Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable

Background: Cellular metabolism generates reactive oxygen species. The oxidation and deamination of the deoxynucleoside triphosphate (dNTP) pool results in the formation of non-canonical, toxic dNTPs that can cause mutations, genome instability, and cell death. House-cleaning or sanitation enzymes that break down and detoxify non-canonical nucleotides play major protective roles in nucleotide metabolism and constitute key drug targets for cancer and various pathogens. We hypothesized that owing to their protective roles in nucleotide metabolism, these house-cleaning enzymes are key drug targets in the malaria parasite.

Methods: Using the rodent malaria parasite Plasmodium berghei we evaluate here, by gene targeting, a group of conserved proteins with a putative function in the detoxification of non-canonical nucleotides as potential antimalarial drug targets: they are inosine triphosphate pyrophosphatase (ITPase), deoxyuridine triphosphate pyrophosphatase (dUTPase) and two NuDiX hydroxylases, the diadenosine tetraphosphate (Ap4A) hydrolase and the nucleoside triphosphate hydrolase (NDH).

Results: While all four proteins are expressed constitutively across the intraerythrocytic developmental cycle, neither ITPase nor NDH are required for parasite viability. dutpase and ap4ah null mutants, on the other hand, are not viable suggesting an essential function for these proteins for the malaria parasite.

Conclusions: Plasmodium dUTPase and Ap4A could be drug targets in the malaria parasite.     

Genome-wide bioinformatics analysis of FMN,SAM-I,glmS, TPP,lysine, purine,cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria

Objectives: A constantly growing number of antibiotic-resistant strains of human pathogenic bacteria is an acute problem. Prolonged illnesses and increasing mortality worldwide mean that there is an urgent need to develop novel antibacterial drugs based on new targets and mechanisms of action. We present in silico analyses of bacterial riboswitches that may be suitable as antibacterial drug targets.

Methods: Most bacterial riboswitches are allosteric cis-acting gene control elements located in the 5?-untranslated region of messenger RNAs. Riboswitches sense specific metabolites and regulate the synthesis of some essential cellular metabolites in many pathogenic bacteria but are not found in humans. We present a complete and comprehensive genome-wide bioinformatics analyses of the suitability of eight riboswitches as antibacterial drug targets in various pathogenic bacteria.

Results: Based on our in silico analyses, we classify the riboswitches in four different groups based on their suitability to be used as antibacterial drug targets. We have estimated that FMN, SAM-I, glmS, TPP, and Lysine riboswitches are promising targets for antibacterial drug discovery.

Conclusion: This research enables us to focus antibacterial drug discovery research only on those riboswitches whose inhibition will result in suppression of the growth of certain pathogenic bacteria.     

基于网络药理学的土鳖虫破血逐瘀作用机制研究

目的:基于网络药理学分析土鳖虫对破血逐瘀相关疾病的作用机制。方法:经文献查阅并结合PubChem、SwissADME、SwissTargetPrediction和TCMSP等数据库对土鳖虫已知成分及其对应靶点进行搜集,并与经GeneCards、OMIM、TTD、HPO数据库搜索得到的“破血逐瘀”相关靶点进行交互分析得到共同靶点;通过蛋白-蛋白质-蛋白质相互作用(PPI)分析、基因本体(GO)分析和京都基因与基因组百科全书(KEGG)分析,构建土鳖虫“成分-靶点-疾病”网络,探讨土鳖虫破血逐瘀功效的作用机制。同时采用体外纤溶实验评价土鳖虫水溶性蛋白质与其他成分的活性差异。结果:筛选得到土鳖虫活性化合物54个,共对应靶点653个;与血瘀相关的17种疾病的16141个作用靶点经交互分析得出两者共有靶点26个。GO和KEGG分析结果表明,土鳖虫已知成分主要涉及嘌呤代谢通路、细胞能量代谢通路、环磷酸鸟苷(cGMP)信号通路、Toll样受体信号通路、醛固酮合成代谢通路、三酰甘油合成通路等13条信号通路,通过干预DNA转录、细胞能量代谢等生物功能发挥药效。同时体外纤溶实验得出土鳖虫水溶性蛋白质较其他成分表现出更强的纤溶活性。结论:土鳖虫已知活性成分并不能很好的证明其对破血逐瘀相关疾病的治疗有显著的效果。结合土鳖虫水溶性蛋白质促纤溶作用,为下一步土鳖虫纤溶物质基础的研究提供参考。     

中药治疗缺血性脑卒中致多器官损伤的研究进展

缺血性脑卒中(cerebral ischemic stroke,CIS)可引发包括心、肝、脾、肺、肾在内的多个器官损伤,该类疾病是由多个病理环节组成,具有复杂的发病机制及高发病率、高致残率和高死亡率的特点,严重者可形成多器官功能障碍综合征(multiple organ dysfunction syndromes,MOD...     

