Constructal entransy dissipation rate minimization for X-shaped vascular networks

Combining with entransy theory, constructal designs of the X-shaped vascular networks(XSVNs) are implemented with fixed total tube volumes of the XSVNs. The entransy dissipation rates(EDRs) of the XSVNs are minimized, and the optimal constructs of the XSVNs are derived. Comparison of the optimal constructs of the XSVNs with two optimization objectives(EDR minimization and entropy generation rate(EGR) minimization) is conducted. It is found that when the dimensionless mass flow rate(DMFR) is small, the optimal diameter ratio of the elemental XSVN derived by EDR minimization is different from that derived by EGR minimization. For the multilevel XSVN, when the DMFR is 100, compared the XSVN with the corresponding H-shaped vascular network(HSVN), the dimensionless EDRs of the elemental, second and fourth order XSVNs are reduced by 26.39%, 15.34% and 9.81%, respectively. Compared with the entransy dissipation number(EDN) of the second order XSVN before angle optimization, the EDN after optimization is reduced by 26.15%, which illustrates that it is significant to conduct angle optimization of the XSVN. Entransy theory is applied into the constructal design of the vasculature with heat transfer and fluid flow in this paper, which provides new directions for the vasculature designs.

Deep Neural Network Based Cardio Vascular Disease Prediction Using Binarized Butterfly Optimization

In this digital era,Cardio Vascular Disease(CVD)has become the lead-ing cause of death which has led to the mortality of 17.9 million lives each year.Earlier Diagnosis of the people who are at higher risk of CVDs helps them to receive proper treatment and helps prevent deaths.It becomes inevitable to pro-pose a solution to predict the CVD with high accuracy.A system for predicting Cardio Vascular Disease using Deep Neural Network with Binarized Butterfly Optimization Algorithm(DNN–BBoA)is proposed.The BBoA is incorporated to select the best features.The optimal features are fed to the deep neural network classifier and it improves prediction accuracy and reduces the time complexity.The usage of a deep neural network further helps to improve the prediction accu-racy with minimal complexity.The proposed system is tested with two datasets namely the Heart disease dataset from UCI repository and CVD dataset from Kag-gle Repository.The proposed work is compared with different machine learning classifiers such as Support Vector Machine,Random Forest,and Decision Tree Classifier.The accuracy of the proposed DNN–BBoA is 99.35%for the heart dis-ease data set from UCI repository yielding an accuracy of 80.98%for Kaggle repository for cardiovascular disease dataset.

Exploring the mechanism of action of Wuzhuyu Decoction for vascular headache based on network pharmacology and molecular docking

Background:The aim of this study is to explore the mechanism by which Wuzhuyu Decoction treats vascular headache.Methods:We utilized the TCMSP database to identify active ingredients and targets of the Chinese herbal medicine,and the Gendcars,OMIM,PharmGKB,TTD,and DrugBank databases were used to screen for disease targets.We constructed the PPI network of targets by utilizing the String database,and GO and KEGG analyses were performed.The"drug-ingredient-target-disease"network diagram was constructed using Cytoscape 3.8.0 software.We analyzed the topological parameters to identify the primary active ingredients and targets of Wuzhuyu Decoction,and subsequently confirmed the findings via molecular docking.Results:A total of 86 active ingredients were obtained,including Quercetin,Kaempferol,Beta-sitosterol,Stigmasterol,and Nuciferin.Fourteen core targets were identified,including JUN,TP53,AKT1,RELA,MAPK1,MAPK14,MYC,MAPK8,CCND1,ESR1,CTNNB1,FOS,NR3C1,and RB1.GO enrichment analysis involved biological processes such as response to drug,response to lipopolysaccharide,and response to molecule of bacterial origin.The cellular components were membrane raft and membrane microdomain,and the molecular functions were catecholamine binding and nuclear receptor activity.The KEGG pathway enrichment analysis demonstrated the potential regulation of 171 pathways by Wuzhuyu Decoction.including the Lipid and atherosclerosis signaling pathway,the Fluid shear stress and atherosclerosis signaling pathway,and the PI3K-AKT signaling pathway.Molecular docking showed that Nuciferin had good binding activity with AKT1(-9.9 kJ/mol),as did Quercetin with AKT1(-9.8 kJ/mol),Stigmasterol with MAPK1(-9.7 kJ/mol),and Kaempferol with AKT1(-9.5 kJ/mol).Conclusion:Wuzhuyu Decoction may exert its therapeutic effect on vascular headache by inhibiting neurogenic inflammation,providing analgesia,and modulating the immune system.

Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis

Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.Data sources: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health(CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.Data selection: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. Outcome measures: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events(TAEs), serious adverse events(SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents(CVAs). Results: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine(mean difference(e) = –0.77, 95% confidence interval(CI): 0.25–1.32; MD = 1.05, 95% CI: 0.18–1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine(MD = –1.30, 95% CI: –2.27 to –0.42; MD = –1.67, 95% CI: –3.36 to –0.06; MD = –2.27, 95% CI: –3.91 to –0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale–cognitive scores compared with placebo. Memantine(MD = 2.71, 95% CI: 1.05–7.29) improved global status(Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg(odds ratio(OR) = 3.04, 95% CI: 1.86–5.41) contributed to higer risk of adverse events than placebo. Galantamine(OR = 5.64, 95% CI: 1.31–26.71) increased the risk of nausea. Rivastigmine(OR = 16.80, 95% CI: 1.78–319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.Conclusion: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.

Multi-target mechanism of triphala in cardio-cerebral vascular diseases based on network pharmacology

OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.

Integrated network pharmacology and experimental verification to explore the mechanism of Sangqi Qingxuan formula against hypertensive vascular remodeling

Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.

Network pharmacology research of Chuanxiong Rhizoma-Acori Tatarinowii Rhizoma in the treatment of vascular dementia

Objective:Using network pharmacology to explore the target and mechanism of Chuanxiong Rhizoma and Acori Tatarinowii Rhizoma in the treatment of vascular dementia(VaD),so as to provide a reference for treating VaD through them.Methods:Traditional Chinese medicine systems pharmacology database and analysis platform were used to screen the main active ingredients and targets of Chuanxiong Rhizoma and Acori Tatarinowii Rhizoma.By means of Gene Cards and Online Mendelian Inheritance in Man(OMIM),targets of VaD were collected.The intersecting targets were obtained by using the Venn map.The String online database was used to build a protein-protein interactions Network and the Metascape database was used to perform GO function enrichment analysis and KEGG pathway enrichment analysis.A“drug-ingredient-target-pathway”network was constructed by Cytoscape software.Autodock vina software was used to conduct molecular docking between targets.Results:A total of 7 active ingredients in Chuanxiong Rhizoma and 4 active ingredients in Acori Tatarinowii Rhizoma were screened.There were 42 active targets of Chuanxiong Rhizoma and 70 active targets of Acori Tatarinowii Rhizoma and 1152 disease targets.After deleting the repeat value,51 drugs targets were obtained.After the intersection,with a total of 25 targets.According to GO and KEGG enrichment analysis,the main biological processes involved include cellular response to lipid,negative regulation of apoptotic signaling pathway,blood circulation,response to a steroid hormone,etc.The main pathways include pathways in cancer,PI3K-Akt signaling pathway,and AGE-RAGE signaling pathway in diabetic complications,etc.Molecular docking showed that the most active docking combinations were AKT1 and Perlolyrine,RELA and FA,MAPK14 and FA,respectively.Conclusion:Chuanxiong Rhizoma and Acori Tatarinowii Rhizoma play an important role in the treatment of VaD mainly by anti-inflammatory and anti-apoptosis.

