New drugs for treatment of severe acute radiation sickness:research advances / 国际药学研究杂志

Through efforts of several generations over the past half century,great advances have been achieved in the develop?ment of radiation countermeasures for the acute radiation sickness(ARS). Convergent studies have disclosed numerous radioprotec?tants with significant radioprotective efficacy which include granulocyte colony stimulating factor(G-CSF),granulocyte macrophage colony stimulating factor(GM-CSF),thrombopoietin(TPO),interleukin-12,derivatives of the bacterial flagellin,androst-5-ene-3β, 17β-diol(AED),beclomethasone 17,21-dipropionate(BDP),vitamin E(and its)derivatives,and genistein. particularly,the two growth factors G-CSF and TPO show greater radioprotective effects. In this paper,we summarize the radioprotective effects of com?pounds or biological agents on severe ARS(SARS),which have been evaluated in large animal models or assembled into a nuclear accident emergency treatment medicine box,and review their research advances in recent years.

Radiation protection effect and its mechanism of multiple nilestriol administrations on the mice with bone marrow type of acute radiation syndrome / 中华放射医学与防护杂志

Objective To understand the radiation protection effect of pre-irradiation administrations of nilestriol on the mice with bone marrow type of acute radiation syndrome after irradiation with 60Co γ-rays,along with its mechanisms for improvement of hematopoiesis.Methods The nilestriol administration protocols were prepared by analysis of peripheral blood cell counts and survival rate experiment on mice.The mechanisms by which the pre-irradiation twice administrations improved the post-irradiation recovery of bone marrow hematopoiesis were studied by the analysis of the surface marker of bone marrow hematopoietic stem/progenitor cells of mice and by the inspection of hematopoietic progenitor cell colony and by using histopathological assessment of bone marrow.Results Pre-irradiation administration of nilestriol at two-or three-day intervals had been shown to increase survival rates up to 100％ in mice exposed to 9.0 Gy γ-rays,which was superior to a single administration (20％,x2 =21.66,21.66,P ＜0.05).The pre-irradiation administration both at one-day or two-day intervals were capable of improving the recovery of peripheral blood counts,including white blood cell (WBC),red blood cell (RBC),and platelet in mice exposed to 6.5 Gy (F =21.33,100.9,49.34,19.19,P ＜ 0.05),showing the better effects than a single administration (F =17.11,63.38,21.89,14.37,P ＜ 0.05).The two-day-interval administration of nilestriol could significantly increase the numbers of bone marrow hematopoietic stem/progenitor cell counts (t =8.58,2.80,P ＜ 0.05) in mice on day 10 after 6.5 Gy irradiation.This also could be capable to significantly improve colony formation,with there being statistical difference compared with single administration(t =4.29,6.34,P ＜ 0.05).Also the administration at two-day-interval were also usefull in reconstruction of hematopoietic cell hyperplasia of bone marrow of irradiated mice.Conclusions As compared with conventional single admination,the pre-irradiation multiple administrations of nilestriol showed significantly improved radiation protection effects.Considering a nuclear medical emergency rescue,it is recommended to follow the pre-irradiation administration of nilestriol at two-day interval,which could obtain the best protection effects at minimum administration frequency.

Radioprotection of Toll-like receptor 5 agonist CBLB502 protein on hemopoiesis injury by irradiation / 国际药学研究杂志

Objective To study the radioprotective potential of CBLB502 protein against hemopoiesis injury by irradiat-ion. Methods C57BL/6J mice were assigned to normal irradiation, and CBLB502 0.2mg/kg 30min pre-irradiation group at random before 6.5 Gy 60Co-γray total body irradiation (TBI). The peripheral blood was obtained to assay hemogram pre and post-irradiation. The bone marrow nucleated cell counts were evaluated in mice at 2 h and 24 h after irradiation. Colony-forming unit (CFU) assay was used to analyze the alteration of hemopoietic progenitor cells in bone marrow. Competitive repopulation assay was conducted to observe the implantation ability of bone marrow cells. The percentage of each lineage hemopoietic cells was measured by flow cytometry analysis. Results CBLB502 significantly alleviated the sharp decrease of peripheral blood counts including leukocyte (WBC), erythrocyte (RBC), and platelet, and accelerated recovery. Counts of various hematopoietic progenitor cell colonies of mouse bone marrow in CBLB502 group were significant higher than those of irradiation group (P<0.01). CBLB502 significantly improved the implantation ability of bone marrow cells. Conclusion CBLB502 showed obvious radioprotective effects on haemopoiesis injury by irradiation.

