中成药治疗缓慢性心律失常临床随机对照试验的网状Meta分析

采用网状Meta分析方法比较治疗缓慢性心律失常中成药的有效性和安全性。计算机检索中国期刊全文数据库(CNKI)、万方数据库(WanFang)、维普数据库(VIP)、SinoMed数据库、PubMed、Cochrane Library,检索时间均为建库至2019年2月。按预先制定的纳入与排除标准进行文献筛选和资料提取。Cochrane系统评价员手册5.3推荐的偏倚风险评估工具对纳入的RCTs进行质量评价。采用WinBUGS软件进行数据分析,STATA软件进行绘图。最终纳入46个中成药治疗缓慢性心律失常的随机对照试验(RCT),涉及4种中成药,3306例患者。网状Meta分析结果显示,心律失常症状改善总有效率共产生7个直接比较和3个间接比较,其中,参仙升脉口服液、参松养心胶囊、心宝丸、宁心宝胶囊联合常规治疗的临床疗效均优于单纯常规治疗,且差异具有统计学意义;中成药疗效排序依次为:参仙升脉口服液>参松养心胶囊>心宝丸>宁心宝胶囊。平均心率监测共产生7个直接比较和3个间接比较,参仙升脉口服液、参松养心胶囊联合常规治疗的疗效均优于单纯常规治疗,且差异具有统计学意义;中成药疗效排序依次为:参仙升脉口服液>参松养心胶囊>心宝丸>宁心宝胶囊。在常规治疗基础上,联用中成药可提高缓慢性心律失常的临床治疗效果。不同的中成药由于纳入的研究数量及质量存在差异,中成药排序结果有待进一步验证。     

优化新生脉散方治疗心力衰竭的网络药理学机制分析

[目的] 运用网络药理学方法分析优化新生脉散方治疗慢性心力衰竭（CHF）的作用机制。[方法] 基于中药系统药理数据库和分析平台（TCMSP）、BATMAN-TCM及UniProt数据库查询优化新生脉散方药物的主要活性成分与相应靶点，利用GeneCards数据库检索CHF相关靶点，通过OmicShare网站分析并结合Cytoscape-v3.6.0软件构建优化新生脉散方中药-化合物-靶点-疾病网络图，使用DAVID数据库对潜在靶点进行基因功能（GO）及京都基因和基因组百科全书（KEGG）通路富集分析。[结果] 根据类药性（DL）、口服吸收利用度（OB）、参数评分（Scorecutoff）筛选出与CHF相关的潜在化合物85种及靶点89个，其中，化合物有quercetin、luteolin、kaempferol等，靶点包括SCN5A、ADRB2、NOS2等。功能富集分析涉及生物过程、分子功能、细胞组分的GO条目共497个，主要参与调控细胞凋亡、增殖及缺氧、炎症反应等方面，KEGG通路富集得到139条，主要与缺氧诱导因子-1（HIF-1）、磷脂酰肌醇3激酶/蛋白激酶B（PI3K-Akt）、肿瘤坏死因子（TNF）信号通路等有关。[结论] 优化新生脉散方治疗CHF具有多成分、多靶点、多途径的作用，为进一步研究优化新生脉散方治疗CHF的潜在复杂机制提供参考方向。     

全国名中医丁书文益气活血解毒法治疗心房颤动的处方用药规律挖掘＊

目的 丁书文教授创新性地提出了心系疾病热毒学说，运用益气活血解毒法治疗房颤疗效显著。本研究以丁教授多年的处方数据为基础，探讨丁教授益气活血解毒法治疗房颤的用药规律。方法 收集来自山东中医药大学附属医院门诊系统的丁书文教授处方数据，筛选出治疗房颤的372个处方，采用关联规则、点式互信息、复杂网络等数据挖掘方法对丁教授的药物配伍和处方进行分析。结果 本研究利用复杂网络分析方法获得了丁教授治疗房颤的核心处方，提示益气活血解毒法是其主要治则治法；利用处方相似性和社团分析方法，获得15组类方，其中3种类方与丁教授总结的三大治法高度符合；为探寻丁教授清热解毒配伍特点，结合关联规则和点式互信息算法，获得了10个丁教授清热解毒配伍药对。结论 数据挖掘技术提供了名医处方数据分析与提炼的可行方法，对丁教授经验的传承和临床应用提供直接可靠的依据。     

The formation of physician patient sharing networks in medicare: Exploring the effect of hospital affiliation

This study explores the forces that drive the formation of physician patient sharing networks. In particular, I examine the degree to which hospital affiliation drives physicians' sharing of Medicare patients. Using a revealed preference framework where observed network links are taken to be pairwise stable, I estimate the physicians' pair‐specific values using a tetrad maximum score estimator that is robust to the presence of unobserved physician specific characteristics. I also control for a number of potentially confounding patient sharing channels, such as (a) common physician group or hospital system affiliation, (b) physician homophily, (c) knowledge complementarity, (d) patient side considerations related to both geographic proximity and insurance network participation, and (e) spillover from other collaborations. Focusing on the Chicago hospital referral region, I find that shared hospital affiliation accounts for 36.5% of the average pair‐specific utility from a link. Implications for reducing care fragmentation are discussed.     

