基于UPLC-Q/TOF-MS与网络药理学探究解语丹治疗中风的活性成分及作用机制

目的:探究解语丹治疗中风的主要活性成分及其作用机制。方法:采用超高效液相色谱-四极杆飞行时间质谱(UPLC-Q/TOF-MS)分析解语丹的化学成分,并借助UNIFI数据库和文献进行结构鉴定。借助SwissADME网站对成分进行代谢参数筛选后,使用Swiss Target Prediction网站预测筛选成分的靶点为解语丹的药物靶点。挖掘GeneCards数据库和NCBI数据库的中风相关疾病靶点。Venny网站取得解语丹治疗中风的靶点。STRING数据库和Cytoscape软件挖掘高置信度作用靶点。R软件对靶点进行GO(基因本体)功能和KEGG通路的富集分析,并构建“药物-成分-靶点-通路-疾病”网络图。结果:共检测出解语丹化学成分102种,包括氨基酸、寡糖类、香豆素类、山酮类、环烯醚萜类、黄酮类、皂苷类、有机酸和生物碱等,筛选分析得到48种活性成分和562个药物靶点,与疾病靶点取交集得97个药物与疾病的共同靶点。STRING得65个高置信度靶点,富集分析得到3209个GO功能进程和190条通路,GO进程主要涉及创口与炎症、血管管径变化及血压调节等GO生物过程类、细胞粘着和细胞凝聚等GO细胞组成类、肽类激素内切酶活性及血红蛋白等GO分子功能类。KEGG通路主要有花生四烯酸代谢、补体和凝血级联、血小板激活流体剪切应力和动脉粥样硬化、脂质和动脉粥样硬化等脂质代谢、凝血功能、动脉粥样硬化等与中风密切相关的通路。结论:解语丹可能是以调节脂质代谢与凝血功能、改善粥样硬化等途径治疗中风,表明解语丹通过多成分介导多靶点,作用于多进程和多通路协同治疗中风的特点。     

糖尿病微血管并发症的机制研究与防控

对糖尿病并发症的始动机制、药物作用靶点的不明确是导致糖尿病并发症治疗药物众多,但真正能实现靶点定向治疗的药物缺少的主要原因。     

基于网络药理学及分子对接探讨黄芩治疗糖尿病的作用机制

目的 基于网络药理学及分子对接探讨黄芩治疗糖尿病的作用机制。方法 从中药系统药理学数据库与分析平台（TCMSP）数据库中筛选黄芩的主要生物活性成分及其作用靶点,在GeneCards、OMIM、TTD、PharmGkb等数据库中获取与糖尿病相关的疾病靶点。构建糖尿病与黄芩的作用靶点韦恩图,获得两者之间的共有靶点。借助STRING数据库生成黄芩治疗糖尿病的蛋白互作网络（PPI）,导出核心靶点,并通过Cytoscape 3.9.1软件绘制“疾病–药物–有效成分–作用靶点”网络图。结合Bioconductor数据库和R 4.3.2软件,对黄芩与糖尿病的交集基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。为了进一步验证药物与靶点之间的相互作用关系,采用分子对接技术进行深入研究。结果 经过筛选,成功识别了36个黄芩主要活性成分,19 201个与疾病相关的靶点基因,96个药物靶点以及94个共有靶点,核心靶点主要涵盖蛋白激酶B1（Akt1）、白细胞介素-6（IL-6）、JUN、环加氧酶2（PTGS2）和雌激素受体1（ESR1）等关键蛋白。GO富集结果显示有1 368个生物过程、165个分子功能、29个细胞组成。KEGG富集分析得到150条通路。分子对接结果显示,黄芩主要活性成分为汉黄芩素、黄芩素、豆甾醇,与疾病核心靶点Akt1、IL-6、JUN对接情况良好。结论 黄芩可能通过主要活性成分汉黄芩素、黄芩素、豆甾醇调节Akt1、IL-6、JUN等靶点治疗糖尿病,初步阐明了黄芩治疗糖尿病可能的作用机制,为糖尿病的临床治疗及预防提供理论依据。     

糖尿病并发症治疗靶点的研究进展

糖尿病是世界上发病率最高的疾病之一,主要以慢性高血糖为特征的代谢紊乱,治疗不当可能导致糖尿病肾病,糖尿病微血管病变、糖尿病神经病变等慢性并发症发生.但关于并发症发生的机制目前尚不明确,目前研究结果表明糖尿病并发症发生与氧化应激、多元醇通路、蛋白质非酶糖激化、蛋白激酶C等相关.在这些通路中可能存在控制糖尿病并发症发生的潜在靶点,以发病机制为靶点的治疗可能会给控制糖尿病慢性并发症发生及发展带来新的希望.     

