Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.Received 30 November 2004; received after revision 24 January 2005; accepted 5 February 2005     

基于附着藻类多样性和TLI的府河水质评价

府河是白洋淀重要的源头河流,其水质直接影响白洋淀水质的优劣.为了了解府河水质的时空变化,2016年4月至11月在府河设置10个采样点,在白洋淀的鲥鯸淀设置1个采样点,对府河附着藻类多样性进行了调查研究,并对府河的水质进行了综合营养评价,分析了其对白洋淀水质的潜在影响. 结果表明:1)府河附着藻类以硅藻门、绿藻门和蓝藻门种类为优势种,共计6门147种(属).从时间维度上,夏季分布最多,秋季分布最少.从空间维度上,鲥鯸淀采样点的种类最多,东湖采样点的种类最少;2)府河附着藻类的Shannon-Wiener多样性指数(H')和Margalef多样性指数(M)具有一致的变化趋势,夏季普遍高于春秋两季,而Pielou均匀度指数(J)秋季较高,H'、M和J最高值均出现在鲥鯸淀采样点,H'和M最低值均出现在望亭采样点,J最低值出现在东湖采样点;3)综合营养状态指数(TLI)表明,春季和夏季水体中以轻度富营养化的水体为主,秋季水体主要以中营养程度为主.从空间维度上看,北湖和鲥鯸淀采样点的TLI普遍较低.不同的评价方法对府河水质的评价结果基本一致.府河水质随季节和空间变化的现象明显,秋季水质最优,春季水质最差,上游水质最差,北湖水质最好.本研究利用2种评价方法对府河水质进行了评价,为府河和白洋淀生态修复提供了基础数据和理论支持.     

Diabetogenic action of alloxan-like derivatives of uric acid

Summary Two new potent diabetogenic substances 4,5-dihydro-4,5-dihydroxyuric acid (1) and 5-hydroxy-pseudouric acid (2) have been found.     

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

Down syndrome — transferrin parallels plasma iron changes

Summary The transferrin level was studied in patients with simple trisomy 21 and with Robertsonian unbalanced translocations 21/22 and 21/14. In all these groups of patients, known to have significantly lowered plasma iron levels, the transferrin levels were found to be decreased with respect to the control group.     

从瑞香狼毒中提取灭蚜活性物质的研究

作者以生物活性跟踪法对瑞香狼毒根的杀蚜活性物质进行了系统的研究,根的粉碎物经过乙醇浸提、分级萃取,分段柱层析与薄层层析相结合,分离纯化得到具有高灭蚜活性物质样品A和B,经HPLC分析,A,B样品均为单一纯品。     

Replication of Gold In-woven Fabric of Korean Goryeo Dynasty on Chinese Draw Loom with a Major Pattern Sheet(da hua lou ji大花楼机)

Introduction Goldin wovenfabricswereproducedinKoreanotlater thanthe8thcentury,sinceagoldneedleandapieceofgold threadoftheGoguryeoDynasty(37B.C.～668A.D.)werediscoveredatJiAncity(集安)[1].Itisreportedthat,thegold in wovenfabricswerelikelyoriginatedintheEasternRoman EmpireandgraduallyspreadtotheEast.InChina,giltfabricswerebroadlyusedduringtheLiao,JinandYuanDynasties. RecordsofgiltfabricsinGoryeoEmperorHyejongPeriod(943～945)maybefoundinKoreanliterature[2].InGoryeo Dynasty(918～1392)…     

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.