Chemistry and biological activities of Viburnum odoratissimum / 药学学报

Viburnum odoratissimum is a folk medicinal plant, it can dredge the meridian passage and contains mainly diterpenes, triterpenes, flavonoids, sesquiterpenes, lignans, coumarin glycosides, etc. Vibsanin-type diterpenoids are the characteristic compounds of V. odoratissimum, and are divided into eleven-membered ring, seven-membered ring, and rearrangement-type. Vibsanin B, vibsanin C and neovibsanin A are the representative compounds of the three subtypes of vibsanin-type diterpenoids respectively. V. odoratissimum has cytotoxic activity, antibacterial activity, fish piscicidal activity and activity of inhibiting the growth of plants, Cytotoxic activity is the main biological activity.

Studies on mechanism of treatment of granulocyte colony-stimulating factor,recombinant human interleukin-11 and recombinant human interleukin-2 on hematopoietic injuries induced by 4.5 Gy γ-rays irradiation in beagles / 中华放射医学与防护杂志

Objective To investigate the mechanism of treatment of granulocyte colony-stimulating factor(rhG-CSF),recombinant human interleukin-11(rhIL-11)and recombinant human interleukin-2 (rhIL-2)on hematopoietic injuries induced by 4.5 Gy60 Coγ-ray irradiation in beagles,and to provide experimental evidence for the clinical treatment of extremely severe myeloid acute radiation sickness (ARS).Methods Sixteen beagle dogs were given 4.5 Gy60 Co γ-ray total body irradiation(TBI),then randomly assigned into irradiation control group,supportive care group or cytokines+supportive care (abbreviated as cytokines)group.In addition to supportive care,rhG-CSF,rhlL-11 and rhIL-2 were administered subcutaneously to treat dogs in cytokines group.The percentage of CD34+cells,cell cycle and apoptosis of nucleated cells in peripheral blood were examined by Flow cytometry.Results After 4.5 Gy 60 Co γ-ray irradiation,the CD34+cells in peripheral blood declined obviously(61.3%and 52.1% of baseline for irradiation control and supportive care group separately).The cell proportion of nucleated cells in Go/G1 phase was increased notably(99.27% and 99.49% respectively).The rate of apoptosis(26.93% and 21.29% separately)and necrosis(3.27% and 4.14%,respectively)of nucleated cells were elevated significantly when compared with values before irradiation(P<0.05) 1 d post irradiation.When beagles were treated with cytokines and supportive care,the CD34+cells in peripheral blood were markedly increased(135.6% of baseline).The effect of G0/G1 phase blockage of nucleated cells became more serious(99.71%).The rate of apoptosis(5.66%)and necrosis(1.60%)of nucleated cells were significantly lower than that of irradiation control and supportive care groups 1 d after exposure.Conclusions Cytokines maybe mobilize CD34+cells in bone marrow to peripheral blood,indce cell cycle block at G0/G1 phase and reduce apoptosis,and eventually cure hematopoieticinjuries induced by irradiation.

Therapeutic effects of combined cytokines on hematopoietic injuries induced by 4.5 Gy γ-rays irradiation in beagles / 中华放射医学与防护杂志

Objectivc To observe the therapeutic effects of combined cytokines on hematopoietic injuries induced by 4.5 Gy60 Co γ-rays irradiation in beagles,and to provide experimental evidences for the clinical treatment of extremely severe myeloid acute radiation sickness(ARS).Methods 16 beagles were given 4.5 Gy60 Co γ-rays total body irradiation,and then randomly assigned into irradiation control group,supportive care group and cytokines group.In addition to supportive care,recombinant human granulocyte colony-stimulating factor (rhG-CSF),recombinant human interleukin-11(rhIL-11)and recombinant human interleukin-2(rhIL-2)were administered subcutaneouly to dogs in cytokines group.Peripheral blood hemogram was examined once every two days.Bone marrow and peripheral blood were collected to proceed colony cultivation 4 d pre-irradiation and 1 and 45 d post-irradiation.Conventional histopathological sections of sternum were prepared to observe the histomorphology changes. Results After irradiation,the population of all kinds of cells in peripheral blood declined sharply.WBC nadir Was elevated(1.04×109/L,but 0.28×109/L and 0.68×109/L for the irradiation control group and the supportive care group separately),the duration of thrombocytopenia was shortened (24 days,but 33 days for the supportive care groug) and red blood cell counts were maintained in the range of normal values after cytokincs treatment in combination.The colony forming efficiency of haemopoietic stem cells(HSCs)in bone marrow and peripheral blood decreased obviously 1 d post irradiation,but recovered to the level of that before irradiation 45 d post irradiation after supportive care and cytokines treatment.Hematopoietic cells disappeared in bone marrow of animals in irradiation control group,but hematopoietic functions were recovered after cytokines were administrated.Conclusions RhG-CSF.rhIL-11 and rhIL-2 used in combination could elevate WBC nadir,accelerate the recovery of leukocytes,platelets and red blood cells and promote the proliferation,differentiation and maturity of HSPCs left in the body after 4.5 Gy γ-rays total body irradiation,eventually restore the hematopoietic function.Hence,combination of rhG-CSF,rhIL-11 and rhIL-2 could serve as better therapeutic strategy to treat extremely severe myeloid ARS.