综合指标与岗位工资结合管理方法初探

介绍了西安医科大学第一附属医院以医院分级管理和工资制度改革为契机，试行综合指标与岗位工资相结合的管理方法，即把医院分级管理的综合目标进行分解，与职工的岗位工资挂钩，通过量化考核，评出分值，然后根据分值计算职工每月的工资和岗位津贴，从分配上体现出多劳多得、工作质量好、服务优者多得的原则。     

Premature ejaculation: focus on therapeutic targets

Background: Premature ejaculation (PE) is poorly defined but the most common male sexual complaint. It can be treated with strategies including oral pharmacotherapy, topical anaesthetics, behavioural therapy and surgery. Although PE is treatable in most, but not all, patients by currently available modalities, long term success rates have been disappointing. An approved treatment so far does not exist. Objective: To review literature on the current and potential therapeutic targets for PE. Methods: Available English–language published literature is reviewed. Results/conclusions: There are many targets for future therapeutic approaches to PE that may address the shortcomings of existing therapy. Selecting the best targets depends heavily on their playing a prominent role in PE. Exploiting the full therapeutic potential of these targets will require additional basic and clinical research.     

CNS drug targeting: have we travelled in right path?

Abstract

Background: Brain disorders, their prevalence and central nervous system (CNS) targeting are now at the rise. However, complexities of blood brain barrier (BBB) have limited the success of CNS targeting. Basic criteria necessary for passive diffusion were believed to influence the CNS drug delivery. However, often, BBB transportation has differed from the dogma of basic criteria.

Purpose: This communication resets the extent to which basic criteria influence the brain delivery, through commanding examples. Further, it appraises the intervention of ABC transporters in BBB transportation, with a special emphasis on P-glycoprotein; and also brings forth the successful CNS transportation of therapeutics achieved through chimeric peptide technology. As a right path to travel, it flickers light on the novel CNS molecular drug targets/biomarkers which are specially expressed by diseased cells.

Conclusion: Screening for right molecular target is of great importance for cost and time effective drug discovery process. The principle of chimeric peptide technology should be applied for CNS targeting; and every diseased cell should be screened for its biomarker. Thanks to glycan/lectin arrays technique which scans expression pattern of transporter and their possible ligands, and paves way for a new dimensional research.     

栝楼桂枝汤治疗脑卒中后下肢痉挛的网络药理学研究

目的 基于网络药理学研究栝楼桂枝汤治疗脑卒中后下肢痉挛的作用机制。方法 利用TCMSP数据库、SwissTarget Prediction数据平台筛选栝楼桂枝汤活性成分靶点,并借助Gephi软件构建活性成分-靶点网络,运用Genecard、DisGeNET、TTD疾病数据库筛选作用于脑卒中、下肢痉挛靶基因,应用STRING平台构建靶蛋白相互作用网络,利用ClueGO软件对靶基因进行GO功能分析,通过DAVID v6.8平台对关键靶点KEGG通路进行分析。结果 栝楼桂枝汤中黄酮类、有机酸类、皂苷类等成分作用于IL6、TNF、EGFR、ESR1、TP53、STAT3、F2等49个关键靶基因;参与横纹肌细胞增殖、骨重塑、平滑肌细胞增殖正调控、肌细胞增殖、内皮细胞增殖等14类生物过程;调控TNF、MAPK、PI3K-Akt、ALS、神经营养、5-羟色胺能神经突触等30条信号通路。结论 栝楼桂枝汤多种活性成分通过抗炎、抗氧化、神经营养及保护等药理作用,以及参与肌细胞增殖等生物过程,从中枢神经系统及外周肌肉组织双向治疗脑卒中后下肢痉挛。     

甘遂与甘草反药相互作用的网络药理学分析

目的:采用网络药理学方法,探讨甘遂和甘草反药配伍后药效/毒性成分的分子作用机制,分析其多成分-多靶点-多通路相互关系。方法:针对甘遂甘草的主要药效/毒性成分——甘遂萜酯A,甘遂萜酯B,甘遂萜酯C,甘草酸,甘草苷,异甘草苷和刺芒柄花素,依据Pharm Mapper数据库构建多成分-蛋白网络,获取的靶点信息利用博奥数据库MAS 3.0系统得到相应通路,通过Cytoscape软件建立成分-靶点-通路网络模型。结果:网络分析表明,甘遂、甘草配伍药效/毒性成分涉及神经-免疫-内分泌-泌尿等相关的61条通路。在调节水和电解质排泄方面药效相反,与肾素血管紧张素系统、类固醇生物合成等通路有关;在抗肿瘤、抗炎、调节免疫方面发挥协同作用,涉及33条通路;两者配伍存在基于肝药酶代谢的毒性增强现象。结论:甘遂与甘草配伍存在药效降低或药效协同和毒性改变等多种情况,体现了中药配伍多成分、多靶点、多途径作用模式,该研究为深入探讨甘遂甘草配伍的分子作用机制提供了参考。     

雷公藤红素抗癌作用的研究进展

通过检索近年来与雷公藤红素相关的国内外文献,并对其进行分析、归纳、总结,从雷公藤红素的抗肿瘤作用机制及相关的靶点、通路等方面进行综述.1995年至今,多方面研究表明雷公藤红素有抗肿瘤作用,其作用机制包括诱导肿瘤细胞凋亡、影响血管生成、影响肿瘤相关的蛋白、通过肿瘤坏死因子及核因子-κB信号通路、以细胞微管为靶点、调节热休克反应等等,但对其体内过程等方面的研究还很少.应进一步针对雷公藤红素体内作用进行研究,为其抗肿瘤作用的发挥奠定坚实的基础.