Integration of single-cell RNA sequencing and network disturbance to elucidate crosstalk between multi-components drug and trigeminal ganglia cells in migraine

OBJECTIVE To clarify the mecha⁃nism of Tou Tong Ning capsule(TTNC)and elu⁃cidate crosstalk between multi-components drug and trigeminal ganglia cells in migraine.METH⁃ODS We integrated single-cell RNA sequencing data and a quantitative evaluation algorithm of the disturbance of multi-target drugs on the dis⁃ease network to explore the specific pathology of TTNC for migraine.Cerebrovascular smooth muscle spasmolytic activity experiment was car⁃ried out to verify the results of bioinformatics analysis.RESULTS TTNC can effectively regu⁃late the functions of synaptic signaling,inflamma⁃tion and immune response,and cerebrovascular smooth muscle.For different cell subtypes of tri⁃geminal ganglia,TTNC can significantly disturb the robustness on neuronal cell networks and non-neural networks(fibroblast and vascular cells),indicating TTNC vasodilation activity of brain vessels and neural regulation activities of various neuro types.Contraction of cerebrovas⁃cular smooth muscle of mouse ex vivo confirmed the vasodilation activity of TTNC and active com⁃pounds(Emodin,Luteolin and Levistilide A).And literature mining confirmed the vasospasmolytic activity and neuroprotective effect activity of TTNC.CONCLUSIONS Integrating single-cell data and network disturbance tools provides a new strategy for the MoA of multi-components drug through cell subtyping.

基于消斑通脉方抗动脉粥样硬化作用机制的网络药理学分析和体外实验验证

目的:利用网络药理学分析方法初步预测消斑通脉方抗动脉粥样硬化(AS)的潜在作用通路和靶点,联合体外细胞实验对其可能机制进行验证。方法:采用中药系统药理学数据库与分析平台(TCMSP)、GeneCards、Swiss Target Prediction和Uniprot等数据库,收集消斑通脉方中活性化合物及对应靶点信息,构建“成分-靶点-疾病”网络,通过蛋白-蛋白互作(PPI)网络预测可能的作用靶点和通路,对交集靶点进行基因本体论(GO)功能富集分析和京都基因与基因组百科全书(KEGG)信号通路富集分析。体外培养人主动脉血管平滑肌细胞(HA-VSMCs)并鉴定,采用氧化低密度脂蛋白(ox-LDL)诱导HA-VSMCs异常增殖并进行鉴定。MTT法检测不同浓度消斑通脉方作用后各组HA-VSMCs增殖活性,确定消斑通脉方安全性。HA-VSMCs分为空白组、模型组(诱导HA-VSMCs异常增殖)、瑞舒伐他汀组(诱导HA-VSMCs异常增殖后采用4μmol·L^(−1)瑞舒伐他汀干预)及低、中和高剂量消斑通脉方组(诱导HA-VSMCs异常增殖后分别采用0.025、0.050和0.100 mg·L^(−1)消斑通脉方干预)。酶联免疫吸附试验(ELISA)法检测各组HA-VSMCs培养上清中人单核细胞趋化蛋白1(MCP-1)、白细胞介素6(IL-6)和白细胞介素8(IL-8)水平,实时荧光定量PCR(RT-qPCR)法检测各组HA-VSMCs中核因子κB(NF-κB)p65 mRNA和成纤维细胞生长因子2(FGF2)mRNA表达水平,Western blotting法检测各组HA-VSMCs中NF-κB p65和FGF2蛋白表达水平。结果:消斑通脉方中含有103种活性成分,可通过作用于189个靶基因发挥抗AS作用,潜在作用靶点包括IL-6、IL-8、血管内皮生长因子A(VEGFA)、核因子κB1(NF-κB1)和RELA(NF-κB p65)等。GO功能分析和KEGG信号通路富集分析,消斑通脉方通过调节脂质、缺氧诱导因子1(HIF-1)、表皮生长因子(EGF)、磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)和NF-κB等信号通路发挥抗AS作用。细胞形态表现和免疫荧光染色结果证明细胞为HA-VSMCs。油红O染色,可观察到大量红色脂滴,表明造模成功。MTT法检测,在一定剂量范围内消斑通脉方对HA-VSMCs增殖率无明显影响,安全性良好。ELISA法检测,与模型组比较,瑞舒伐他汀组和不同剂量消斑通脉方组HA-VSMCs培养上清中MCP-1和IL-6水平降低(P<0.05或P<0.01),0.050和0.100 mg·L^(−1)消斑通脉方组HA-VSMC培养上清中IL-8降低(P<0.01);与瑞舒伐他汀组比较,不同剂量消斑通脉方组HA-VSMCs培养上清中MCP-1降低(P<0.01),0.050和0.100 mg·L^(−1)消斑通脉方组HA-VSMCs培养上清中IL-8降低(P<0.01)。与模型组比较,瑞舒伐他汀组和不同剂量消斑通脉方组HA-VSMCs中NF-κB p65 mRNA表达水平降低(P<0.01),瑞舒伐他汀组及0.050和0.100 mg·L^(−1)消斑通脉方组HA-VSMCs中FGF2 mRNA表达水平降低(P<0.01);与瑞舒伐他汀组比较,0.050和0.100 mg·L^(−1)消斑通脉方组HA-VSMCs中NF-κB p65和FGF2 mRNA表达水平降低(P<0.05或P<0.01)。与模型组比较,瑞舒伐他汀组和不同剂量消斑通脉方组HA-VSMCs中NF-κB p65和FGF2蛋白表达水平降低(P<0.01);与瑞舒伐他汀组比较,0.050和0.100 mg·L^(−1)消斑通脉方组HA-VSMCs中NF-κB p65蛋白表达水平降低(P<0.01),0.100 mg·L^(−1)消斑通脉方组HA-VSMCs中FGF2蛋白表达水平降低(P<0.01)。结论:消斑通脉方具有抗炎、抑制HA-VSMCs增殖和抗AS作用,其作用机制可能与NF-κB/FGF2通路失活有关。

