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.     

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.     

多胺与植物衰老关系研究进展

多胺作为生理活性物质与植物衰老关系密切。本文综述了近十多年来多胺对衰老的调控作用,从调节细胞膜的理化性质、生物大分子合成作用以及多胺与乙烯的关系等方面阐述了多胺延缓衰老的机制,比较了多胺和影响衰老的植物激素在信号转导过程中的作用。     

Diallyl trisulfide induces apoptosis and inhibits proliferation of A549 cells in vitro and in vivo

Lung cancer is the leading cause of cancer-related mortality all over the world. In recent years, pulmonary adenocarcinoma has surpassed squamous cell carcinoma in frequency and is the predominant form of lung cancer in many countries. Epidemiological investigations have shown an inverse relationship between garlic (Allium sativum) consumption and death rate from many cancers. Diallyl trisulfide (DATS) is one of the garlic-derived compounds (also known as: organosulfer compounds, OSC). DATS can induce apoptosis and inhibit the growth of many cancer cell lines. Our study demonstrated that the apoptotic incidents induced by DATS were a mitochondria-dependent caspase cascade through a significant decrease of the anti-apoptotic Bcl-2 that resulted in up-regulation of the ratio of Bax/Bcl-2 and the activity of caspase-3, -8, and -9. Eventually, DATS induced the apoptosis and inhibited the proliferation in a concentration- and time-dependent manner. Furthermore, by establishing an animal model of female BALB/c nude mice with A549 xenografts, we found that oral gavage of DATS significantly retarded growth of A549 xenografts in nude mice without causing weight loss or any other side effects compared with the control group. All the evidence both in vitro and in vivo suggested that DATS could be an ideal anti-cancer drug.     

鸡减蛋综合征病毒（EDSV—76）末端前体蛋白的基因结构分析

从中国发病鸡群中分离的鸡减蛋综合征病毒弱毒株ＡＡ－２,经常规方法提取其病毒核酸后,组建了完整的限制性内切酶ＰｓｔＩ及ＨｉｎｇⅢ水解片段的基因文库,并对其中ＨｉｎｄⅢ,－ＳａｃⅠ进行了序列测定。同源比较分析证明：其Ｌ链含编码病毒末端前体蛋白,容量为５８０个氨基酸残基的开放读码框架。     

若尔盖人-狼冲突现状与管理研究

大中型食肉动物肇事事件导致人类与野生动物关系恶化,给生物多样性保护工作带来巨大的挑战。若尔盖湿地是我国三大湿地之一,湿地、草原分布广泛,生物多样性丰富,畜牧业发达,但近年来狼(Canis lupus)捕杀牲畜的肇事事件时有发生。为了解若尔盖野生狼肇事件的空间分布以及牧民对人-狼冲突管理的看法,本研究于2022年对若尔盖县13个乡镇83个行政村进行走访调查。结果表明：(1)多数受访者(66.0%)认为在过去5年内,若尔盖县野生狼数量有所增加;(2)狼肇事事件具有明显的空间分异性,最严重的是包座乡。包座乡临近山区,该区域牧场面积广阔、牧民饲养牲畜数量多等原因导致该镇发生狼肇事事件较多;(3)对于狼肇事,绝大多数牧民(85.0%)更希望采取经济补偿或者驱赶措施,只有少数牧民(9.4%)希望采取捕杀的措施;(4)影响牧民对狼肇事管理措施的偏好因子中,受教育程度、年龄、民族以及被杀牲畜数量有显著影响。建议加强狼种群监测管理,采取措施减少狼捕杀牲畜,优化补偿机制,缓解当地牧民与狼之间的矛盾。本研究为当前若尔盖县野生动物保护和管理决策提供了依据,对其他地区大型食肉动物与当地居民冲突管理具有借鉴意义。     

关于晚古生代楔叶属(楔叶纲)的名实问题

简要回顾Sphenophyllum Koenig和Sphenophyllum Brongniart的研究历史,详细讨论该属命名中存在的问题。这两者是基于相同的模式（即Sphenophyllites emarginatus Brongniart,1822）建立的。根据2006年《国际植物命名法规》（维也纳法规）规则32．1,14．4和附录Ⅲ,Sphenophyllum Koenig因没有明确的发表日期（出版年）,故为非法名称,应予废弃;而Sphenophyllum Brongniart因广为使用已被提议为保留名,其命名异名Sphenophyllites Brongniart,1822应被废弃。因此,正确名称应是Sphenophyllum Brongniart,1828。     

Mouse zona pellucida glycoproteins mZP2 and mZP3 undergo carboxy-terminal proteolytic processing in growing oocytes.

The extracellular coat, or zona pellucida, of the mouse egg consists of three glycoproteins, called mZP1-3. The glycoproteins are synthesized and secreted concomitantly by growing oocytes during their 2-3-week growth phase. Each of the glycoproteins has a consensus furin cleavage site (-Arg-X-Lys/Arg-Arg-) near the C-terminus of their polypeptide. Here, several approaches were employed to determine whether nascent mZP2 and mZP3 are cleaved at the consensus sites, -Arg-Ser-Lys-Arg- and -Arg-Asn-Arg-Arg-, respectively, prior to secretion. Molecular mass determinations of deglycosylated mZP2 and mZP3 suggest that their polypeptides are approximately 9 and approximately 7 kDa smaller, respectively, than predicted from exon sequences. Two-dimensional thin-layer chromatographic analyses were also carried out to identify amino acids released from the C-terminus of mZP2 and mZP3 by carboxypeptidase B. On the basis of exon sequences, there are no Arg residues at the predicted C-terminus of the mature glycoproteins. However, for both mZP2 and mZP3, Arg residues were released by carboxypeptidase B, consistent with processing at the consensus furin cleavage site. Furthermore, an antiserum raised against an mZP3 peptide, located downstream of the consensus furin cleavage site, failed to label purified mZP3 on Western immunoblots. The antiserum also failed to label the zona pellucida of oocytes examined by laser scanning confocal microscopy. Collectively, these results strongly suggest that mZP2 and mZP3 are processed at their consensus furin cleavage site prior to secretion and incorporation into the zona pellucida.