左金丸抗幽门螺杆菌感染的分子网络调控机制研究

目的基于网络药理学和生物信息学方法探究左金丸抗幽门螺杆菌(Hp)感染的分子网络调控机制。方法通过中药系统药理学数据库和分析平台(TCMSP)检索左金丸化学成分,筛选并预测其入血活性成分和作用靶点,检索疾病数据库中与Hp感染相关的作用靶点,构建左金丸成分靶点与疾病靶点的交互网络,获得左金丸抗Hp的特征性基因;通过DAVID6.8数据库对上述特征性基因进行GO功能富集和KEGG通路富集分析;利用Cytohubba筛选出左金丸抗Hp感染的关键靶点。结果通过TCMSP筛选、预测得到左金丸32个入血活性成分和197个作用靶点。GO分析共得到199条富集结果,其中生物过程包含炎症反应、RNA信号转录、信号传导等152条,细胞组分包含细胞核、细胞外基质、蛋白复合物等19条,分子功能包含细胞因子活性、DNA结合、ATP结合等28条。KEGG分析结果显示,Jak-STAT信号通路、T细胞受体信号通路、细胞周期信号通路、Wnt信号通路等65条通路与左金丸抗Hp感染密切相关。经Cytohubba筛选得到CXCL8、IL10、IL4、VEGFA、MMP9等10个关键基因。结论左金丸抗Hp感染具有多成分、多靶点、多通路协同作用的特点,可为其活性成分研究和抗Hp药效及机制研究提供依据。     

丹参治疗微循环障碍作用机制的“成分-靶点-通路”多层次互作网络模型研究

目的基于网络药理学分析丹参治疗微循环障碍的分子生物学机制。方法借助TCMSP、PubChem Search、Genecards数据库和Swiss target prediction在线工具得到丹参的活性成分治疗微循环障碍的作用靶标,利用Cytoscape 3.3.0软件构建丹参活性成分-微循环障碍作用靶标网络,通过STRING数据库构建靶蛋白相互作用(PPI)网络,通过生物学信息注释数据库(DAVID)进行基因本体(GO)生物学过程和京都基因与基因组百科全书(KEGG)通路富集分析。结果从丹参中共筛选出治疗微循环障碍的65个相关活性成分,并发现微循环障碍相关的9个关键靶点。GO和KEGG通路富集分析发现,丹参治疗微循环障碍可能与氧化还原、钙离子稳态等生物过程有关,能够调节血管内皮生长因子信号通路、神经突触信号传导、催产素信号通路、醛固酮-调节钠重吸收等信号通路。结论丹参治疗微循环障碍体现了多成分、多靶点、多途径的作用特点,为进一步开展丹参治疗微循环障碍作用机制研究提供了新的思路和方法。     

基于网络药理学的济脉通片降压机制研究

目的 采用网络药理学阐明济脉通片多成分-多靶点-多途径的作用理念，为进一步研究济脉通片降压药效物质基础和机制提供一定理论参考。方法 通过TCMSP数据库，结合口服利用度（≥ 30%）和类药性分析（≥ 0.18）参数，筛选济脉通片的活性成分；通过Drugbank和TCMSP数据库进行靶点预测分析；通过GENCARD数据库筛选出高血压疾病相关基因；结合DAVID和KEGG数据库进行GO分析和通路分析；使用Cystoscope软件构建"化合物-靶点-作用通路"网络图。结果 经筛选后得到济脉通片的33个化合物，148个潜在靶基因并映射到了223条信号通路，其中31条信号通路与高血压的发生发展密切相关，其中AGE-RAGE signaling pathway in diabetic complications、PI3K-Akt signaling pathway、TNFsignaling pathway、Adrenergic signaling in cardiomyocytes和Focal adhesion为重要的通路枢纽。结论 济脉通片主要通过多成分、多靶点、多通路调节血管内皮功能、炎症反应、钙钠离子转运、糖脂代谢等参与血管舒张、改善炎症、调节机体代谢、调节离子转运等而产生降压作用。     

