9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha.

Vitamin A (retinol) and its natural derivatives are required for many physiological processes. The activity of retinoids is thought to be mediated by interactions with two subfamilies of nuclear retinoic acid receptors, RAR and RXR. The RARs bind all-trans retinoic acid (t-RA) with high affinity and alter gene expression as a consequence of this direct ligand interaction. RXR alpha is activated by t-RA, yet has little binding affinity for this ligand. t-RA may be converted to a more proximate ligand that directly binds and activates RXR alpha, and we have developed a method of nuclear receptor-dependent ligand trapping to test this hypothesis. Here we report the identification of a stereoisomer of retinoic acid, 9-cis retinoic acid, which directly binds and activates RXR alpha. These results suggest a new role for isomerization in the physiology of natural retinoids.     

视黄素受体介导的视黄素（retinoids）抗癌作用

对近年来视黄素受体介导视黄素抗癌作用机理的研究进展作一综述,主要有：1）视黄素受体;2）视黄素受体与细胞生长;3）视黄素受体与孤生受体的的相关性;4）视黄素受体对AP-1活性的抑制作用;5）视黄素受体介导的信号转导途径。通过研究,对于探讨视黄素受体的功能、阐明视黄素的抗癌机理、合成更多的受体选择性视黄素具有重要的现实意义。     

Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid.

Retinoid response pathways are mediated by two classes of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A central question is whether distinct response pathways are regulated by these two classes of receptors. The observation that the stereoisomer 9-cis-retinoic acid binds with high affinity to RXRs suggested that this retinoid has a distinct role in controlling RXR activity, but it was almost simultaneously discovered that RXRs function as auxiliary receptors for RARs and related receptors, and are essential for DNA binding and function of those receptors. Hence, although RARs seem to operate effectively only as heterodimeric RAR/RXR complexes, RXRs themselves apparently function predominantly, if not exclusively, as auxiliary receptors. Here we report that 9-cis-retinoic acid induces RXR homodimer formation. Our results demonstrate a new mechanism for retinoid action by which a ligand-induced homodimer mediates a distinct retinoid response pathway.     

"一锅煮"合成新型类维生素A酸甲叉二酯

为了改善类维生素A酸的疗效,利用两分子类维生素A酸与一分子二溴甲烷偶联,设计合成了具有结构对称性的4种类维生素A酸甲叉二酯,即全反式维A酸甲叉二酯、异维A酸甲叉二酯、阿维A酸甲叉二酯、阿达帕林甲叉二酯,并以1H NMR,MS对它们进行了结构确证.     

大鼠再生肝8种细胞的PPARγ信号通路相关基因转录谱预示脂类代谢活动

为了解大鼠肝再生中肝细胞、胆管上皮细胞、卵圆细胞、星形细胞、窦内皮细胞、库普弗细胞、陷窝细胞、树突状细胞等8种肝脏细胞的PPARγ信号通路相关基因转录谱及其预示的脂类代谢活动,按本卷2期张丽君[1]等方法分离大鼠再生肝8种细胞,检测它们的PPARγ信号通路基因表达谱,分析其预示的生理活动.结果表明,41个PPARγ信号通路相关基因在大鼠肝再生中发生了有意义的表达变化,其中上调、下调和上/下调的基因为9、9、23个,呈现15种表达相关性.相应细胞的基因数为10、6和1,10、12和2,7、7和0,16、8和3,18、7和1,10、6和1,11、20和0,13、9和4.它们的转录谱预示,胆管上皮细胞和星形细胞的脂肪合成、星形细胞和树突状细胞的胆固醇代谢、8种肝脏细胞的脂肪酸运输和脂肪细胞分化、星形细胞、窦内皮细胞和树突状细胞的脂肪酸氧化和糖异生、胆管上皮细胞和树突状细胞的能量代谢增强.上述结果表明,PPARγ信号通路与大鼠肝再生密切相关.     

Identification of a second human retinoic acid receptor

We have previously described a human complementary DNA that encodes a novel protein which is homologous to members of the steroid/thyroid nuclear receptor multigene family. This novel protein (hap for hepatoma) exhibits strong homology with the human retinoic acid receptor (RAR) which has been recently characterized. To test the possibility that the hap protein might also be a retinoid receptor, a chimaeric receptor was created by replacing the putative DNA binding domain of hap with that of the human oestrogen receptor (ER). The resulting hap-ER chimaera was then tested for its ability to trans-activate an oestrogen-responsive reporter gene (vit-tk-CAT) in the presence of possible receptor ligands. Here we show that retinoic acid (RA) at physiological concentrations is effective in inducing the expression of this reporter gene by the hap-ER chimaeric receptor. This demonstrates the existence of two human retinoic acid receptors designated RAR-alpha and RAR-beta.     

部分水解瓜尔豆胶对高脂高糖饮食诱导小鼠代谢紊乱的调节作用

部分水解瓜尔豆胶(partially hydrolyzed guar gum,PHGG)是一种有益于代谢平衡的可溶性膳食纤维,但其对糖脂代谢紊乱的调节效果及其潜在机制尚不明确。利用高脂高糖饮食诱导小鼠16周,使其产生明显的脂代谢紊乱和胰岛素抵抗,进一步通过检测小鼠糖耐量、血清生化指标、脂肪形态、肠道短链脂肪酸及相关mRNA的表达,考察PHGG对模型小鼠的糖脂代谢稳态及肠道环境的调节作用。结果表明:长期高脂高糖饮食条件下,PHGG组小鼠比模型组小鼠的体质量增长率减缓,空腹血糖降低,葡萄糖耐量和胰岛素耐量显著提升；血清中的甘油三酯、总胆固醇、低密度脂蛋白胆固醇和游离脂肪酸可分别降低21.56%、32.67%、25.66%和22.91%,明显抑制了脂肪积累。PHGG将肠道胰高血糖素样肽-1的分泌提升并恢复到67.76pmol/L,盲肠中的丁酸含量比模型组提升了7.14倍。定量PCR显示,PHGG干预后小鼠短链脂肪酸受体GPR43的蛋白表达水平比模型组提升了63.30%。本研究表明,PHGG通过调节短链脂肪酸影响脂联素、胰岛素的分泌,进而改善高脂高糖饮食引起的糖脂代谢紊乱,可以应用于辅助糖脂代谢调控的功能性食品开发中。     

全反式维甲酸对HL—60细胞hTERT基因表达和端粒酶活性的影响

目的：探讨全反式维甲酸（ATRA）诱导HL－60细胞分化过程中人类端粒酶逆转录酶（hTERT)蛋白表达和端粒酶活性的改变,方法：应用间接免疫荧光标记法通过流式细胞仪检测hTERT蛋白含量的变化;采用多聚酶链反应－酶联免疫反应（PCR－ELISA）方法检测ATRA处理HL－60细胞前后端粒酶活性的改变,用碘化丙锭染色经流式细胞仪检测细胞周期的变化,结果：ATRA作用于HL－60细胞后,细胞内hTERT蛋白含量逐渐降低,细胞的端粒酶活性相应受到抑制。结论：在IL－60细胞分化过程中,可以通过hTERT基因的表达下调而抑制端粒酶的活性。     

全反式维甲酸三氧化二砷联合化疗治疗急性早幼粒细胞性白血病的临床研究

目的：观察全反式维甲酸、三氧化二砷双诱导联合化疗对急性早幼粒细胞性白血病的疗效和特点．方法：对36例急性早幼粒细胞性白血病患者给予全反式维甲酸、三氧化二砷双诱导,达完全缓解后。序贯应用全反式维甲酸、三氧化二砷,联合小剂量化疗,观察缓解时间和药物不良反应．结果：36例中2例早期因脑出血而死亡,其余均完全缓解,完全缓解率达94．4％,达完全缓解的时间为21～70d．结论：本方案治疗急性早幼粒细胞性白血病能够获得很高的完全缓解率,降低了复发率,缩短了诱导时间,可望长期生存,疗效确切、可靠．     

多不饱和脂肪酸与红冬孢酵母低温适应性的关系研究

以一株产油酵母——红冬孢酵母(Rhodosporidium kratochvilovae)YM25235作为出发菌株,分析其低温生长适应性与细胞膜流动性、膜脂脂肪酸含量的变化和多不饱和脂肪酸合成关键基因——Δ12-脂肪酸脱氢酶基因mRNA表达水平的关系.结果显示,YM25235在5～35 ℃温度条件下均能生长,最适生长温度为30 ℃.低温条件下细胞膜流动性明显降低,但是多不饱和脂肪酸质量分数由从30 ℃时的24.35%增加到15 ℃时的40.32%,而且15 ℃时Δ12-脂肪酸脱氢酶基因mRNA水平提高了3.4倍.结果说明低温条件下细胞膜流动性下降,导致多不饱和脂肪酸合成相关基因表达水平提高,使得细胞膜脂中多不饱和脂肪酸含量增加,促进了菌株低温生长适应性.     

Cloning and identification of a novel human glioma differentiation related gene GDR1

In order to identify the genes associated with glioblastoma differentiation, some ESTs, expressed differentially in the control cell and the differentiated human glioblastoma cell line BT-325 induced by the all-trans retinoid acid, have been isolated by the method of DDRT-PCR. Of the 46 ESTs sequenced, 19 are from new genes. A full-length 1 535-bp cDNA, termed gene GDR1, has been isolated from the human cDNA library using the probe designed according to one of the novel ESTs, HGBB098. The open reading frame of GDR1 gene encodes a putative protein containing 334 amino acid residues. Blast against the current GenBank DNA and protein sequence database did not reveal significant homology with any known proteins. RT-PCR shows that GDR1 mRNA level increased in the differentiated BT-325 cells after being treated with RA. The different expression patterns of GDR1 mRNA in human tissues have been detected through the multiple tissue Northern blot hybridization.     

利用TRV过表达和沉默系统验证植物油脂合成相关基因的功能

为探究烟草脆裂病毒过表达和沉默系统进行油脂相关基因研究的可能性,该研究克隆了拟南芥的WRI1和FAD2基因,分别构建了TRV过表达和沉默载体. 利用瞬时侵染技术侵染本氏烟草,取材料进行RT-PCR和脂肪酸含量检测. 结果显示在过表达WRI1基因的本氏烟草中,侵染叶和非侵染叶的WRI1基因及其相关参与脂肪酸合成基因ACP1、KAS1和BCCP2等都有明显上调,且脂肪酸含量检测结果显示分别增加16%和28%. 在沉默FDA2基因的本氏烟草植株中,发现多不饱和脂肪酸含量分别减少约25%和24%. 因此,利用TRV系统对油脂相关基因进行研究是可能的.     

L-肉碱及耐力运动对过氧化物酶体增殖物激活受体影响的研究

过氧化物增殖物激活受体(PPARs)是一类能被脂肪酸以及外源性过氧化物酶体增殖剂(PP)等激活的核内受体，它与脂肪代谢以及脂肪分化、沉积密切相关。L-肉碱、适度的运动可改善脂质代谢，而脂质代谢的中间以及最终代谢产物是PPARs的配体，PPARs被其激活又进一步影响脂质代谢。