加味桃核承气汤防治糖尿病胃轻瘫作用机制及网络药理学分析

目的:运用网络药理学技术分析加味桃核承气汤治疗糖尿病胃轻瘫的作用靶点和相关信号通路,进一步分析其防治糖尿病胃轻瘫的理论基础和作用机制。方法:运用中药系统药理学成分分析平台(bioinformatics analysis tool for molecular mechanism of TCM,BATMAN-TCM)数据库获取加味桃核承气汤的化学成分及作用靶标基因,从comparative toxicogenomics database(CTD)数据库收集糖尿病胃轻瘫的靶标基因,将两者取交集后得到加味桃核承气汤--糖尿病胃轻瘫靶基因交集,运用STRING构建蛋白质间相互作用网络,并将结果进行网络可视化展示,通过Cytospace软件Clue GO,Clue Pedia插件进行加味桃核承气汤--糖尿病胃轻瘫靶基因交集的基因本体论(gene ontology,GO)分析和京都基因与基因组百科全书(KEGG)通路富集分析,并将结果进行可视化展示。最后利用CTD数据库并结合文献学习,获取交集基因于糖尿病胃轻瘫的疾病治疗作用。结果:加味桃核承气汤的621个靶点基因中有25个靶点与糖尿病胃轻瘫相互关联,该方可能通过影响MLNR,SST,PTGS1,HRH2,HTR3A,HTR4,HTR7,NOS3基因表达,改善胃肠激素水平,影响血清素与其受体结合,活化腺苷酸环化酶(adenylate cyclase,AC),诱导环磷酸腺苷(cyclic adenosine monophosphate,c AMP),蛋白激酶A(protein kinase A,PKA)表达,从而激活AC/c AMP/PKA信号通路,并调节Ca2+/K+通道的开放,控制离子平衡,继而促进胃平滑肌适应,收缩胃平滑肌以调节胃容量,同时改善胃酸分泌,保护胃黏膜,不排除改善血管收缩功能、血流动力学的可能。结论:网络药理学方法科学分析加味桃核承气汤通过多方面防治糖尿病胃轻瘫的作用机制,阐释其中医药多靶点、多通路防治糖尿病胃轻瘫的治疗优势,为加味桃核承气汤后续的实验研究提供研究方向和理论参考。     

Effect of Acupoints on Acupuncture-Moxibustion and its Therapeutic Mechanism

The clinical efficacy of acupuncture-moxibustion(AM) mainly depends on acupoints, but the relationship between the acupoints and AM remains unclear. Improving clinical efficacy and clarifying the mechanisms of AM is critical. We found that the specificity and sensitivity of acupoints, the skill of operation, and reasonable amount of stimulation can significantly improve the efficacy of AM. In addition, some studies have shown that Neural-Endocrine-Immune network and metabolites are involved in this process, clarifying the therapeutic mechanism of acupoints. Therefore, how to effectively use acupoints to improve the clinical efficacy of AM is one of the key issues in need of an urgent solution. In summary, this article reviewed the Chinese and English databases on the clinical efficacy and underlying mechanisms of acupoints to clarify the relationship between acupoints and AM efficacy and ultimately improve clinical efficacy through effective and rational use of acupoints.     

基于网络药理学探讨祛湿通脉法在类风湿性关节炎中的作用

目的通过网络药理学探究全蝎、益母草、金钱草治疗类风湿性关节炎(rheumatoid arthritis,RA)的药理机制,为祛湿通脉法的临床运用提供理论依据。方法基于TCMSP、TCMID数据库搜集全蝎、益母草、金钱草成分及靶点,通过Cytoscape软件构建成分-靶点网络;通过TTD、DrugBank数据收集RA相关靶点,在STRING数据库构建靶点互作PPI网络。在Genomics数据库分析药物和疾病共有靶点,并利用Cytoscape软件中Cluego插件分析共同靶点的信号通路,最后构建成分-靶点-通路网络图并分析。结果益母草、金钱草、全蝎发挥治疗RA的成分可能是槲皮素、山柰酚等;发挥治疗作用的靶点可能包括IL-6、TNF、JUN、PTGS1、PTGS2、PIK3CG等;其关键作用通路包括L-17信号通路、肿瘤坏死因子信号通路、NF-κB信号通路等13条。结论益母草、金钱草、全蝎治疗RA作用的药理学机制可能是通过多组分、多靶点、多通路实现,祛湿通脉法运用于RA治疗具有一定的价值。     

