioprotecting effect of nervous tissue.

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.

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

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。

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.

Quality Characteristics and Radioactive Contamination of Wood Pellet Imported in Italy

The problem of Caesium-137 (137 Cs) contamination of the imported wood pellet used for burning has been reported in Italy since June 2009. Since then, sampling and analysis were performed at the crossing border points of the provinces of Trieste and Gorizia, on request of the Health and Customs Border Bureau. This paper presents the results of the analysis performed on 65 samples from August 2010 to March 2012, which covered a total of products over 1500 tons of various origins, imported from Eastern Europe and the Balkans. Most of the samples showed very low 137 Cs activity concentrations;only a few hot spots showed 137 Cs activity concentrations higher than 100 Bq·kg-1. The results of dose evaluations for wood pellet stoves users under the hypotheses assumed in this study were largely below the threshold of radiological relevance.

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.

Analysis of Radium Isotopes in Surface Waters nearby a Phosphate Mining with NORM at Santa Quiteria,Brazil

The radium isotopes 226Ra and 228Ra were analyzed in surface water at six points in the neighborhood of a mine of phosphate, associated with uranium, in the region of Santa Quitéria, state of Ceará, Brazil. Water samples were collected during twenty months, filtered and the concentrations of activity determined in the soluble and particulate phases. The results were analyzed using the Principal Component Analysis (PCA) for ordination of environmental data, and also by ANOVA, Tukey and Z tests to compare sets of data considering the radionuclides, the two analyzed phases and the six collecting points. The PCA identified four groups that included all collecting points, using aggregation features such as radionuclide and analyzed phase. The first group is composed by the samples of 226Ra in the soluble phase;the second group by samples of 226Ra in the particulate phase;the third one by 228Ra in the soluble phase, and finally, the fourth group by 228Ra in the particulate phase. This last group has two discrepant points (01 and 06). Statistical analysis identified differences between the concentrations of activity of radionuclides (228Ra higher than 226Ra) and in analyzed phases (soluble phase higher than the particulate one) but showed no differences between sampled points.

International Recommendations on Calculation of Absorbed Dose in Biota:A Comprehensive Revue

Since the early times, radioprotection has been focused on the human being. Currently this approach has changed, being now also necessary to take care of the protection of the environment from unwanted effects of ionizing radiation. To this end, several institutions (UNSCEAR, ICRP, IAEA, DOE, ACRP) and consortia of institutions (FASSET, ERICA) have established procedures in order to protect the biota of such effects. Developed procedures are based on the calculation of the absorbed dose in biota (ICRP, DOE, IAEA), or on environmental risk assessment―ERA (DOE, ACRP, FASSET, ERICA);but even in this latter approach the parameters used are related to the absorbed doses in biota. The calculation of dose is the standard procedure in human radioprotection, and this points such an approach as the most interesting for providing a convergence between human and nonhuman (= biota) radioprotections. On the other hand, the ERA approach is easier to apply, because this methodology is used in several countries for non-radioactive contamination assessments. Since the world radioprotection system follows a number of institutions (UNSCEAR, ICRP, IAEA and regulatory institutions of member countries) that use dose calculation, this appears to be the way for biota radioprotection. We here review and comment the evolution of the concepts and approaches of the recommendations for radioprotection of non-human biota.

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.

An UPLC-MS/MS method to monitor Estriol injection and comparison of pharmacokinetic characteristics after irradiation

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 ofγ-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。