雨虎属Ras同系物-Ⅰ基因及其与口腔肿瘤间的关系

雨虎属Ras同系物(arh)-Ⅰ基因参与细胞周期调控和信号通路的传导,从而负向调节细胞生长和诱发程序性细胞死亡。arh-Ⅰ基因在卵巢、乳腺和胰腺等癌细胞中均有表达缺失,即arh-Ⅰ基因与肿瘤的形成和发展密切相关。本文就arh-Ⅰ基因的定位与结构、作用途径和与肿瘤间的关系等研究进展作一综述。     

RASSF1A Hypermethylation is Associated with Aflatioxin B1 and Polycyclic Aromatic Hydrocarbon Exposure in Hepatocellular Carcinoma

Background/Aims: RASSF1A hypermethylation is frequently observed in hepatocellular carcinomas (HCC). But the possible related risk factors and prognosis evaluation for this epigenetic alteration are still unknown. Methodology: Methylation status, mRNA and protein expression of RASSF1A, aflatoxin B1 (AFB1) and polycyclic aromatic hydrocarbon (PAH)-DNA adducts, were examined in 103 cases of HCC. Results: The expression of RASSF1A mRNA (20/103, r=-0.665) and protein (21/103, r=-0.761) were negatively related to RASSF1A hypermethylation (82/103). Multivariate analysis indicated that RASSF1A hypermethylation was related to AFB1- (p=0.046) and PAH-DNA adducts (p=0.040). Other factors including smoking, alcohol drinking, hepatitis B virus infection and clinicopathological parameters were not significantly associated with RASSF1A methylation. No difference in overall survival was observed between patients with and without RASSF1A hypermethylation (p=0.267). Conclusions: AFB1- and PAH-DNA adducts may be associated with RASSF1A hypermethylation in hepatocarcinogenesis. RASSF1A methylation status may not be a proper predictor of overall survival for HCC.     

冷应激建立家兔动脉粥样硬化不稳定斑块模型的方法和评价

目的 探讨建立冷应激家兔腹主动脉粥样硬化不稳定斑块模型的方法和评价. 方法60只雄性纯种新西兰大白兔,数字抽签随机分为3组(每组20只).冷应激组高脂喂养加球囊损伤,此外除手术后1周每天置于4℃环境中给予冷应激刺激1h,持续到第20周;球囊损伤组单纯高脂喂养加球囊损伤;对照组普通颗粒饲料喂养无特殊处理.20周末观察血脂、炎性因子、斑块形态、斑块组成成分及新生血管形成的变化. 结果 冷应激组与球囊损伤组兔血脂比较.差异无统计学意义.冷应激组氧化型低密度脂蛋白(ox-LDL),超敏C反应蛋白(hs-CRP)、白细胞介素(IL)-8分别为(56.1±14.3)mg/L、(149.1±78.3)mg/L、(97.6±17.9)μg/L,高于球囊损伤组(42.9±13.8)mg/L、(94.5±57.3)mg/L、(57.5±18.3)μg/L,差异有统计学意义(t值分别为2.78、6.91、14.94,均P＜0.05);冷应激组巨噬细胞含量为(30.9±5.6)％,高于球囊损伤组(18.7±4.8)％,差异有统计学意义(t=6.88,P＜0.05);斑块内新生血管生成率冷应激组74.1％(23/31),高于球囊损伤组的20.0％(5/20),差异有统计学意义(x2=16.26,P＜0.05),对照组无斑块形成. 结论 冷应激结合高脂饮食加球囊损伤可成功建立兔动脉硬化不稳定斑块模型,其方法优于传统单纯高脂饮食加球囊损伤.     

Metabolic Effects of Intraoperative Amino Acid Infusion in Mongrel Dogs

Background: Intraoperative amino acid infusion can attenuate the decrease in core temperature, but the metabolic effects are uncertain. Methods: Thirty-six healthy mongrel dogs undergoing ileectomy under general anesthesia were infused intraoperatively with normal saline or 18 compound amino acids at 6, 12, and 24 kJ·kg(-1)·h(-1) (NS, 6-, 12-, and 24-kJ groups) and studied until 24 h after the operation. Blood glucose, plasma insulin, free fatty acids, and triglyceride concentrations were determined at 7 defined time points. Muscle aminograms, urinary urea, and 3-methylhistidine excretions were measured before and after the operation. Results: Blood glucose and plasma insulin increased amino acid dose dependently during the operation and in the early period after the operation. Free fatty acids were significantly lower in the 12- and 24-kJ groups compared with the NS group at the end of the operation. The negative nitrogen balance was alleviated dose dependently in the amino acid groups on operation day. The urinary 3-methylhistidine decreased significantly during the first 24 h after the operation in the 24-kJ group, while it increased in the other groups with the largest increase in the NS group. Basic, branched-chain, and aromatic amino acids in the vastus lateralis muscle increased dose dependently at the end of the operation in the amino acid groups. Conclusion: Intraoperative amino acid infusion has the dose-dependent effects of increasing blood glucose, inhibiting fat mobilization and muscle protein breakdown.     

Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11β-hydroxysteroid dehydrogenase type 1

Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11β-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11β-HSD1 with an IC(50) of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11β-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11β-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11β-HSD1 inhibitors suitable for in vivo evaluation in rodent models.     

Selenoprotein S expression in the rat brain following focal cerebral ischemia

Recent studies on cerebral ischemic stroke have demonstrated the importance of the inflammatory response. Ongoing inflammatory insults have been implicated as a secondary mechanism underlying neuronal injury induced by ischemia, and anti-inflammatory strategies have gained considerable interest. Selenoprotein S (SelS), which is an endoplasmic reticulum resident protein, is known to promote cell survival by regulating inflammation. Moreover, SelS has been shown to be responsive to ischemia in cultured astrocytes. A Finnish report revealed that a variation in the SelS gene locus is associated with a higher predisposition to ischemic stroke in humans, suggesting a crucial role for SelS in protection against brain ischemia. However, the time-course of SelS expression following cerebral ischemia in vivo remains unknown. In the present study, we show, for the first time, differential SelS expression from 3 h to 7 days after reperfusion in rats with transient focal cerebral ischemia induced by a 1-h middle cerebral artery occlusion. We found that the SelS protein level decreased in the ischemic core 3–7 days after reperfusion. Furthermore, SelS expression was upregulated in the ischemic penumbra adjacent to the ischemic core 3–7 days after reperfusion and is matched by reactive astrogliosis. Thus, we propose that the upregulation of Sels represents a reaction of astrocytes against inflammatory stimuli, and the findings of this study open a new chapter in the research of the interrelationships between SelS and cerebral ischemic stroke.