基于DARTS技术的丹参素钠直接结合靶蛋白鉴定

目的：鉴定丹参素钠在人脐静脉内皮细胞中可能直接结合的靶蛋白。方法：首先利用药物亲和反应靶点稳定技术（DARTS）,结合聚丙烯酰胺凝胶电泳（SDS-PAGE）及基质辅助激光解吸电离飞行时间串联质谱（MALDI-TOF/TOF-MS）鉴定丹参素钠在人脐静脉内皮细胞（HUVEC）中可能直接结合的靶蛋白,并通过免疫印迹法（Western blotting）进行验证。然后采用表面等离子共振技术（SPR）分析丹参素钠与其潜在靶标蛋白的结合动力学参数。结果：丹参素钠在HUVEC细胞中特异性结合CD44蛋白,两者之间的结合常数为4.84×10-4 mol·L-1。结论：丹参素钠可能通过结合靶蛋白CD44发挥心血管的保护作用。     

Implications of Off‐Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach

Study Objective

Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5‐hydroxytryptamine (5‐HT). No systematic process currently exists for evaluating cumulative 5‐HT and off‐target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5‐HT drugs in serotonin syndrome (SS) reports.

Data Sources

Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data.

Design

An in‐house bioinformatics TargetSearch program ( http://dxulab.org/software ) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off‐target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria.

Measurements and Main Results

A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple‐receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05–2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29–1.79). 5‐Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17–0.81 and mean PRR 0.49, 95% CI 0.15–0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria.

Conclusion

The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off‐target receptor activity may help explain differences in severity of toxicity and clinical presentation.     

Estimation Strategies for Reacting to the Identification of an Association Between the Genome and Adverse Drug Reactions

The availability of high-resolution genetic profiling raises the possibility, during the course of a drug development program, of discovering a subset of patients at particular risk of an adverse drug reaction who might be excluded from subsequent randomization into studies and identified as unsuitable for post-licensing use. Such methods depend on the estimation of the risk of adverse drug reactions for patients with differing genetic profiles followed by an assessment of the risks and benefits of their exposure to the drug. In this paper we explore the performance of a number alternative statistical methods for the estimation of risk in terms of the success of the subsequent exclusion rules. The approaches were evaluated using a single-nucleotide polymorphism dataset concerning HIV patients at risk of hypersensitivity to the drug abacavir. Overall we found that a method based on LASSO performed better than the alternatives that we studied, which included a decision-theoretic Bayesian approach, and that its performance suggested suitability for its prospective implementation.     

利用Access开发适合医院使用的药物识别系统

目的 开发适合医院使用的药物识别系统,通过中立、客观的参照物(照片)进行准确识别药物.方法 收集药品图片及相关信息,应用Access软件编制“药品识别查询系统”数据库并进行系统测试.结果 成功建立了一套药物识别系统,其平均识别成功率(S)可达93.3％.结论 该系统操作简便,与临床密切结合,有利于提高药品治疗质量和合理用药水平.     

Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.     

DNA Methylation as a Target for Drug Design

DNA methylation is essential for normal embryonic development. Distinctive genomic methylation patterns must be formed and maintained with high fidelity to ensure the inactivities of specific promoters during development. The mutagenic and epigenetic aspects of DNA methylation are especially interesting because they may lead to the inactivation of genes which are involved in human carcinogenesis. The mutagenicity of 5-Methylcytosine (5mC) and the role of promoter hypermethylation in gene silencing, particularly in cancer, suggest a clinical significance for the design of novel DNA methylation inhibitors which may be utilized to reverse the effects of DNA methylation.     

关木通与川木通的生药鉴别

木通为具有清热、利尿、通乳的中药,通常使用的有关木通与川木通之分.由于20世纪90年代相继出现了马兜铃、关木通、青木香等含有马兜铃酸成份的中药对肾脏产生危害甚至导致肾功能衰竭事件[1].2003年国家药品监督管理局取消了关木通的药用标准.川木通为毛莨科植物,不含有马兜铃酸成份,对肾脏无害.关木通和川木通形态特征非常相似,且不良反应的差异很大,故二者的鉴别尤为重要.     

加强网上信息管理，保障人民用药安全

药品是一种特殊的商品 ,任何形式的滥用或误用均可造成对人体健康甚至生命的损害。即便是ＯＴＣ药也同样如此。所以 ,大多数国家的政府都对药品的销售和使用严加控制 ,对药品的广告和宣传资料也有相应的审查、管理制度。比如我国就已规定 :处方药只准在专业性医药报刊进行广告宣传 ,非处方药经审批后方可在大众传播媒介进行广告宣传[1 ] 。但是 ,随着互联网的日益壮大 ,国内外众多医药企业都意识到其中蕴含的无限商机 ,即使在中国目前对网上售药管制严格 ,但他们还可以通过企业网站或其它诸如开设“医药导购系统”、“健康顾问”等方式 ,较…     

生物信息学在基因和药物发现中的应用

在基因组研究蓬勃发展的今天，生物信息学已不可避免地渗入到药物的研究和开发中，在药物靶点的发现和确立中起着重要作用。本文综述了生物信息学在药物和基因发现中的作用，包括通过对基因组序列、基因多态性、基因表达、序列标签等的确定和选择，发现适当的药物作用靶点。     