Intelligent Imaging: Radiomics and Artificial Neural Networks in Heart Failure

BackgroundOur previous work with ¹²³iodine meta-iodobenzylguanidine (¹²³I-mIBG) radionuclide imaging among patients with cardiomyopathy reported limitations associated with the prognostic power of global parameters derived from planar imaging [1]. Employing multivariate analysis, we further showed the regional washout associated with territories adjacent to infarcted myocardium obtained from single-photon emission computed tomography imaging (SPECT) yielded superior prognostic power over the other planar and SPECT indices in predicting future cardiac events [1]. The aim of this study was to apply an artificial neural network (Neural Analyser version 2.9.5) to the original data from the same patient cohort to evaluate the most potent prognostic index for future cardiac events among patient with cardiomyopathy.MethodsThe original data were reevaluated using an artificial neural network (Neural Analyser version 2.9.5). There were 84 input variables in the original 22 patients from clinical data, electrocardiogram (rest, stress, and continuous ambulatory electrocardiogram recording), transthoracic echocardiography, coronary angiogram, sestamibi myocardial perfusion SPECT, planar and SPECT 123I-mIBG, and genetic and biomarkers, detailed in the previous work. A single binary output was a cardiac event or no cardiac event in the follow-up period.ResultsFollowing training and validation phases, the optimal number of inputs was determined to be two with a training loss of 0.025 and selection loss <0.001. The final architecture had inputs of a change in left ventricular ejection fraction (Δ > −10%) and 123I-mIBG planar global washout (>30%), two hidden layers of 6 and 1 node, respectively, and a binary output. Using receiver operator characteristics analysis demonstrated an area under the curve of 0.75 correlating to a sensitivity of 100% and specificity of 50%.ConclusionThe premise that regional washout of 123I-mIBG SPECT from noninfarcted tissue is the best predictor of cardiac events was built on has a sound and logical foundation. By artificial neural network analysis; however, 123I-mIBG planar global washout of >30% was shown to be the best indicator for risk of cardiac event when accompanied by a decline in left ventricular ejection fraction of >10%. Further investigation should be undertaken assessing assimilation into big data and the potential for automated feature extraction from raw image datasets with convolutional neural networks.     

黄芪-莪术药对基于网络药理学的抗大肠癌分子机制

目的:运用计算机网络药理学技术预测黄芪-莪术药对治疗大肠癌的作用靶点和信号通路,进一步分析其抗大肠癌物质基础和作用机制。方法:通过Therapetutic Target Database(TTD),Drugbank数据库收集大肠癌疾病作用靶点;从中药系统药理学分析平台(TCMSP)获得黄芪、莪术所含中药成分;运用Chem Mapper,Pharm Mapper数据库预测所选中药成分作用的疾病靶点;采用Cytoscape软件建立"化合物-疾病靶点"网络模型;利用Clue GO插件对靶点进行基因功能(GO)分析和基于京都基因与基因组百科全书(KEGG)通路富集分析。结果:黄芪-莪术药对活性化合物-大肠癌疾病靶点网络包含56个化合物和54个靶点,关键靶点涉及AMP激活蛋白激酶α1(PRKAA1),前列腺素内过氧化物合酶1(PTGS1),环氧化酶2(PTGS2),胸苷酸合成酶(TYMS),肝羧酯酶1(CES1),血管内皮生长因子B(VEGFB),血管内皮生长因子A(VEGFA),谷胱甘肽S-转移酶P(GSTP1),丝氨酸羟甲基转移酶(gly A)等;靶点的基因功能偏向于肽基酪氨酸的磷酸化,调节细胞外调节蛋白激酶(ERK) 1和ERK2信号串联,内皮细胞凋亡过程的负调节等;重要的KEGG通路涉及癌症通路,Ras信号通路,Rap1信号通路,磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)信号通路等。结论:黄芪-莪术药对通过抑制肿瘤细胞增殖分化、促进肿瘤细胞凋亡、抗肿瘤新生血管生成以及增强机体免疫的多表型干预的网络模式产生抗大肠癌活性,其作用信号通路与Ras信号通路,Rap1信号通路,PI3K/Akt信号通路最为相关。     

基于网络药理学挖掘溃疡性结肠炎“扶正”治则的潜在机制

目的:通过数据库检索与网络药理学方法探讨溃疡性结肠炎"扶正"治则的潜在机制。方法:从中医E百数据库检索溃疡性结肠炎相关方剂,检索方式为"主治肠澼/久痢/痢疾",筛选所检索到的处方并进行药物种类、用药频次统计分析,选择溃疡性结肠炎治疗的常用扶正药物。将选择后的扶正药物输入中药系统药理学分析平台检索所有化学成分和作用靶点,构建化合物-靶点相互作用网络图;通过Digsee数据库筛选溃疡性结肠炎相关靶点,构建疾病-靶点相互作用网络图;筛选两个网络图的核心靶点,利用DAVID工具对核心靶点进行富集分析。结果:数据库共检索到溃疡性结肠炎相关方剂731首,根据纳入、排除标准筛选后获得处方304首,中药220味,经用药频次统计后,以甘草、人参、白术为溃疡性结肠炎扶正治则的代表药物。基于药代动力学ADME参数对上述药物的化学成分进行筛选和靶标预测,共得到136个蛋白靶点;将化合物-靶点、疾病-靶点的蛋白质—蛋白质相互作用网络图合并,以"节点连接度""节点介度"和"节点紧密度"为评价标准,筛选共有靶点129个;对入选靶标进行京都基因与基因组百科全书(KEGG)富集分析,以P值筛选出前20条通路在溃疡性结肠炎方面具有作用。结论:扶正药物治疗溃疡性结肠炎作用的发挥是多靶点、多通路的整体效应,挖掘了溃疡性结肠炎扶正治则的潜在机制,为进一步实验研究提供了理论基础。     

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system

BackgroundAlthough colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs.MethodsBased on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected.ResultsA total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event of colitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27–69 days) among all monotherapies.ConclusionsICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.     

Early life Adversity,functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6

ObjectiveExposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity.MethodsThree-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity.ResultsHigher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: β_indirect −0.0234, 95% CI: −0.0573 to −0.0074; CTQ physical neglect: β_indirect = −0.0316, 95% CI: −0.0741 to −0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (β_indirect = −0.0618, 95% CI: −0.1523 to −0.285).ConclusionThis work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6′s association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.     

基于方剂构成信息的知识发现和关联网络构建挖掘海洋中药海马历代用药经验＊

目的 通过对含海马方剂构成信息进行数据挖掘和知识发现，构建关联网络，分析海马的历代应用情况，挖掘海马用药配伍经验，发现海马潜在功效和主治病症，为海马的临床应用和开发提供依据。方法 以《中医方剂大辞典》《中国药典》《中华医典》等多部著作为方源，收集含有海马的相关方剂，并进行频数分析、关联规则挖掘和关联网络的构建。结果 共筛选有文献记载的含海马方剂154首。从剂型看，大多为散剂，从方剂分布年代来看，海马的应用虽然有很长历史，但是古代应用并不广泛，现代应用较多。通过对配伍药物进行分析发现，与海马配伍频率较高的是“鹿茸”、“熟地黄”、“肉苁蓉”等补益药物。从功效主治方面看，大多数方剂具有“补肾”、“温阳”、“益精”等传统功效外，还具有健脑等功效；主治病症中，除“阳痿”、“癥瘕”、“疔疮”等《中国药典》所记载的疾病之外，还可治疗“虚劳”、“健忘”、“瘿病”、“不寐”、“痹证”、“小便淋沥或不通”等。对其进行关联关系分析发现，海马配伍补肾温阳的效果较为明显，多用于治疗阳痿，且腰痛、虚劳、遗精、健忘、不育等疾病的治疗与补肾关系密切；在治疗癥瘕时，多与醋、樗鸡、干漆、硇砂、斑蝥、水蛭、没药、当归配伍。结论 该研究不仅发现了含海马方剂的常用剂型、分布年代和药物配伍规律，发现了历代医家应用海马的临床经验，还探索了海马的潜在应用价值。海马作为一味海洋中药，具有温、补、托、消等特性，除常用于治疗阳痿外，还可用于治疗腰痛、健忘、瘿病、不寐、痹证等病症，这些研究结果可为拓展海马的临床应用提供理论基础及依据。