静息态功能磁共振成像在血管性认知障碍患者默认网络研究中的应用进展

血管性认知障碍是由脑血管疾病导致的一种从轻度认知功能障碍至痴呆的综合征,由于缺乏敏感性和特异性生物标志物,早期不易鉴别和诊断。血管性认知障碍患者脑网络连接异常的脑区多位于默认网络,其异常变化的功能连接与患者的认知障碍程度相关。静息态功能磁共振成像技术是一种常用的检测静息态大脑内在活动的方法,应用静息态磁共振不同分析技术探索血管性认知障碍患者默认网络异常变化有助于深入研究血管性认知障碍的发病机制,并提供客观的影像依据。该文主要综述静息态功能磁共振成像技术在血管性认知障碍患者默认网络研究中的应用成果,为血管性认知障碍的精准诊断和评估提供新思路。

基于网络药理学和实验验证探讨益肺宣肺降浊方治疗血管性痴呆的机制研究

目的通过网络药理学以及动物实验探讨益肺宣肺降浊方治疗血管性痴呆(VaD)模型大鼠的分子机制。方法通过TCMSP数据库平台筛选益肺宣肺降浊方的有效成分以及相关靶点,因麦冬无法在TCMSP数据库找到,利用查阅文献以及BATMAN-TCM生物信息学分析工具检索麦冬的成分。通过疾病数据库(GeneCards)获取VaD相关靶标并预测益肺宣肺降浊方治疗VaD的潜在靶点。通过STRING和Cytoscape 3.7.2软件绘制“复方活性成分-交集靶点”网络结构,同时建立PPI网络模型并找到关键靶点。对益肺宣肺降浊方治疗VaD的靶标进行GO富集分析与KEGG通路富集分析。29只老鼠随机分为假手术组、模型组、中药组以及西药组。运用2-VO法(双侧颈总动脉永久性结扎法)造模,水迷宫检验大鼠学习记忆行为;HE染色观察各组动物海马CA1区病理变化,荧光检测各组大鼠大脑VEGF的含量,ELISA检测各组大鼠脑组织IL-6和TNF-α含量;采用Western blot检测Nrf2、HO-1、P-Akt/Akt以及NF-κB的蛋白表达水平。结果共获得益肺宣肺降浊方靶点380个,与VaD二者基因交集靶点为183个;交集核心靶点基因PPI网络构建包含92个节点和2610条边。GO结果提示与VaD治疗相关的生物学进程包括对脂多糖、氧化应激,细胞迁移的反应等,KEGG富集分析提示关键的通路涵盖NF-κB、Akt、VEGF、NOD样受体信号等通路。治疗后,与模型组大鼠对比,中药组穿越平台次数明显增多,海马CA1区组织结构及细胞形态完整及少有细胞变性,Nrf2、Akt及HO-1表达水平显著增高,NF-κB表达水平明显下降(P<0.05),炎症指标IL-6、TNF-α明显下调(P<0.01),免疫单荧光显示中药组血管内皮因子含量增加,同时抗氧化因子SOD活性提高,氧化损伤因子MDA含量下降(P<0.05)。结论网络药理学分析提示益肺宣肺降浊方可通过调控多条信号通路以及生物过程治疗VaD,益肺宣肺降浊方提高Nrf2、P-Akt/Akt及HO-1、VEGF蛋白表达水平,改善VaD大鼠海马CA1区神经细胞变性,且可能是通过激活AKT/Nrf2/HO-1改善VaD海马区病变,抑制氧化损伤以及下调NF-κB通路,减少神经炎症,进而改善VaD模型大鼠认知功能。

