[Objective]A Meta-analysis of the efficacy and safety of tonifying kidney and promoting blood circulation in the treatment of chronic kidney disease.[Methods]By searching CNKI,VIP,Wanfang Data,SinoMed,PubMed,Web of Science databases,the kidney tonifying and blood circulation method combined with conventional Western medicine treatment was used as the test group,and the conventional Western medicine treatment group was used as the control group,and the related words such as"kidney and blood circulation","chronic kidney disease"were used as the search terms,and the randomized controlled trials were used as the retrieval targets.Relevant studies meeting the inclusion criteria were evaluated by the"risk of bias assessment"tool recommended by Cochrane Reviewer's Handbook 5.0.1,and the data were analyzed by Revman 5.4.1 software.[Results]In the 18 articles included,taking the clinical efficiency,blood creatinine,urea nitrogen,uric acid,glomerular filtration rate,severity of adverse reactions as outcome indicators,it was concluded that the efficacy of the experimental group was higher than that of the control group,with statistical difference(P<0.05).[Conclusion]The method of tonifying kidney and activating blood circulation has curative effect on chronic kidney disease.

糖尿病肾病(diabetic nephropathy,DN)是糖尿病(diabetes mellitus,DM)的最严重和最常见的并发症之一[1].随着DM发病率和死亡率逐年增加[2],DN的患病率急剧上升,同时DN已成为慢性肾衰竭的主要原因之一[3].然而,现代医学对其认识仍不完善,治疗仍存在较多挑战.DN归属于中医"消渴病肾病"、"水肿""尿浊"等范畴.传统中医药作为一种补充替代药物,具有不可比拟的优势.

According to the theoretical basis of deficiency and stasis in traditional Chinese medicine, Professor Zhang Daning proposes the pathogenesis of diabetic kidney disease（DKD）from the theory of kidney deficiency and blood stasis and develops the therapy of tonifying kidney and activating blood.In clinical practice, the DKD patients mainly present the syndrome of kidney deficiency and blood stasis, which is complicated with dampness turbidity or dampness toxin sometimes.Accordingly, tonifying kidney and activating blood is the fundamental therapy, which can be supplemented with the therapy of invigorating spleen and expelling dampness.The therapy of invigorating spleen and replenishing kidney is essential, and importance should be attached to activating blood and resolving stasis throughout the whole treatment process.Treatment by stages should be employed according to the etiology and pathogenesis, and prescriptions should be modified according to the characteristics of disease procession.

慢性肾衰竭( chronic renal failure,CRF)是各种肾脏疾病发展到最后阶段的临床综合征,以体内代谢产物蓄积,水、电解质及酸碱平衡失调以及全身多系统受累为主要表现.该病起病隐匿,病因复杂,临床常见恶心呕吐、腰痛、乏力、尿少、浮肿、皮肤瘙痒、贫血等症,据此本病可归属于中医虚劳、关格、癃闭、肾风等范畴.中医药在治疗CRF方面积累了丰富的临床经验,同时对延缓CRF进展有确切的疗效及特色[1].

Ethnopharmacological relevance: Diabetic nephropathy (DN) is one of the most common and serious microvascular complications of Diabetes mellitus (DM). The inflammatory response plays a critical role in DN. Schisandra Chinensis Mixture (SM) has shown promising clinical efficacy in the treatment of DN while the pharmacological mechanisms are still unclear.Aim of the study: In this study, a network pharmacology approach and bioinformatic analysis were adopted to predict the pharmacological mechanisms of SM in DN therapy. Based on the predicted results, molecular docking and in vivo experiments were used for verification.Materials and methods: In this study, the candidate bioactive ingredients of SM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and supplementing according to the literature. SM putative targets and the verified targets were acquired from TCMSP and SiwssTartgetPrediction Database. DN-related target genes were collected from GeneCards, OMIM, DisGeNET databases, and microarray data anal-ysis. Biological function and pathway analysis were performed to further explore the pharmacological mecha-nisms of SM in DN therapy. The protein-protein interaction (PPI) network was established to screen the hub gene. The Receiver Operating Characteristic (ROC) analysis and the molecular docking simulations were performed to validate the potential target-drug interactions. The fingerprint spectrum of multi-components of the SM was characterized by UPLC-MS/MS. The signaling pathways associated with inflammation and hub genes were partially validated in SD rats.Results: A total of 36 bioactive ingredients were contained, and 666 component-related targets were screened from SM, of which 50 intersected with DN targets and were considered potential therapeutic targets. GO analyses revealed that the 50 intersection targets were mainly enriched in the inflammatory response, positive regulation of angiogenesis, and positive regulation of phosphatidylinositol 3-kinase(PI3K) signaling. KEGG analyses indi-cated that the PI3K-Akt signaling pathway was considered as the most important pathway for SM antagonism to the occurrence and development of DN, with the highest target count enrichment. PPI network results showed that the top 15 protein targets in degree value, VEGFA, JAK2, CSF1R, NOS3, CCR2, CCR5, TLR7, FYN, BTK, LCK, PLAT, NOS2, TEK, MMP1 and MCL1, were identified as hub genes. The results of ROC analysis showed that VEGFA and NOS3 were valuable in the diagnosis of DN. The molecular docking confirmed that the core bioactive ingredients had well-binding affinity for VEGFA and NOS3. The in vivo experiments confirmed that SM signif-icantly inhibited the over-release of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor receptor (TNF)-alpha in DN rats, while regulating the PI3K-AKT and VEGFA-NOS3 signaling pathways.