基于可视化分析的2型糖尿病治疗药物近期研究进展

目的探讨和描述2型糖尿病治疗药物的研究热点和近期进展情况。方法以Web of Science核心合集数据库中有关2型糖尿病及其治疗药物的文献为对象,借助可视化软件CiteSpaceV分析,获得关键词共现图谱和文献共被引图谱。结果现有文献研究表明,具有新靶点和新作用机制的治疗药物如肠促胰素类药物、SGLT-2抑制剂、选择性过氧化物酶体增殖物激活受体调节剂等用于2型糖尿病的治疗。结论目前针对新靶点和新作用机制的2型糖尿病治疗药物研究已大量进入临床阶段,治疗效果显著\副作用小\多靶点的长效药物已成为研发重点。     

基于“异病同治”探讨脉络通颗粒对胸痹和中风的作用机制

目的 基于网络药理学方法 ,探讨脉络通颗粒异病同治胸痹和中风的作用机制。方法 通过中医药整合药理学研究平台(TCMIP) V2.0数据库结合文献查找获取脉络通颗粒药物的成分和靶点,通过TCMIP与GeneCards数据库筛选胸痹和中风的相关靶点。利用STRING平台绘制药物治疗疾病的蛋白相互作用(PPI)网络,筛选核心靶点。通过Cytoscape3.8.0中ClueGO插件进行GO富集和KEGG富集,并将结果可视化。结果 共获得脉络通颗粒249个化学成分和965个靶点,胸痹和中风相关靶点分别为798、701个。脉络通颗粒共同治疗胸痹和中风的作用靶点为76个。经分析,脉络通颗粒异病同治胸痹和中风与AKT1、APP、INS等靶点相关,涉及神经递质水平的调节、一氧化氮合酶活性、电压依赖性钙通道复合体等生物过程,主要通过低氧诱导因子-1(HIF-1)信号通路、补体和凝血级联、5-羟色胺能突触等通路发挥异病同治的治疗作用。结论 脉络通颗粒通过调控HIF-1信号和神经递质、抑制免疫反应、参与机体代谢等多种途径异病同治胸痹和中风。     

基于GPR119靶点的抗糖尿病药物研究进展

糖尿病是一种常见的慢性代谢性疾病,主要表现为高血糖及一些微血管并发症,严重影响人类的健康。随着对糖尿病发病机制的深入研究,出现了许多具有新作用靶点和新作用机制的药物。其中G蛋白偶联受体119激动剂受到人们的关注。本文对基于GPRll9靶点的抗糖尿病药物的研究进行综述。     

全球糖尿病治疗药物研发及市场态势

糖尿病是常见慢性代谢性疾病,随着我国人口老龄化与生活方式的变化,糖尿病从少见病变成一个流行病,糖尿病患病率从1980年的0.67%飙升至2017年的10.9%,当前,糖尿病具有患病率高、病情不可逆和后期并发症多的特点。除了生活方式干预疗法,包括饮食和锻炼计划外,药物治疗仍是糖尿病治疗的重要方法之一。尽管目前已有多种不同机制的降糖药物,但是63%的2型糖尿病患者仍然得不到有效的治疗,因此开发糖尿病治疗创新药物仍是当务之急。综述了全球糖尿病治疗药物的数量、研发阶段、药物靶点及作用机制、研发机构和销售等情况,展望糖尿病药物研发前景。

     

网络药理学和分子对接法研究麦门冬汤防治2型糖尿病的分子机制及其验证

目的 结合网络药理、分子对接技术和实验验证，分析麦门冬汤防治2型糖尿病的可能作用机制。方法 从中药系统药理学数据库分析平台筛选麦门冬汤方剂中各药材的成分，采用SwissTargetPrediction和PharmMapper数据库筛选中药成分的靶点；在OMIM、Drugbank、Genecards、Genbank等数据库中查找2型糖尿病的相关靶点；用Cytoscape构建“药物-成分-靶点”的网络图，筛选关键化合物。应用STRING数据库建立蛋白质相互作用网络图，并通过Cytoscape的相关功能进行拓扑分析，筛选核心靶点。在Metascape在线分析平台，进行基因本体(GO)功能富集分析和基因组百科全书(KEGG)通路富集分析，研究其作用的分子机制，并对关键靶点进行分子对接验证。实验验证采用50 mmol高糖及25μmol棕榈酸诱导小鼠胰岛瘤细胞，建立体外2型糖尿病细胞模型，对细胞模型采用不同剂量的麦门冬汤水煎液干预后，Cell Counting Kit 8(CCK8)检测药物对细胞增殖的影响，Western blot检测关键蛋白的表达。结果 从麦门冬汤中筛选出166个活性成分，靶标...     