基于营卫理论探讨桂枝-赤芍配伍重塑肿瘤血管微环境的网络药理学机制

目的:采用网络药理学方法预测桂枝-赤芍配伍影响肿瘤血管生成的潜在靶点和通路,从分子网络药理学水平探索该配伍重塑肿瘤血管微环境的网络药理学机制。方法:采用中药系统药理学数据库与分析平台(TCMSP)检索桂枝、赤芍的化学成分和潜在靶点,选择口服生物利用度≥30%和类药性≥0.18作为化学成分筛选条件;在GeneCards数据库中检索血管生成的靶点;利用Cytoscape 3.6.0软件绘制桂枝-赤芍配伍-化合物-靶点-血管生成网络;使用STRING 11.0在线软件构建蛋白质-蛋白质相互作用(PPI)网络并挖掘核心靶点;采用David Bioinformatics Resources数据库对该复方活性成分潜在的靶点网络中的蛋白进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析。结果:桂枝-赤芍配伍的33种有效成分作用于血管生成过程的77个靶点,PPI网络的核心靶点包括蛋白激酶B(Akt)1、JUN、白细胞介素6、基质金属蛋白酶、血管内皮生长因子A、一氧化氮合酶2和缺氧诱导因子-1α等多个蛋白。GO功能富集分析提示,该配伍的关键蛋白主要参与了DNA结合转录激活剂活性、血红素结合、抗氧化活性、核受体活性和转录因子活性等生物过程。KEGG通路富集分析显示,该配伍参与了缺氧诱导因子-1(HIF-1)信号通路、肿瘤蛋白53信号通路、细胞凋亡信号通路、表皮生长因子受体酪氨酸激酶抑制剂耐药信号通路、血管内皮生长因子(VEGF)信号通路和磷脂酰肌醇3激酶-Akt信号通路等,提示桂枝-赤芍配伍与肿瘤血管生成的关系最为密切。结论:桂枝-赤芍配伍中的黄芩素、谷甾醇和鞣花酸等成分可能通过HIF-1信号通路、VEGF信号通路影响肿瘤血管生成,干预肿瘤的生物学行为。

MCFNet:融合上下文信息的多尺度视网膜动静脉分类网络

针对由于血管类间具有强相似性造成的动静脉错误分类问题,提出了一种新的融合上下文信息的多尺度视网膜动静脉分类网络(multi-scale retinal artery and vein classification network,MCFNet),该网络使用多尺度特征(multi-scale feature,MSF)提取模块及高效的全局上下文信息融合(efficient global contextual information aggregation,EGCA)模块结合U型分割网络进行动静脉分类,抑制了倾向于背景的特征并增强了血管的边缘、交点和末端特征,解决了段内动静脉错误分类问题。此外,在U型网络的解码器部分加入3层深度监督,使浅层信息得到充分训练,避免梯度消失,优化训练过程。在2个公开的眼底图像数据集(DRIVE-AV,LES-AV)上,与3种现有网络进行方法对比,该模型的F1评分分别提高了2.86、1.92、0.81个百分点,灵敏度分别提高了4.27、2.43、1.21个百分点,结果表明所提出的模型能够很好地解决动静脉分类错误的问题。

通过整合的生物信息学方法鉴定H和L型血管内皮细胞中的ceRNA网络

目的:H型血管是一种骨特异性微血管亚型(CD31hiEmcnhi),在成血管-成骨耦联机制中具有重要的调节作用。研究报道H和L型血管在骨骼生理和病理条件下发挥不同的作用,它们之间的遗传差异仍有待阐明。本研究旨在通过整合的生物信息学方法构建H和L型血管内皮细胞中关键差异表达(differential expression,DE)基因的竞争性内源RNA(competitive endogenous RNA,ceRNA)网络。方法:从ArrayExpress和基因表达综合(Gene Expression Omnibus,GEO)数据库中下载相关原始数据,通过Limma R-Bioconductor包筛选H和L型血管间的DE lncRNAs、DE miRNAs和DE mRNAs,构建总ceRNA网络,随后根据蛋白质相互作用(protein-protein interaction,PPI)网络筛选出上调和下调的关键基因,以此精细化ceRNA网络并对关键基因进行富集分析。最后,通过流式细胞术和real time RT-PCR进行随机验证。结果:共鉴定出1 761个DE mRNAs、187个DE lncRNAs和159个DE miRNAs,通过相互作用关系构建总ceRNA网络;通过PPI网络筛选出6个上调(Itga5、Kdr、Tjp1、Pecam1、Cdh5、Ptk2)和2个下调(Csf1r、Il10)的关键基因,并以此构建关键基因相关的ceRNA亚网络。上调的关键基因主要富集在血管生成与血管凋亡的负调控;流式细胞术和real-time RT-PCR的结果与生物信息学分析结果一致。结论:本研究根据所筛选的关键基因提出上调和下调的H型和L型血管内皮细胞相关的ceRNA网络,为H型和L型血管内皮细胞在骨代谢中的调控机制提供了新见解。

利用斑马鱼模型和网络药理学研究荷丹胶囊血管保护作用的主要活性成分

目的利用斑马鱼模型和网络药理学方法研究荷丹胶囊的血管保护作用主要活性成分,为后续深入研究提供科学依据。方法采用血管转基因标记的CZ55系斑马鱼为实验动物,评价荷丹胶囊对斑马鱼血管损伤的保护作用;通过中医药整合药理学研究平台TCMIP、TCMSP、Gencards数据库、String平台、Cytoscape软件构建荷丹胶囊中荷叶、丹参、山楂、番泻叶、补骨脂的主要化学成分与作用靶点的相互作用网络,并筛选中药活性成分,同时利用分子对接进行成分与靶点结合能评价,然后采用斑马鱼模型对筛选的活性成分进行二次验证。结果斑马鱼实验结果显示荷丹胶囊具有显著保护血管内皮损伤的作用;网络药理学筛选和分子对接结果提示丹参酮ⅡA、荷叶碱、补骨脂异黄酮醛、槲皮素可能是荷丹胶囊发挥药效的重要物质基础;斑马鱼实验结果显示,丹参酮ⅡA、槲皮素具有明显的血管保护活性。结论荷丹胶囊中丹参酮ⅡA、槲皮素可能是发挥血管保护作用的重要物质基础,具有多靶点整合调节的作用特点。

基于网络药理学和分子对接探究半夏-陈皮-天南星治疗血管性痴呆的机制

目的:基于网络药理学探究半夏-陈皮-天南星治疗血管性痴呆的作用机制。方法:使用中药系统药理学数据库分析平台(TCMSP)获取药物有效成分并且预测靶点。获取2D结构图,并录入PhramMapper数据库获得成分靶点。使用4种数据库,包括PharmGKb、GeneCards、DrugBank、Therapeutic Target Database来预测疾病靶点。使用Venny 2.1韦恩图绘制平台获取药物疾病交集靶点。使用STRING数据库构建蛋白质-蛋白质相互作用网络。使用R语言和CytoScape软件中CytoNCA APP获取核心靶点。通过R语言中BiocManager包和OrgDb包等和R Studio软件进行京都基因与基因组百科全书(KEGG)和基因本体论(GO)富集分析。使用CytoScape软件,建立“药物-成分-靶点-通路”网络关系图。结果:获得药物核心成分8个,为β-谷甾醇、谷甾醇、黄芩苷、豆甾醇、黄芩素、贡多酸、10,13-二十碳二烯酸和分生孢子素。核心靶点14个,主要为细胞肿瘤抗原p53(Cellular Tumor Antigen p53,TP53)、前列腺素G/H合酶2(Prostaglandin G/H Synthase 2,PTGS2)、MAP激酶活化蛋白激酶3(MAP kinase-activated Protein Kinase 3,MAPK3)、半胱氨酸天冬氨酸蛋白酶3(Caspase-3,CASP3)、转录因子Jun(Transcription Factor Jun,JUN)、RAC-α丝氨酸/苏氨酸蛋白激酶(RAC-alphaserine/threonine-protein Kinase,AKT1)、白蛋白(Albumin,ALB)和缺氧诱导因子1α(Hypoxia-inducible Factor 1-alpha,HIF1A)等。GO富集分析中的生物过程主要为对氧气水平降低的反应、蛋白质定位建立的调节、对异生素刺激的反应和磷代谢过程的正向调节等;细胞组分主要为蛋白激酶复合物、受体复合物、谷氨酸能突触和血液微粒等;分子功能主要为激酶调节剂活性、一氧化氮合酶调节剂活性和MAP激酶活性等。KEGG富集主要包括等癌症通路、脂质和动脉粥样硬化、糖尿病性心肌病、血清素能突触、长寿调节途径和多巴胺能突触等前20个信号通路。结论:半夏-陈皮-天南星在治疗血管性痴呆病中具有多种成分、多个靶点、多条通路共同发挥作用的特点。

当归散改善克罗米芬诱导子宫内膜血管发育不良的生物机制探讨

[目的]基于网络药理学和动物实验,探究当归散及其拆方对克罗米芬诱导子宫内膜血管发育不良的作用效果。[方法]通过中药系统药理学数据库与分析平台(TCMSP)、Swiss Target Predicition数据库获取当归散成分及靶点,利用人类基因数据库(Gene Cards)、人类孟德尔遗传(OMIM)数据库检索克罗米芬导致子宫内膜血管发育不良相关的疾病靶点,两者取交集后,构建“中药-成分-靶点”网络图、蛋白互作(PPI)网络,进行GO功能、京都基因和基因组百科全书(KEGG)通路富集分析。模型组和各给药组大鼠于动情期后第1天起,连续5 d灌胃克罗米芬混悬液造模;各给药组每日分别予阳性对照药物阿司匹林、当归散、川芎-当归-芍药、黄芩-白术供试液,连续8 d。免疫组化法测定大鼠子宫内膜微血管密度、血管内皮生长因子(VEGFA)及其受体血管内皮生长因子受体1(FLT1)、血管内皮细胞生长因子受体2(KDR)、血管生成素(Ang)1、Ang2及其受体内皮细胞TEK酪氨酸激酶(Tie2)的表达。[结果]网络药理学得到VEGFA、表皮生长因子受体(EGFR)、成纤维细胞生长因子2(FGF2)、KDR、原癌基因酪氨酸蛋白激酶(SRC)、FLT1等当归散核心作用靶点24个,GO富集分析涉及生物过程1 524个条目、细胞组分36个条目和分子功能94个条目,KEGG通路富集得到磷脂酰肌醇-3-激酶-蛋白激酶(PI3K-Akt)信号通路、Rap1信号通路、松弛素信号通路等118条通路。与正常组相比,模型组子宫内膜微血管密度显著降低,VEGFA及其受体FLT1、KDR,Ang1、Ang2及其受体Tie2表达水平显著下降(P<0.01)。与模型组相比,各药物组微血管密度提高,KDR、FLT1、Ang1、Ang2、Tie2表达升高(P<0.05或P<0.01);除黄芩白术组,其余各用药组大鼠子宫内膜VEGFA的表达水平均显著升高(P<0.01)。[结论]当归散及其拆方可以不同程度地改善克罗米芬造成的大鼠子宫内膜微血管密度下降,恢复VEGFA及其受体FLT1、KDR,Ang1、Ang2及其受体Tie2表达水平,提高子宫内膜容受性。