类风湿性关节炎新靶点药物治疗进展

类风湿性关节炎是一种病因未明的慢性系统性疾病,目前临床上对此类患者的治疗主要以药物治疗为主。本文通过介绍小分子化学合成类药物、JAK抑制剂、靶向IL-17药物,以探讨类风湿性关节炎靶点药物的作用机制及其治疗进展情况,旨在为临床治疗类风湿性关节炎提供新的方向。     

mPGES-1——一个新的药物开发靶点

综述膜结合型前列腺素E2合酶-1（mPGES-1）的生物学性质、生理和病理作用,以及将其作为一个新的药物作用靶点用于药物开发的可能性。mPGES-1是3种前列腺素E2合酶之一,属于诱导型表达的酶,能被致炎因子诱导而大量表达,在多种疾病,如关节炎、炎症相关性发热和疼痛、动脉粥样硬化及癌症的病理生理过程中均发挥着重要作用。     

新分子靶位mTOR与新抗肿瘤靶向药物雷帕霉素

在复杂的生命过程中,细胞生长和细胞增殖是连续而密不可分的两个过程,细胞生长是大分子合成引起细胞质量或大小的增加,而细胞增殖是细胞分裂导致细胞数量的增加,它们共同作用产生了器官、机体和肿瘤。细胞增殖的重要调控器是细胞周期蛋白依赖性激酶(CDK,cyclin-dependentkinases),然而细胞生长的重要调控器是哺乳动物雷帕霉素靶位mTOR(mammaliantargetofrapamycin),mTOR的活性依赖于营养、能量(ATP)、生长因子和一些酶的调控。小分子化合物雷帕霉素(Rapamycin)与FKBP12(FK506bindingprotein12)形成复合物,然后与mTOR蛋白激酶结合产…     

Functional Screening of Drug Target Genes

Background and objectives: A number of recent studies surveying single nucleotide polymorphisms within the exonic regions of human genes have revealed a significant number of such variants, including many non-synonymous variants. This highlights the need to directly identify, within individual clinically well-defined patients, those variants that alter protein function as well as structure. We report on the development of a novel phenotypic screening process that combines high-throughput molecular cloning techniques with functional expression utilizing the cell-based assay R-SAT. Methods: We applied the phenotypic screening process to an analysis of the m1 muscarinic acetylcholine receptor (CHRM1) gene in a cohort of 74 individuals, including 48 diagnosed with neurodegenerative disease, primarily Alzheimer disease, who have been stratified according to their clinical response to the acetylcholinesterase inhibitor donepezil. Phenotypic screening of the CHRM1 gene involved PCR-based amplification from genomic DNA and heterologous expression in mammalian cells. Results: Phenotypic screening yielded functional responses to the agonist carbachol displaying a mean potency (?pEC50 ± standard deviation) of 5.8 ± 0.2, which did not differ from that observed with expression of the wild-type receptor gene (6.0 ± 0.3). No altered levels of constitutive receptor activity were observed. Dideoxy sequencing did not reveal any non-synonymous variants in the coding exon of this gene within this clinical cohort, while detecting three synonymous variants. Conclusion: The results confirm that the m1 receptor gene (CHRM1) is not highly polymorphic in the human population, suggesting that genetic variation within the coding exon of this gene is not a contributing factor to the clinical variability observed during treatment of dementia with cholinergic enhancement therapies.     

G—四链体DNA：抗肿瘤药物的潜在靶点

除了常见的双链DNA,某些富含G碱基的DNA序列通过四个鸟嘌呤环的互联作用可折叠成四链螺旋结构,这样的DNA二级结构被称为G－四链体。本文综述了G－四链体可能在生物学么及作为抗肿瘤药物潜在靶点能与其相互作用的化合物的研究与开发。     

浅谈基层药检所正确采用药品标准的体会

目的做好基层药检所药品标准的采用和管理工作。方法通过工作实践,自建药品标准查询系统,探讨如何正确采用药品标准。结果与结论将采用药品标准的方法和需要注意的问题加以总结。     

Using Compartments to Model Drug Delivery from Biodegradable Polymers

Polymeric drug delivery systems can improve patient compliance, decrease toxicity and prolong therapeutic effects for a wide range of therapeutic treatments, by controlling drug release. Polymer delivery system development can be facilitated by mathematical models. We present here a new compartmental model that will be more familiar to pharmaceutical professionals and equally as effective as common diffusion equation-based models. The compartmental model considers both polymer degradation and drug diffusion to predict drug release. The model is adapted into three different geometries for different polymer delivery scenarios: membranes, fibres and particles. Model parameters are derived in terms of diffusion coefficients. Polymer-drug binding interactions and distributions of fibre/particle diameters are incorporated to the model. The model is validated by comparison to common diffusion equation-based solutions and fitting to experimental data. It is shown how the model for drug release can be incorporated into existing distribution models to predict plasma concentrations of an in vivo administration. A user-friendly Python implementation of the model is available on Github, at https://github.com/spirt-t/compartments_model     

Q TRAP在药物代谢研究中的应用

三重四极杆质谱仪在定量分析方面较优,而离子阱质谱仪则在定性分析方面较优。Q TRAP质谱仪将三重四极杆质谱仪和离子阱质谱仪的功能以一种新的方式结合在一起,既保留了串联四极杆质谱仪的优点,如母离子扫描、中性丢失扫描、选择反应监测的功能,又克服了传统3D离子阱质谱仪诸如低质量截止点(1/3效应)等缺点,是一台集定性与定量功能于一体的质谱仪。该文介绍了QTRAP四极杆-线性离子阱质谱仪的基本原理和分析策略,并简述其在药物代谢研究方面的应用。     

TRPV1 Channel: A Potential Drug Target for Treating Epilepsy

Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5''-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsyTaken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures.