Establishment of a molecular platform for screening thalidomide derivatives with potential high anti-tumor activities / 国际药学研究杂志

objective To establish a molecular platform for screening thalidomide derivatives with potential high anti-tumor activities. Methods Human cereblon(CRBN) and Ikaros family zinc finger protein 1(IKZF1) cDNA were amplified and cloned into pXJ40-myc and pcDNA3-FLAG vectors respectively. Then the two constructs were transfected into 293T cells and the anti-tumor activities of thalidomide and its derivatives were reflected by their effects on the binding between CRBN and IKZF1 proteins. Results Both CRBN and IKZF1 were successfully expressed in 293T cells. Thalidomide and two of its derivatives were found to enhance the interaction between CRBN and IKZF1 significantly. Conclusion A molecular platform was successfully established for screening thalidomide derivatives with potential high anti-tumor activities and two thalidomide derivatives could potentiate the binding between CRBN and IKZF1, suggesting that they possess potential anti-tumor activities.

Changes of vital signs in dog progressive cirulatory failures induced by soman / 中华急诊医学杂志

Objective To investigate the changes of vital signs and the damage of important organs in dog progressive circulatory failures induced by soman.Method Seven male dogs,weighing(12～15)kg,were injected intramuscularly 1/3 LD sornan(1 LD=10μg/kg)per ten minutes.The moan blood pressure decreased to (40～45)mmHg was defined as circulatory failure.The changes of heart rate,blood pressure.and hemodynamic parameters were evaluated by an eight-channel direct-witing oscillograph,blood gas,pH value,electrolyte,and the damage of important organs were observed before and after sornan injection.Statistical analysis of the data was performed using the self control t test with the SAS 6.12 Software Program.Results In anesthetized dogs intoxicated with sornan,the circulatory failure was characterized by the significant decreases in blood pressure,heart rate and hemodymrnic parameters(P<0.05).Partial pressure of oxygen was less than 60 mmHg,saturation of oxygen Was less than 90% and partial pressure of carbon dioxide was greater than 50 mmHg in arterial blood of the dog model.These results showed mix respiratory failure occurred during intermittent positive pressure.Significant metabolic acidosis was induced by soman[pH(7.345±0.064)vs.(6.956±0.022),P<0.01].The concentralion of sodium ion and chloride ion in blood were changed gently.The concentrations of GTP,GOT,Cr,BUN,CK-MB and LDH were increased significantly(P<0.05),which showed multiple important organs including liver,kidney and heart were damaged by sornan.Conclusions The severe progressive circulatory failure induced by cholinesterase inhibitor sornan leads to the darnage of vital signs and important organs significantly.

Advances in study of endogenous protective mechanisms of cardiac ischemia/reperfusion injuries / 中国药理学通报

Currently ischemic preconditioning is one of the most efficacious ways to treat ischemia reperfusion via triggering endogenously protective system. However, pharmacologic preconditioning has been produced due to the difficulty of performing ischemia preconditioning. Pharmacologic preconditioning, including both receptors and non-receptors, is actively investigated for the treatment of ischemia reperfusion.

Effects of new derivatives of 1H-isoindole-1,3(2H)-dione on angiogenesis in chick chorioallantoic membranes / 中国药理学通报

Aim To investigate the effects of new derivatives of 1H-isoindole-1,3(2H)-dione on angiogenesis in chick chorioallantoic membranes(CAM). Methods The blood vessels of CAM were calculated to determine the antiangiogenic effects of different new compounds. Results Among the 18 new derivatives of 1H-isoindole-1,3(2H)-dione , compound 1,2,3,4,11 and 13 showed significant inhibition on angiogenesis of CAM.Conculsion The 6 new derivatives of 1H-isoindole-1,3(2H)-dione screened out in this experiment may be novel angiogenesis inhibitors.

Effects of iptakalim hydrochloride on myocardial ATP-sensitive potassium channels / 中国药理学通报

AIM To investigate the effects of iptakalim hydrochloride(Ipt) on potassium currents in cardiomyocytes derived from guinea pig and on the specific binding of glibenclamide (Gli) with sulfonylurea receptor(SUR_ 2A ) of ATP-sensitive potassium channel (K_ ATP ) in cardiac membranes derived from Wistar rats. The effects of Ipt on the association and dissociation kinetic processes of Gli binding with SUR_ 2A of K_ ATP in cardiac preparations were also determined. METHODS The effects of Ipt on potassium currents in cardiomyocytes were observed by using patch clamp technique(whole cell recording) after application of the drug in the bath. The experiments of the ass ociation and dissociation kinetic processes of K_ ATP blocker [ 3H]Gli binding with cardiac membranes were used. RESULTS (1)The potassium current-voltage curves (I-U curves) of cardiomyocytes derived from guinea pig were upward shifted by Ipt at the concentrations of 1 and 100 ?mol?L -1 . Within 5 minutes after application of the drug, the current amplitude increased to 124.9%?9.5%(n=5)and 151.6%?11.2%(n=7)of initial current amplitude respectively(P