血清VNN1及CCN2检测对2~4期慢性肾脏病并发急性肾损伤的预测价值

目的分析2~4期慢性肾脏病(CKD)患者血清血管非炎性因子(VNN1)、细胞交流网络因子2(CCN2)水平及对并发急性肾损伤(AKI)的预测价值。方法选取2020年3月—2022年3月重庆医科大学附属第一医院梁平医院肾内科诊治2~4期CKD患者102例为CKD组,根据是否并发AKI,分为AKI亚组28例和非AKI亚组74例,以同期体检的健康者60例为健康对照组。Pearson相关分析血清VNN1、CCN2与肾疾病指标的相关性;多因素Logistic回归分析影响2~4期CKD患者并发AKI的因素;受试者工作特征曲线分析血清VNN1、CCN2及二者联合对2~4期CKD患者并发AKI的预测价值。结果CKD组患者血清VNN1、CCN2水平高于健康对照组(t=34.043,16.383,P均<0.001)。AKI亚组血肌酐、血尿酸、血尿素氮、24 h尿蛋白定量及血清VNN1、CCN2水平均高于非AKI亚组(t/P=4.842/<0.001,3.578/0.001,5.268/<0.001,3.876/<0.001,20.046/<0.001,10.791/<0.001)。2~4期CKD患者血清VNN1、CCN2与血肌酐、血尿酸、血尿素氮、24 h尿蛋白定量呈显著正相关(VNN1:r/P=0.627/<0.001,0.624/<0.001,0.521/<0.001,0.705/<0.001;CCN2:r/P=0.646/<0.001,0.610/<0.001,0.536/<0.001,0.689/<0.001)。血肌酐、血尿素氮、血尿酸、24h尿蛋白定量、血清VNN1、CCN2升高是影响2~4期CKD患者并发AKI的独立危险因素[OR(95%CI)=1.602(1.268~2.022),1.652(1.263~2.161),1.594(1.252~2.028),1.579(1.196~2.086),1.568(1.131~2.176),1.673(1.124~2.385)]。血清VNN1、CCN2及二者联合预测2~4期CKD患者并发AKI的AUC为0.814、0.822、0.890,二者联合的AUC大于单一指标检测(Z=4.675、4.513,P均<0.001)。结论2~4期CKD患者血清VNN1、CCN2升高,两者是影响2~4期CKD患者并发AKI的独立危险因素,且二者联合对2~4期CKD并发AKI具有较高的预测价值。

川芎-当归药对治疗血管性痴呆的网络药理学研究

目的:通过网络药理学的方法探索川芎-当归药对治疗血管性痴呆的作用机制。方法:应用中药系统药理学数据库与分析平台(TCMSP)、GeneCards数据库检索,获得当归-川芎药对与血管性痴呆的交集靶点。构建交集靶点蛋白质-蛋白质相互作用网络及共同靶点的相互作用网络图,并对交集靶点进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析。结果:共筛选出川芎-当归药对活性成分13个,作用靶点155个,血管性痴呆靶点1215个,取交集后获得共同作用靶点76个。核心成分为β-谷甾醇、杨梅酮、叶酸;核心靶点为丝裂原活化蛋白激酶(Mitogen-Activated Protein Kinase,MAPK)14、MAPK10。GO富集分析显示,以上共同作用靶点主要参与血管生成、细胞外调节蛋白激酶(Extracellular Regulated Protein Kinases,ERK)1和ERK2级联的正向调节、细胞内类固醇激素受体信号传导途径和凋亡过程的正调控等细胞生物过程。KEGG富集结果显示,交集靶点富集的信号通路中与血管性痴呆相关的主要有动脉粥样硬化相关信号通路、突触相关通路、肿瘤坏死因子(Tumor Necrosis Factor,TNF)信号通路等。分子对接结果显示,川芎-当归药对的核心成分与核心靶点均结合稳定。结论:川芎-当归药对治疗血管性痴呆的作用是多靶点、多途径的,其作用机制可能与动脉粥样硬化、血清突触、TNF等信号通路相关。