基于网络药理学和分子对接技术探讨渴络欣治疗糖尿病肾病活性成分及作用机制

目的 通过网络药理学和分子对接方法,探讨渴络欣治疗糖尿病肾病(diabetic nephropathy,DN)的关键活性成分及分子机制。方法 通过中药系统药理分析平台获得渴络欣活性成分及对应靶点。通过GeneCards、OMIM数据库得到DN相关疾病靶点,筛选得到DN药物靶点。运用Cytoscape软件绘制活性成分-靶点网络图和蛋白质-蛋白质相互作用网络图,对作用靶点进行基因本体论及京都基因和基因组数据库功能富集分析。通过Autodock Vina软件对以上筛选得到的渴络欣主要活性成分与关键靶点进行分子对接验证。结果 渴络欣可通过57种活性成分作用于97个靶基因以发挥对DN的治疗作用,主要活性成分有9种,可通过影响氧化应激、炎症反应、缺氧应答、代谢调节及细胞凋亡等,调控信号通路参与到治疗过程中。分子对接结果显示槲皮素、木犀草素及毛蕊异黄酮对关键靶点的亲和力最强,可能为渴络欣中的核心作用分子。结论 渴络欣治疗DN的潜在作用机制为多靶点、多通路,其中槲皮素、木犀草素及毛蕊异黄酮可能为渴络欣中的核心作用分子。     

Annexin A1 in the brain--undiscovered roles?

Annexin A1 (ANXA1) is an endogenous protein known to have potent anti-inflammatory properties in the peripheral system. It has also been detected in the brain, but its function there is still ambiguous. In this review, we have, for the first time, collated the evidence currently available on the function of ANXA1 in the brain and have proposed several possible mechanisms by which it exerts a neuroprotective or anti-neuroinflammatory function. We suggest that ANXA1, its small peptide mimetics and its receptors might be exciting new therapeutic targets in the management of a wide range of neuroinflammatory diseases, including stroke and neurodegenerative conditions.     

Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke

The glutamate receptor was one of the most intensely investigated targets for neuroprotection. However, numerous clinical trials of glutamate receptor antagonists for the treatment of stroke were unsuccessful. These failures have led to pessimism in the field. But recent advances could provide hope for the future. This minireview looks beyond the traditional mechanism of glutamate-receptor-driven excitotoxicity to identify other mechanisms of ionic imbalance. These advances include findings implicating sodium-calcium exchangers, hemichannels, volume-regulated anion channels, acid-sensing channels, transient receptor potential channels, nonselective cation channels and signaling cascades that mediate crosstalk between redundant pathways of cell death. Further in vivo validation of these pathways could ultimately lead us to new therapeutic targets for stroke, trauma and neurodegeneration.     

Progress in the identification of stroke-related genes: emerging new possibilities to develop concepts in stroke therapy

Stroke is a very complex disease influenced by many risk factors: genetic, environmental and comorbidities, such as hypertension, diabetes mellitus, obesity and having had a previous stroke. Neuroprotective therapies that have been found to be successful in laboratory animals have failed to produce the same benefits in clinical trials. Currently, a re-analysis of the clinical trial failures is underway and new therapeutic approaches using the growing knowledge from neurogenesis and neuroinflammation studies, combined with the information from gene expression studies, are taking place. This review focuses on possible ways to identify therapeutic targets using the new discoveries in neuroinflammation and intrinsic regenerative mechanisms of the brain. Molecular events associated with ischaemia trigger an environment for inflammation. Within the ischaemic region and its penumbra, a battery of chemokines and cytokines are released, which have both detrimental and beneficial effects, depending on the specific timepoint after injury and the current activation status of microglia/macrophages. Preventive therapies and treatments for stroke may be established by identifying the genes that are responsible for the induction of those phenotypic changes of microglia/macrophages that switch them to become players in tissue repair and regeneration processes. To aid in the establishment of new target sources for novel therapeutic agents, animal stroke models should closely mimic stroke in humans. To do so, these models should take into account the various risk factors for stroke. For example, hypertensive animals have a more vulnerable blood-brain barrier that in turn may trigger a greater degree of damage after stroke. Furthermore, in aged animals an accelerated astrocytic and microglial reaction has been observed and the regenerative capacity of aged brains is not as high as young brains. Improvements in animal models may also help to ensure better success rates of potential therapies in clinical studies. Inflammation in the brain is a double-edged sword--characterised by the deleterious effect of nerve cell damage and nerve cell death, as well as the beneficial influence on regeneration. The major challenge to develop successful stroke therapies is to broaden the knowledge regarding the underlying pathologic processes and the intrinsic mechanisms of the brain to drive regenerative and plasticity-related changes. On this basis, new concepts can be created leading to better stroke therapy.     

Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

The mood stabilizers lithium, valproate and lamotrigine are traditionally used to treat bipolar disorder. However, accumulating evidence suggests that these drugs have broad neuroprotective properties and may therefore be promising therapeutic agents for the treatment of neurodegenerative diseases, including stroke. Lithium, valproate and lamotrigine exert protective effects in diverse experimental stroke models by acting on their respective primary targets, ie, glycogen synthase kinase-3, histone deacetylases and voltage-gated sodium channels, respectively. This article reviews the most recent findings regarding the underlying mechanisms of these phenomena, which will pave the way for clinical investigations that use mood stabilizers to treat stroke. We also propose several future research avenues that may extend our understanding of the benefits of lithium, valproate and lamotrigine in improving stroke outcomes.     

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts.Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s.Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences.Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.     

Deciphering the pharmacological mechanism of the Chinese formula Huanglian-Jie-Du decoction in the treatment of ischemic stroke using a systems biology-based strategy

Aim:

Huanglian-Jie-Du decoction (HLJDD) is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HLJDD in the treatment of ischemic stroke using systems biology approaches.

Methods:

Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD targets were identified by calculating topological features, including ''Degree'', ''Node-betweenness'', ''Closeness'', and ''K-coreness''. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation.

Results:

A total of 809 putative targets were obtained for 168 compositive compounds in HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology (GO) annotation system and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HLJDD targets had strong binding efficiencies.

Conclusion:

This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HLJDD and their putative targets and ischemic stroke-related pathways.     

Mechanism of neuronal death in ischemic stroke北大核心CSCD

Stroke is the second leading cause of death in the world, of which about 60 % - 80 % are ischemic stroke. Ischemic stroke will inevitably cause the damage of neurons in the core area. With the increase of ischemic time, other neurons in the ischemic penumbra will also die due to the loss of " signal connection", and further lead to body dysfunction. In view of the complexity of neuronal death mechanism after ischemic stroke, understanding the action principle of death mechanism can better save ischemic penumbra neurons. This review mainly expounds several main mechanisms and potential therapeutic targets of neuronal death after ischemic stroke, so as to provide basis and help for the improvement of action mechanism research and drug development. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Systems pharmacology dissection of the anti-stroke mechanism for the Chinese traditional medicine Xing-Nao-Jing

Xing-Nao-Jing (XNJ) is a well-known injection that has been extensively applied in clinical treatment of stroke in China. However, the underlying mechanism of clinical administration of XNJ in stroke remains unclear. In this study, a systems pharmacology strategy based on pharmacokinetic and pharmacodynamics data was applied to analyze the pharmacological effect of XNJ on stroke. Sixteen active compounds were filtered from XNJ through Drug-likeness (DL) and Brain-blood-barrier (BBB) evaluations. Ninety-four potential targets of these active components were identified by SysDT and SEA. Biological process and pathway enrichment analyses of these targets demonstrated that XNJ exerted anti-stroke effects by biological processes and pathways, such as the response to oxidative stress, regulation of blood pressure, calcium signaling pathway, and apoptosis. Integrating the compound-target network and stroke-related PPI network, we found that Akt1, HIF-1α and ITGB2 may play key roles in the treatment of stroke. The experiments demonstrated that oxycurcumenol may prevent PC12 cells from oxidative stress-induced cell damage. Our study indicates that XNJ has an effect on stroke by protecting neuro cells from oxidative stress-induced cell damage via HIF1α, and the research strategy at the systems pharmacology level is feasible to reveal the mechanisms of novel lead compounds from natural products.     

Tyrosine Kinase Inhibitors as a New Therapy for Ischemic Stroke and other Neurologic Diseases: Is there any Hope for a Better Outcome?

The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer’s disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer’s disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases.