Design,synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties

The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC₅₀ values and significant selectivity towards other S-adenosyl-_L-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC₅₀ value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.     

左右半结肠癌多组学分子特征差异的研究进展

结肠癌(colon cancer,CC)是一种常见的恶性肿瘤,其发病率和死亡率均占癌症前列.根据解剖学位置,CC可分为左半结肠癌(left-sided colon cancer,LCC)和右半结肠癌(right-sided colon cancer,RCC),两者在临床特征上表现出较大的差异.近些年来,随着生物学技术和...     

转录因子在植物干旱应激中的功能研究进展

转录因子是一种多功能蛋白,在感知应激信号、应答相应应激基因表达及传导应激信号中起着关键作用。干旱是影响植物生长发育的主要非生物胁迫之一。为了适应干旱环境,植物发展了复杂的分子机制,其中转录因子可同时控制多种途径调控干旱应激,是操纵调控和应激响应途径的有力工具。近年来,越来越多的植物转录因子的功能被阐明,了解转录因子在干旱应激的功能,对植物的工程抗旱有重要的实践意义。综述转录因子在植物干旱应激中的功能研究进展,以期为今后转录因子的研究和利用提供理论依据,培育具有较强抗旱能力的植物。     

Immune-related microRNAs are abundant in breast milk exosomes

Breast milk is a complex liquid rich in immunological components that affect the development of the infant's immune system. Exosomes are membranous vesicles of endocytic origin that are found in various body fluids and that can mediate intercellular communication. MicroRNAs (miRNAs), a well-defined group of non-coding small RNAs, are packaged inside exosomes in human breast milk. Here, we identified 602 unique miRNAs originating from 452 miRNA precursors (pre-miRNAs) in human breast milk exosomes using deep sequencing technology. We found that, out of 87 well-characterized immune-related pre-miRNAs, 59 (67.82%) are presented and enriched in breast milk exosomes (P < 10(-16), χ(2) test). In addition, compared with exogenous synthetic miRNAs, these endogenous immune-related miRNAs are more resistant to relatively harsh conditions. It is, therefore, tempting to speculate that these exosomal miRNAs are transferred from the mother's milk to the infant via the digestive tract, and that they play a critical role in the development of the infant immune system.     

电针诱导心肌缺血大鼠延髓头端腹外侧区nNOS和iNOS差异表达

许多研究表明,延髓头端腹外侧区(rostral ventrolateml medulla,RVLM)的NO/NOS系统参与心血管活动的中枢调节.本实验以结扎Wistar大鼠左冠状动脉前降支法建立急性心肌缺血(acute myocardial ischemia,AMI)动物模型,观察针刺"内关"穴改善AMI大鼠的心功能作用,同时检测大鼠RVLM区神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)表达的变化,进而探讨针刺治疗AMI的中枢机制.实验观察显示,AMI大鼠心功能各项指标减弱,伴随外周血去甲肾上腺素(norepinephrine,NE)和脑钠肽(brain natriuretic peptide,BNP)水平显著升高,同时RVLM区nNOS阳性神经元数和nNOS mRNA表达升高,而iNOS水平则降低.针刺"内关"穴(Pe 6)(每天30 min,连续5天)改善心功能,降低AMI大鼠血清中NE和BNP的水平,同时升高iNOS并降低nNOS在RVLM的表达.以上结果提示,针刺治疗心肌缺血的同时可以调节iNOS/NO和nNOS/NO在RVLM的变化,这可能与针刺通过调节RVLM区的NO含量进而降低交感传出,从而改善AMI大鼠的心功能有关.     

稻瘟病菌群体的分子遗传学研究II.广东省2000年度稻瘟病菌群体遗传结构的时空特性

利用随机扩增多态性DNA技术对广东省2000年度稻瘟病菌群体的遗传结构进行了分析。以相似性系数为0.62阀值时,可将采集于广东省三大生态稻作区、早稻和晚稻生长季节的104个菌株划分为14个遗传宗谱;其中宗谱5和宗谱8的菌株数各占总数的25%,为优势宗谱;宗谱4和12的菌株数各占总数的14.4%和9.6%,为亚优势宗谱;其余的29个菌株,分别归属于其它10个宗谱,其中有5个宗谱是单菌株宗谱。本年度稻瘟病菌群体的遗传结构呈现明显的区域性特性:遗传结构呈由北向南多样化的趋势;各个稻作区甚或亚区有其特异性的宗谱。本年度稻瘟病菌群体的遗传结构也显示分明的生长季节特性:来源于早稻和晚稻生长季节的菌株完全分属于宗谱图的上下两个半区,彼此之间不存在共同的宗谱;而且后者的遗传宗谱要比前者的复杂、多样。研究还表明,虽然稻瘟病菌群体的遗传结构2000年度与1998-1999年度的比较存在较大的差异,但是两者仍然具有良好的相承性和可比性。如何进一步验证和把握稻瘟病菌群体的遗传结构所表现出的时空特性是值得我们进一步探讨的重要课题。     

聚乙烯醇生物降解研究进展

聚乙烯醇(PVA)是一种在纺织和化工行业中广泛使用的难降解的高分子聚合物。随着人们对纺织工业清洁生产的关注,如何在退浆工艺中就实现对PVA的生物降解、减少PVA废水的排放,并避免化学退浆过程中高温和氧化造成的棉纤维损伤,是近年来纺织生物技术领域的研究热点。由于PVA降解菌种类不多、培养周期长,PVA降解酶酶活不高、提取不容易等原因,使PVA的生化降解研究还局限在PVA降解菌的筛选、PVA降解酶的酶学性质研究等方面,PVA降解酶还未在纺织工业上得到应用。本文综述了近年来国内外在PVA降解菌筛选、PVA降解酶提取及酶学性质、PVA生化降解机理等方面的研究进展,并讨论了PVA生化降解研究中存在的问题及发展方向。     

湖南产五步蛇蛇毒磷脂酶A_2的热稳定性

本文测定了湖南产五步蛇蛇毒磷脂酶Ａ２在不同温度保温后的酶活性,结果表明此酶具有一定的热稳定性。     

濒危药用植物桃儿七的离体培养研究

以桃儿七种子诱导的无菌苗为材料,研究了外源激素对芽诱导、增殖和生根的影响,建立了桃儿七离体培养再生体系。结果表明：芽诱导阶段,采用3.0 mg·L^-1 6-BA+0.5 mg·L^-1 GA₃激素组合,出芽率最高可达85-71%,缩短出芽时间30~40 d,在添加3.0 mg·L^-1 6-BA+0.2 mg·L^-1 IAA的MS培养基上利于增殖,增殖速度快,增殖系数1.63。以WPM+1.5 mg·L^-1 IAA+0.5 mg·L^-1 NAA的培养基培养30 d 后,生根率可达60.1%。