Clotting mechanism in beagles irradiated by 4.5 Gy γ-rays / 中华放射医学与防护杂志

Objective To explore the clotting mechanism in beagles irradiated by 4.5 Gy γ-rays after treatment with supportive care,or supportive care and combined cytokines.Methods Sixteen beagles were divided into irradiation control group,Supportive care group and combined cytokines treatment group.Platelet aggregation test,thrombelagtography (TEG) and the time measurement were analyzed in vitro.Results In irradiation group and supportive care group,the platelet aggregation rates in beagles were decreased markedly and the k value of TEG was increased 7 d post-irradiation,while those indexes in combined cytokines treatment group changed little.At 14 d post-irradiation,each parameter of TEG in irradiated group changed obviously.The values of r,k,r+k and M were elevated significantly,clotting time and the maximum coagulation time of thrombus delayed,the Ma value was decreased markedly,and the maximum elasticity amplitude of thrombus was diminished.All parameters in combined cytokines treatment group were better than those in supportive care group.The thrombin time was prolonged obviously in irradiated group 14 d post-irradiation,while the thrombin time was the longest at 2-3 weeks post irradiation in supportive care group and combined cytokines treatment group(P>0.05).Conclusions Cytokines could improve the platelet aggregation and the blood clotting functions of beagles suffering from acute radiation sickness.

Initial research of screening for the differentially expressed proteins in beagles irradiated with 4.5 Gy60 CO γ-rays by two-dimensional gel electrophoresis and mass spectrometry / 中华放射医学与防护杂志

Objective To explore the mechanisms of cytokines on acute radiation disease in irradiated beagles.Methods The sera of beagles irradiated with 4.5 Gy γ-rays with cytokines treatment was collected at different time points post irradiation.The two-dimensional gel electrophoresis(2-DE)was used to isolate and compare the differentially expressed proteins in sera.HD-MS was used to analyze the differentially expressed proteins with significance,and the amino acid sequences should be determined. Results High resolution 2-DE gel map was obtained.There were six differentially expressed proteins in sera of irradiated beagles at different time points.Four protein spots were successfully identified by MS.A significant spot was identified as serum amyloid A(SAA)by HD-MS,with relative molecular mass of 13 077 and isoelectfie point of 6.26.Expression of SAA was not found 1 d pre-irradiation and 36 d postirradiation,but increased slightly 1 d(0.2166)and significantly 14 d post-irradiation(0.4577). Conclusions The expression of serum amyloid A was consistent with the process of acute radiation injury,which might indicate the turnover of the disease.

Experimental therapeutic effect of combined cytokines on beagle dogs exposed to 4.5 Gy γ-rays / 中华放射医学与防护杂志

Objective To evaluate the effects of combined administration of recombinant human interleukin-11(rhIL-11),recombinant human G-CSF(rhG-CSF)and recombinant human interleukin-2 (rhIL-2)on acute radiation sickness(ARS)beagles.Methods Sixteen beagle were irradiated with 4.5 Gy60 Co γ-rays to establish ARS models,and were divided into irradiation control group,supportive care group and combined cytokines treatment group.After irradiation irradiation control group was given no treatment,the dogs in supportive care group received purely symptomatic treatment,while combined cytokines treatment group received rhIL-11 50μg/(kg·d)and rbG-CSF 10μg/(kg·d)subcutaneously(0-14 d)and rhIL-2 1×1 06 U/d(29-43 d)besides symptomatic treatment.Manifestation and characteristics of ARS beagles were observed,and the survival time were recorded.At last,post-mortem examination and histological examination were performed.Results All animals underwent nausea,diarrhea and fever.After irradiation,all animals in irradiation control group died in two weeks,and the mean survival time was 12.7 d,while only one died at 33 d in supportive care group.All dogs in combined cytokine group survived at 45 day after exposure,and their haematopoiesis and gastrointestinal tract were recovered.Conclusions Combination of rhIL-11 + rhG-CSF + rhIL-2 treatment could be significantly effective on ARS beagles irradiated by 4.5 Gy60 Co γ-rays,which could accelerate injured haemotopoiesis and intestinal tract recovery,increase the survival rate and improve the life quality of animals.