Functional network analysis reveals potential repurposing of β-blocker atenolol for pancreatic cancer therapy

BackgroundThe survival rate of patients with pancreatic cancer is low; therefore, continuous discovery and development of novel pancreatic cancer drugs are required. Functional network analysis is an integrated bioinformatics approach based on gene, target, and disease networks interaction, and it is extensively used in drug discovery and development.ObjectiveThis study aimed to identify if atenolol, a selective adrenergic inhibitor, can be repurposed for the treatment of pancreatic cancer using functional network analysis.MethodsDirect target proteins (DTPs) and indirect target proteins (ITPs) were obtained from STITCH and STRING databases, respectively. Atenolol-mediated proteins (AMPs) were collected from DTPs and ITPs and further analyzed for gene ontology, KEGG pathway enrichment, genetic alterations, overall survival, and molecular docking.ResultsWe obtained 176 AMPs that consisted of 10 DTPs and 166 ITPs. Among the AMPs involved in the pancreatic cancer pathways, several AMPs such as MAPK1, RELA, MAPK8, STAT1, and STAT3 were identified. Genetic alterations in seven AMPs were identified in 0.9%–16% of patients. Patients with high mRNA levels of MAPK1, RELA, STAT3, GNB1, and MMP9 had significantly worse overall survival rates compared with patients with low expression. Molecular docking studies showed that RELA and MMP9 are potential target candidates of atenolol in the treatment of patients with pancreatic cancer.ConclusionIn conclusion, atenolol can potentially be repurposed to target pancreatic cancer cells by modulating MMP9 and NF-κB signaling. The results of this study need to be further validated in vitro and in vivo.Graphical abstractElectronic supplementary materialThe online version of this article (10.1007/s40199-020-00375-4) contains supplementary material, which is available to authorized users.     

Comprehensive analysis of the relationship between competitive endogenous RNA (ceRNA) networks and tumor infiltrating-cells in hepatocellular carcinoma

BackgroundThe innovation of immune checkpoint blockade (ICB) represents a promising shift in the treatment of advanced hepatocellular carcinoma (HCC). However, response to ICB has varied largely due to the high tumor heterogeneity and complex tumor microenvironment (TME). The competitive endogenous RNA (ceRNA) network also plays an important role in tumor occurrence and progression, but its relation with tumor-infiltrating immune cells (TICs) remains largely unexplored in HCC. The overriding objective of our study was thus to construct a prognosis-related risk model and to further evaluate the relationship between ceRNA networks and TICs.MethodsDifferentially expressed gene (DEG) analysis was performed to identify the differentially expressed RNAs. Lasso and multivariable Cox regression analyses were used to construct risk models, which were assessed by the area under the receiver operating characteristic curve (AUC of ROC) and Kaplan-Meier (K-M) curves. Then, a single-sample gene set enrichment analysis (ssGSEA) algorithm was adopted to dissect the TICs in HCC samples. Nomograms were constructed and calibration curves were used to verify the discrimination and accuracy of the nomograms. Finally, integration analysis was performed to validate the correlation of ceRNA and TICs.ResultsIn the study, 7 differentially expressed RNAs [5 messenger RNA s (mRNAs) and 2 micro RNAs (miRNAs)] were incorporated to construct a ceRNA risk model. The AUC of the 1-, 3-, and 5-year overall survival (OS) were 0.784, 0.685, and 0.691 respectively. Likewise, 7 types TICs were in the TICs signature model and the AUC of the 1-, 3-, and 5-year OS were 0.706, 0.731, and 0.721 respectively. The integration analysis showed that 7 pairs of mRNA-TICs and 1 pair of miRNA-TICs had a close relation (all correlation coefficients >0.2, P<0.001).ConclusionsThrough constructing two risk models based on ceRNA network and TICs, we identified the hub RNAs and key TICs in the progression and prognosis of HCC, and further explored the relationship between ceRNA and TME. Importantly, targeting these hub RNAs may facilitate the remodeling of the TME and be a potential therapeutic alternative to enhancing the response to ICB, thus improving the prognosis of HCC patients.