胆碱,氟化钠和阿托品对呋喃丹急性中毒的联合解救作用

胆碱(Ch)和NaF对呋哺丹(Fu )急性中毒小鼠有保护作用,Ch、NaF,阿托品三者合用对Fu急性中毒动物的防治作用均显著优于阿托品单用。大鼠离体膈神经膈肌、豚鼠离体空肠和大鼠肝脏代谢实验及对大鼠全血胆碱酯酶(ChE)活力测定的结果表明,NaF的抗毒作用可能是由于其对神经肌肉接头和/或神经节中的N受体的抗脱敏作用;而Ch则可能通过其对ChE的保护和/或加速被抑制ChE的复能,阻碍Ach到达M受体部位而发挥作用。     

肝细胞生长因子和表皮生长因子对体外肝细胞生长的影响

取成年小鼠肝细胞在RPMI1640培养液中加热60℃胎肝提取液(FE_(60)HSS),加热80℃胎肝提取液(FE_(80)HSS)及加热60℃成年雄性小鼠颌下腺提取液(M_(60)EGF),用I~(125)UdR掺入法测定其肝细胞DNA合成,结果显示FE_(60)HSS为8575±17cpm,FE_(80)HSS为4788±990cpm,M_(60)EGF为4592±1120cpm,和对照组1902±657cpm比较差异有非常显著意义(P值均<0.01)。FE_(60)HSS组对细胞DNA合成较FE_(80)HSS明显,说明HSS对加热80℃不很稳定。     

Synthesis and antitumor evaluation ofcis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and-uridine analogues

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), {[N-(2′,3′,5′-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine}dichloroplatinum (II) (6a), {[N-(2′,3′,5′-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine}dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatiate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4a) and 6-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2′,3′,5′-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2′,3′,5′-tri-O-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.     

Erythropoietin Just Before Reperfusion Reduces Both Lethal Arrhythmias and Infarct Size via the Phosphatidylinositol-3 Kinase-Dependent Pathway in Canine Hearts

Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 ± 1.6%, low dose (100 IU/kg): 22.1 ± 2.4%, control: 40.0 ± 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.     

Manipulation of myocardial alpha-tocopherol levels fails to affect reperfusion arrhythmias or functional recovery following ischemic challenge in the rat heart

Summary Antioxidants that act as free radical scavengers have the potential to inhibit lipid peroxidation. It has previously been proposed that a relationship exists between free radicals, lipid peroxidation and reperfusion-induced arrhythmias. We have therefore examined the ability of the lipid-soluble antioxidant, alpha-tocopherol, to decrease the incidence of reperfusion-induced arrhythmias. We have shown that the myocardial alpha-tocopherol content can be significantly increased from its control value of 65.3±5.6 nmoles/g wet wt of heart to 115.0±15.6 nmoles/g wet wt of heart (p<0.01) by chronic intraperitoneal pretreatment and that it can be decreased, to 21.1±3.7 nmoles/g wet wt of heart (p<0.01), by chronic dietary manipulation. Rat hearts isolated from either of these groups, or from placebo-treated control animals, were subjected to 5 or 10 min coronary artery occlusion and were subsequently reperfused; there were no significant differences between the incidence and duration of VF and VT or the incidence and number of VPBs in these three groups. The effect of alpha-tocopherol manipulation on metabolic and functional recovery of working hearts subjected to 20 min global ischemia was subsequently examined and no significant changes were observed. Cardiac output recovered to 82±4, 81±6 and 76±5% of its preischemic value in the control, enriched and depleted groups, respectively. In conclusion, myocardial alpha-tocopherol content appears to bear no relation to the severity of reperfusion-induced arrhythmias or to the resistance of the heart to ischemic injury.     

DNA interactions of dinuclear Ru arene antitumor complexes in cell-free media

We recently synthesized and characterized water-soluble dinuclear Ru^II arene complexes, in which two {(η⁶-p-isopropyltoluene)RuCl[3-(oxo-κO)-2-methyl-4-pyridinonato-κO₄]} units were linked by flexible chains of different length [(CH₂)_n (n = 4, 6, 8, 12)]. These new dinuclear ruthenium drugs were found to exert promising cytotoxic effects in human cancer cells. In the present work DNA modifications by these new dinuclear Ru^II arene compounds, which differed in the length of the linker between the two Ru^II centers, were examined by biochemical and biophysical methods. The complexes bind DNA forming intrastrand and interstrand cross-links in one DNA molecule in the absence of proteins. An intriguing aspect of the DNA-binding mode of these dinuclear Ru^II compounds is that they can cross-link two DNA duplexes and also proteins to DNA—a feature not observed for other antitumor ruthenium complexes. Thus, the concept for the design of interhelical and DNA-protein cross-linking agents based on dinuclear Ru^II arene complexes with sufficiently long linkers between two Ru centers may result in new compounds which exhibit a variety of biological effects and can be also useful in nucleic acids research.     

The effect of mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices

Positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu5) have promising therapeutic potential. The effects of selective mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices have not been previously reported. The current study demonstrated that the selective mGlu5 receptor positive allosteric modulator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)-methyl]phenyl}-2-hydrobenzamide (CPPHA) potentiated the response to a subthreshold concentration of 3,5-dihydroxy-phenylglycine (DHPG) on extracellular signal-regulated protein kinase (ERK) and cyclic-AMP responsive element-binding protein (CREB) activity, as well as N-methyl d-aspartate (NMDA) receptor subunit NR1 phosphorylation in cortical and hippocampal slices. These results suggest that allosteric modulators of mGlu5 receptor could have physiologically significant effects by potentiating the actions of glutamate.     

活体实验性胰腺炎动物模型的选择

为探讨胰腺炎的发病机制、病因、病理生理及治疗方法 ,已建立了众多的活体胰腺炎动物模型。由于活体胰腺炎模型具有操作相对简单、容易控制、便于观测全身变化指标和利于治疗研究等优点 ,目前应用较多 ,而正确选择一种既适合实验设计目的 ,又简单易行 ,重复性好的模型是进行胰腺炎研究的基本条件之一