CARDIOPROTECTIVE EFFECT OF l-GLUTAMATE IN OBESE TYPE 2 DIABETIC ZUCKER FATTY RATS

• 1 Because diabetic hearts have an increased threshold for cardioprotection by ischaemic preconditioning (IPC), we hypothesized that protection by l ‐glutamate during reperfusion is restricted in Type 2 diabetic hearts. Previously, we found that l ‐glutamate‐mediated postischaemic cardioprotection mimics IPC.
• 2 Rat hearts were studied in a Langendorff preparation perfused with Krebs’–Henseleit solution and subjected to 40 min global no‐flow ischaemia, followed by 120 min reperfusion. l ‐Glutamate (0, 15 and 30 mmol/L) was added to the perfusate during reperfusion of hearts from non‐diabetic (Wistar‐Kyoto) and diabetic (Zucker diabetic fatty (ZDF)) rats, studied at 16 weeks of age. The infarct size (IS)/area‐at‐risk (AAR) ratio was the primary end‐point. Expression of l ‐glutamate excitatory amino acid transporter (EAAT) 1 (mitochondrial) and EAAT3 (sarcolemmal) was determined by quantitative polymerase chain reaction and immunoblotting.
• 3 The ISS/AAR ratio did not differ between control hearts from Wistar‐Kyoto and ZDF rats (0.52 ± 0.03 and 0.51 ± 0.04, respectively; P = 0.90). l ‐Glutamate (15 mmol/L) significantly reduced the IS/AAR ratio in non‐diabetic hearts, but not in diabetic hearts, compared with their respective controls. The higher concentration of l ‐glutamate (30 mmol/L) reduced infarct size in diabetic hearts to the same degree as in non‐diabetic hearts (IS/AAR 0.35 ± 0.03 (P = 0.002) and 0.34 ± 0.03 (P = 0.004), respectively). The mitochondrial l ‐glutamate transporter EAAT1 was downregulated in hearts from ZDF rats at both the mRNA and protein levels (P < 0.0005 and P < 0.0001, respectively). However, there was no change in EAAT3 expression at the protein level. Myocardial l ‐glutamate content was increased by 43% in diabetic hearts (P < 0.0001).
• 4 Hearts from obese diabetic rats have an elevated threshold for metabolic postischaemic cardioprotection by l ‐glutamate. These findings may reflect underlying mechanisms of inherent resistance against additional cardioprotection in the diabetic heart.

     

3-甲基芬太尼衍生物立体异构体的 QSAR 研究

用比较分子力场分析(CoMFA)方法研究了3-甲基芬太尼和羟甲芬太尼立体异构体的三维定量构效关系(3D-QSAR)。所得CoMFA-QSAR模型有很好的预测能力(γ²_{cros-validated}=0.716,n_{optimalcomponent}=5,γ²_conventional=0.999,s=0.052,F=1305.1),模型中,被研究化合物的构象可能就是其活性构象。以AM1方法进行量子化学计算,获得上述可能活性构象的结构参数及空间位置参数。基于这些参数,用偏最小二乘法(PLS)获得了被研究化合物的QSAR方程。所得PLS-QSAR模型具有较好的预测能力,并且显示被研究化合物的镇痛活性取决于分子中负电性的哌啶氮原子(N_PA)净电荷以及哌啶氮原子、羰基氧原子、1-β-苯环、4-N-苯环、3-甲基和2′-羟基的空间位置。     

抗三尖杉酯碱HL-60细胞的抗程序性细胞死亡及其克服

三尖杉酯碱(harringtonin,HT)是中国产植物海南粗榧(Cephalotaxus hainanensis Li)中提取的一种抗肿瘤药物,对急性粒细胞白血病、急性单核细胞白血病有较好疗效⁽¹⁾。三尖杉酯碱可非常有效地诱导敏感HL-60细胞程序性死亡(apoptosis,Apo)^(2,3)。但超过半致死剂量(IC₅₀)近百倍的HT却不能诱导抗三尖杉酯碱细胞HT12程序性死亡。如用维拉帕米(verapamil,Vp)10μg·mL^-1逆转多药抗性后,HT虽可诱导HT12细胞程序性死亡,但与敏感细胞相比,出现程序性细胞死亡的时间大大推迟,用药浓度也提高约10倍。这些结果提示:程序性细胞死亡可能作为肿瘤细胞是否已形成抗药性的标志之一,同时也说明程序性细胞死亡相关因子可能参与肿瘤细胞抗药性的形成。     

Regulation of hematopoiesis II: the role of polyamine inhibition on helper or suppressor influences of the thymus

We have previously suggested in murine model systems, that two cell subpopulations with differing proliferative capacity, from the thymus, modify the growth of erythroid progenitor cells in vitro. In order to further characterize these populations, we have specifically inhibited polyamine biosynthesis; this pathway is essential for the process of cell replication. Thus, alpha-difluoromethyl ornithine (DFMO) was used to block the conversion of ornithine to putrescine, the first and rate- limiting step in polyamine biosynthesis. We observed a threefold increase in hematopoietic progenitors (CFU-S and CFU-E) from bone marrow in animals treated with DFMO. We further examined the effect of DFMO on accessory "helper" and "suppressor" cells from the thymus and observed an increase in helper activity with an elimination of suppressor activity. All of these effects of DFMO were specific for inhibition of polyamine biosynthesis, since simultaneous addition of the depleted biosynthetic product, putrescine, restored suppressor activity. We conclude that polyamine biosynthesis is required acutely for accessory cell regulation of hematopoiesis.