Effects of iptakalim hydrochloride on hypertensive cardiac remodeling / 中国药理学通报

AIM To study the experimental therapeutic effects of iptakalim hydrochloride(Ipt) on hypertensive cardiac remodeling in spontaneously hypertensive rats(SHR) and stroke prone spontaneously hypertensive rats(SHRsp). METHODS SHR at the age of 12 week old were treated ig with lisinopril 12 mg?kg -1 ?d -1 or Ipt 3 mg?kg -1 ?d -1 , once a day for 30 days. Age matched Wistar rats were used as normal control. 10 week old SHRsp were treated ig with Ipt 0 25,1 0 and 4 0 mg?kg -1 , once a day for 12 weeks. Age matched Wistar rats were used as normal control. After killing animals, the effects of Ipt on hypertensive cardiac remodeling were investigated. RESULTS During the 4 week experimental period, the systolic blood pressure(SBP) and heart rates(HR) of the untreated SHR were increased progressively. Ipt 3 mg?kg -1 ?d -1 could decrease SBP effectively and inhibit the increasing tendency of HR. Ipt had no effects on hypertensive cardiac remodeling in SHR. Under the same experimental conditions, lisinopril 12 mg?kg -1 ?d -1 could decrease SBP effe-ctively and had no effects on HR. The hypertensive cardiac remodeling could be alleviated by lisinopril. During the 12 week experimental period, the SBP of the untreated SHRsp were increased progressively. Ipt 0 25,1 0 and 4 0 mg?kg -1 could decrease the SBP of SHRsp effectively. Ipt at the doses of 0 25 and 1 0 mg?kg -1 had no effects on heart rates. But in the 4th week after administration of Ipt 4 0 mg?kg -1 , significant decrease in heart rates was observed. Compared with Wistar rats, the weight of left ventricle and septum(LV+S) and the ratio of LV+S to body weight(LV+S/BW) in untreated SHRsp were elevated significantly. Ipt 0 25, 1 0 and 4 0 mg?kg -1 ?d -1 could decrease LV+S and LV+S/BW significantly. CONCLUSION Ipt could decrease SBP of SHR and SHRsp effectively. The effects of Ipt on hypertensive cardiac remodeling were related with the experimental therapeutic period. After having been treated with Ipt for 4 weeks, the hypertensive cardiac remodeling could not be reversed. But after having been treated with Ipt for 12 weeks, the hypertensive cardiac remodeling could be reversed significantly.

Changes of hemodynamic parameters and ECG in circulatory failure rats induced by organophosphate insecticides / 中国病理生理杂志

AIM: To investigate the changes of hemodynamic parameters and ECG in circulatory failure rats induced by organophosphate insecticides DDV and parathion.METHODS: Healthy Wistar male rats,weighing(320?20)g,were treated with organophosphate insecticides by ip.to induce circulatory failure.When the mean blood pressure(MBP) decreased to 45 mmHg,the changes of hemodynamic parameters and ECG were observed.RESULTS: In circulatory failure rats,SBP,DBP,MBP,HR,LVDP,IP,+dp/dtmax,-dp/dtmax,Vpm and +dp/dtmax/IP changed dramatically(P

Effects of iptakalim hydrochloride on the association and dissociation kinetic processes of [~3H] glibenclamide binding with ATP-sensitive potassium channels in artery smooth muscles and its crosstalk with nucleotides / 中国药理学通报

AIM To investigate the effects of iptakalim hydrochloride(Ipt) on the association and dissociation kinetic processes of [ 3H]glibenclamide(Gli) binding with sulfonylurea receptor(SUR 2B ) of ATP sensitive potassium channel (K ATP ) in vascular smooth muscles derived from Wistar rats,and to compare the properties of Ipt with those of nucleotides. The interactions between Ipt and nucleotides were also determined. METHODS The experiments of the association and dissociation kinetic processes of K ATP blocker[ 3H]Gli binding with endothelium denuded aorta smooth muscles were used. RESRLTS (1)The specific bindings of[ 3H]Gli with SUR 2B were not displaced by Ipt at the concentrations of 10 pmol?L -1 ～ 0 5 mmol?L 1 . Ipt 100 ?mol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B . (2)Opposite to Ipt, ATP 1 mmol?L -1 accelerated the association kinetic process and retarded the dissociation kinetic process of [ 3H]Gli binding with SUR 2B There was an interaction between ATP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (3) Similar with Ipt, ADP 1 mmol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B , there was an interaction between ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (4)Different from ATP and ADP, UDP had no effect on the association and dissociation kinetic process of [ 3H]Gli binding with SUR 2B . And there was not interaction between UDP and Ipt. CONCLUSION Ipt had no affinity with the binding sites of K ATP blocker in SUR 2B , but had negative allosterical modulation on it. The modulatory properties of Ipt were opposite to those of ATP, similar with those of ADP and different from those of UDP. There were interactions between ATP, ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B , but there was not interaction between UDP and Ipt.

Effect of iptakalim on prevention isoprenaline induced cardiomyocytes hypertrophy / 中国药理学通报

Aim To investigate the effect of iptakalim on neonatal cardiomyocytes hypertrophy induced by isoprenaline(ISO).Methods Hypertrophy in neonatal rat cardiac myocytes was established via culture with ISO.Total protein content was measured by Lowrys method.The fluorescence intensity of intracellular Ca2+ was detected respectively with Fluo-3/AM loading by the laser confocal microscopy.Results ① 1?10-5mol?L-1 ISO can activated ?-AR completely;② the total protein of cardiomyocytes and intracellular i was markedly decreased by treatment with IPT and represented a dose-dependent manner.Conclusion IPT could inhibit the increase of protein content of cardiomyocytes induced by ISO,which may be contributed to the decease of intracellular Ca2+ concentration.