目的:整合网络药理学方法阐释四神丸治糖尿病肾病的潜在机制.方法:从中药系统药理学数据库与分析平台、中药分子机制的生物信息学分析数据库、Swiss Target Prediction、STITCH和ChEMBL数据库检索四神丸的药物成分及对应靶点.利用DisGeNET、GeneCards和CTD数据库识别糖尿病肾病的疾病基因;在GEO数据库获取糖尿病肾病的数据集,利用limma包和RRA方法筛选稳健差异表达基因,整合疾病数据得到疾病靶点.构建韦恩图,得到复合靶点.然后,基于STRING数据库构建蛋白质-蛋白质相互作用网络,根据拓扑学参数筛选四神丸治疗糖尿病肾病的核心靶点.通过Cytoscape软件构建成分-靶点网络和成分-靶点-通路网络.利用DAVID数据库对复合靶点进行基因本体(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.最后,分子对接模拟验证主要活性成分与核心靶标之间的结合力.结果:筛选出有效成分121个,有效成分作用靶点542个,有关糖尿病肾病的靶点3 832个.四神丸治疗糖尿病肾病的枢纽基因集为蛋白激酶B1、肿瘤坏死因子、白细胞介素1β等.活性成分为油酸、亚油酸、二氢吴茱萸卡品碱、吴茱萸酰胺等.分子对接模拟显示,核心活性化合物与枢纽基因具有较高的结合活性.结论:四神丸是通过多成分、多靶点和多途径发挥对糖尿病肾病的治疗作用,且作用机制集中体现在晚期糖基化终末产物(AGE)-AGE受体信号通路、TNF信号通路等通路上.

Background: Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD), and inflammation is the main causative mechanism. Schisandra chinensis fruit Mixture (SM) is an herbal formulation that has been used for a long time to treat DKD. However, its pharmacological and molecular mechanisms have not been clearly elucidated. The aim of this study was to investigate the potential mechanisms of SM for the treatment of DKD through network pharmacology, molecular docking and experimental validation.Methods: The chemical components in SM were comprehensively identified and collected using liquid chromatography-tandem mass spectrometry (LC-MS) and database mining. The mechanisms were investigated using a network pharmacology, including obtaining SM-DKD intersection targets, completing protein-protein interactions (PPI) by Cytoscape to obtain key potential targets, and then revealing potential mechanisms of SM for DKD by GO and KEGG pathway enrichment analysis. The important pathways and phenotypes screened by the network analysis were validated experimentally in vivo. Finally, the core active ingredients were screened by molecular docking.Results: A total of 53 active ingredients of SM were retrieved by database and LC-MS, and 143 common targets of DKD and SM were identified; KEGG and PPI showed that SM most likely exerted anti-DKD effects by regulating the expression of AGEs/RAGE signaling pathway-related inflammatory factors. In addition, our experimental validation results showed that SM improved renal function and pathological changes in DKD rats, down-regulated AGEs/RAGE signaling pathway, and further down-regulated the expression of TNF-alpha, IL-1 beta, IL-6, and up-regulated IL-10. Molecular docking confirmed the tight binding properties between (+)-aristolone, a core component of SM, and key targets.Conclusion: This study reveals that SM improves the inflammatory response of DKD through AGEs/RAGE signaling pathway, thus providing a novel idea for the clinical treatment of DKD.

Objective . In order to decipher the bioactive components and potential mechanisms of the traditional Chinese medicine (TCM) formula Sishenwan (SSW) for diabetic nephropathy (DN), we integrated network pharmacology and bioinformatics. Methods . The candidate compounds of SSW and relative targets were obtained from the TCMSP, BATMAN-TCM, SiwssTartgetPrediction, STITCH, and ChEMBL web servers. The UniProt database was used to translate the target names into gene names, and then constructed the herbal-compound-target network. DN-related targets were ascertained based on OMIM, CTD, GeneCards, DisGeNET, and GEO. Furthermore, there was a protein-protein interaction (PPI) network to explore the overlapping targets between SSW and DN, which focused on screening the pivotal targets by topology. GO and KEGG enrichment analyses were carried out to further understand the potential functions associated with the effect of SSW against DN. Eventually, molecular docking simulations were performed to validate the binding affinity between major bioactive components and hub genes. Results. A total of 120 candidate active compounds and 542 corresponding drug targets were derived, in which 195 targets intersected with DN. Then, KEGG pathway analysis showed that several signaling pathways were closely related to the process of SSW against DN, including the AGE-RAGE signaling pathway in diabetic complications, the TNF signaling pathway, and IL-17 signaling pathway, ect. The PPI network analysis identified PTGS2, CREB1, ESR1, TNF, IL1B, INS, AKT1, PPARG , and JUN were the top 9 hub targets. The molecular docking confirmed that the bioactive compounds of SSW had a firm binding affinity with hub targets. Conclusions . As a whole, the present study revealed that SSW exerted therapeutic effects on DN via modulating multi-targets with multi-compounds through multi-pathways.

目的 系统评价补肾活血法联合常规化学药治疗糖尿病肾病(diabetic kidney disease,DKD)的有效性及安全性.方法 计算机检索CNKI、万方、PubMed、Cochrane Library等数据库,检索时间从2011年1月-2021年9月,筛选近10年关于补肾活血法治疗.DKD的临床随机对照试验(randomized controlled trial,RCT),其中对照组施以常规西医基础治疗,试验组在对照组基础上配合使用主要功效为补肾活血的中药口服剂.采用Cochrane风险偏倚评估工具进行文献质量评价,使用RevMan 5.3软件进行统计学分析.结果 最终纳入28篇RCTs,共计2365例患者.Meta分析结果显示,试验组相对于对照组能有效提高临床疗效[OR=3.59,95％CI(2.85,4.52),P＜0.01],显著降低肌酐水平[SMD=-0.61,95％CI(-0.71,-0.51),P＜0.01]、24h尿蛋白水平[SMD=-0.57,95％CI(-0.69,-0.45),P＜0.01]、尿素氮水平[SMD=-0.51,95％CI(-0.62,-0.40),P＜0.01]、尿白蛋白排泄率[SMD=-1.45,95％CI(-1.57,-1.32),P＜0.01]、尿 β2微球蛋白[SMD=-0.41,95％CI(-0.62,-0.20),P＜0.01],有效调节血糖,包括降低空腹血糖[MD=-0.23,95％CI(-0.31,-0.14),P＜0.01]、餐后2 h 血糖[MD=-0.34,95％CI(-0.50,-0.17),P＜0.01]以及糖化血红蛋白[MD=-0.27,95％CI(-0.35,-0.19),P＜0.01],并且具有一定的用药安全性[OR=1.00,95％CI(0.51,1.94),Z=0.00(P=1.00)].结论 基于补肾活血法的中西医结合治疗糖尿病肾病具有良好临床疗效,有一定的安全性,但受纳入文献质量和数量的限制,上述结论仍需更多大样本、多中心RCT进一步验证.

目的 采用网络药理学方法,探索五味子合剂治疗糖尿病肾病"成分-靶点-通路"的调控网络,探讨其作用机制.方法 采用中药系统药理学数据库与分析平台(TCMSP)结合文献报道补充,筛选五味子合剂的活性成分及作用靶点;通过Gene Cards数据库、OMIM数据库、Dis Ge NET数据库,筛选糖尿病肾病的相关靶点;利用Draw Venny Diagram1在线程序,获取药物和疾病的交集靶点;通过Cytoscape软件构建"药物-成分-关键靶点-疾病"网络;采用蛋白质相互作用(PPI)网络数据库(STRING)构建靶PPI网络,获取关键靶点;对交集靶点进行基因本体(GO)及京都基因和基因组百科全书(KEGG)通路富集分析;采用分子对接进行验证;根据网络药理学结果进行动物作用机制实验验证.结果 网络分析显示,五味子合剂中筛选得到36个活性成分,PPI最终筛选出关键靶点,包括SRC、STAT3、MAPK1等;KEGG富集分析关键靶点主要富集在AGE-RAGE、PI3K-Akt、Ras、ErbB、MAPK等信号通路中;分子对接结果显示核心成分与核心靶点具有较好的构象;通过实验验证,五味子合剂可明显改善大鼠肾脏病理改变,降低大鼠肾组织重组与合成蛋白(SRC)蛋白表达水平.结论 通过网络药理学与实验验证,揭示了五味子合剂作用于糖尿病肾病(Diabetic Nephropathy,DN)多靶点、多通路的特点,与调控SRC蛋白表达水平有关,为进一步研究提供了依据.