Effect of Steroidal Saponin TSA on the Recovery of Sensorimotor Function after Cerebral Ischemia in Rats / 中国康复理论与实践

@# bjective To investigate the effect of Steroidal Saponin TSA on the recovery of sensorimotor function after cerebral ischemia in rats. Methods Cerebral ischemia was induced by middle cerebral artery occlusion in rats which were divided into 6 groups: vehicle, TSA 15 mg/kg, 30 mg/kg, 60 mg/kg，Angong Niuhuang (ANGH) 400 mg/kg and sham. Animals received drug administration 3～14 d after ischemia. Sensorimotor function was evaluated with beam-walking and adhesivetape-exposing performance 3 d, 7 d, 10 d, and 14 d after ischemia. Neural cell injury in the sensorimotor cortex ipsilateral to ischemia was studied with hematoxylin-eosin stain. Immunohistochemistry Methods were used to measure the vascular endothelial growth factor (VEGF) protein and the angiogenesis of the area around infarction tissue. Results Animals receiving TSA at a dosage of 30 mg/kg and 60 mg/kg recovered better in beam-walking and adhesivetape-exposing performance than vehicles, and the improvement became significant 14 d after ischemia. Treatment with TSA 30 mg/kg、60 mg/kg also significantly reduced the neural cell loss in sensorimotor cortex and increased the expression of VEGF protein and the microvascular density. Conclusion TSA can improve the recovery of sensorimotor function follwing focal cerebral ischemia in rats, which may involve the neural cells protection, promoting the expression of VEGF and angiogenesis after ischemia.

Effects of pervanadate on radiation-induced G2/M arrest and apoptosis in BET-2 cells / 肿瘤研究与临床

Objective To study the effects of Pervanadate(Per) on BET-2 cells cell cycle arrest and apoptosis induced by ionizing radiation. Methods The BET-2 cells were radiated with 0, 1, 3, 5, 7, 10 Gy and divided into PTP(protein tyrosine phosphatases)-specific inhibitor Per-treated group and non-pervanadate group(served as a control) and then incubated after ?-ray irradiation. Cell cycle and apoptosis were measured by FCM and Hematoxylin-Eosin staining at different time phases. Results G2/M phase arrest and apoptosis were induced in a pattern of dose-effect and time-course after irradiation in the BET-2 cells. In Per-treated group, G2/M phase arrest increased more notably, and apoptosis decreased markedly. Conclusions These studies suggested that Pervanadate potentialy enhance the ratio and prolong the term of G2/M phase arrest, and facilitate the damaged hematopoietic cells to be repaired, remarkably prevent radiated-cells from apoptosis.

Research progress in improving brain function by Anemarrhena asphodeloides Bge and its effective components / 中国药理学通报

Saponin and sapogenin are main components in chinese medicine Anemarrhena asphodeloides Bge.Modern research has shown that Anemarrhena asphodeloides Bge and its effective components could markedly enhance the ability of learning and memory in dementia animals,as well as improve the descent of brain function.The effect was related with many factors such as inhancing the cholinergic receptor(M,N),improving the activity of ChAT and inhibiting the activity of AChE,regulating the balance of ? receptor-cAMP and M receptor-cGMP,improving the metabolite of free radicals in model animal brains and so on.

Hematopoietic growth factors and acute radiation sickness / 解放军医学杂志

In more than ten years, hematopoietic factors have been approved to be effective in the treatment of radiation sickness. But there are still some problems in the clinical application, such as suitable cases, dosage, administrative timing, and drug combination. Due to those problems, the efficacy was undermined. Our experimental treatment study showed that hematopoietic factors should be administered early after the radiation exposure. The efficacy of early administration group is better than the one treated in acute phase of radiation sickness. There is also a limit of application duration but not the longer the better. RhTPO along can not induce the granulocytopoiesis and rhG-CSF can not improve the recovery of megakaryopoiesis. Hematopoietic factors do not increase the chromosome mutation rate of tumor cells. We did not observe bone marrow stem cell or progenitor cell exhaustion after we treated those animals for a second cycle of hematopoietic factors or exposed those treated animals to radiation again. RhG-CSF is more effective in the recovery of granulocytopoiesis than rhGM-CSF. RhIL-11 can increase the recovery of three cell lines of bone marrow, especially megakaryopoiesis. We recommended the combination of hematopoietic factors in the treatment of acute radiation sickness. RhG-CSF plus rhIL-11 is a preferred combination.