Study on the Mechanism of Mulberry Twig Improving Hyperuricemia Based on Network Pharmacology and Molecular Docking
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摘要: 目的：探讨桑枝（mulberry twig）治疗高尿酸血症（HUA）的可能作用靶点及机制。方法：于TCMSP、Batman-TCM、PubMed、CNKI等数据库进行检索，获取桑枝组分群，借助SwissTargetPrediction及PharmMapper等平台获取桑枝成分靶点；并利用GeneCards和OMIM在线平台收集整理HUA相关靶点；将HUA靶点与桑枝组分靶点取交集，得到共有靶点；利用STRING官方平台和Cytoscape软件获取蛋白互作网络图，并借助后者获取“化合物-靶点-通路”网络作用图；采取DAVID平台展开GO和KEGG富集分析；借助分子对接（Molecular docking）手段对分析结果加以验证。结果：筛选出桑枝潜在活性组分45个，组分靶点620个，HUA相关靶点1277个，共有靶点128个，经网络拓扑分析，得到VEGFA、SRC、PIK3CA、MAPK1、IL6、TNF等13个核心靶点以及木犀草素、槲皮素、环桑色烯、桑辛素M、桑色素、山奈酚、异鼠李素等10个活性组分。GO富集分析条目共获取295条（P<0.01），其中，生物过程（BP）共212个，主要包括细胞增殖正相调控、凋亡过程负相调控等；细胞组成（CC）共31个，靶点主要存在于质膜及细胞质等；分子功能（MF）共52个，主要涉及蛋白质结合、ATP结合等；KEGG富集共获取信号通路78条（P<0.01），主要包括Cancer、TNF、TRP、Toll-like receptor等信号通路。分子对接结果表明潜在活性组分与核心靶点结合优良。结论：本研究初步表明桑枝治疗HUA作用具有多组分、多靶点、多信号通路的特点，为后期深入研究桑枝潜在活性组分治疗HUA的分子机制奠定科学依据。Abstract: Objective: To explore the possible target and mechanism of mulberry twig in the treatment of hyperuricemia (HUA). Methods: Batman-TCM, TCMSP, PubMed, CNKI databases were used to obtain components of mulberry twig, component-related targets were collected through SwissTargetPrediction and PharmMapper online analysis platform. HUA targets were collected through GeneCards and OMIM databases. The intersection of disease targets and component targets was taken to obtain shared targets, protein interaction networks were constructed using the STRING database and the Cytoscape software, the compound-target-pathway network was constructed by Cytoscape software. The GO and KEGG enrichment analysis were performed using the DAVID database. Molecular docking was used to verify the results. Results: A total of 45 active components of mulberry twig, which corresponding to 620 targets, 1277 related disease targets of HUA, 128 intersecting targets for active components and HUA were screened out. After topological analysis, there were 13 core targets including VEGFA, SRC, PIK3CA, MAPK1, IL6, TNF, etc. And 10 active components including Luteolin, Quercetin, Cyclomulberrochromene, Moracin M, Morin, Kaempferol, Isorhamnetin, etc. 295 GO entries (P<0.01) and 78 KEGG (P<0.01) signal pathways were obtained by enrichment analyses. Among them, there are 212 biological processes (BP), which mainly included positive regulation of cell proliferation and negative regulation of apoptosis processes, 31 cell composition (CC), with targets mainly located in the plasma membrane and cytoplasm, molecular functions (MF) 52 in total, mainly related to protein binding, ATP binding, etc. KEGG enrichment analysis mainly involved such signaling pathways as Cancer, TNF, TRP and Toll-like receptor. Molecular docking revealed a good binding activity of the main active components to the core targets. Conclusions: This study preliminarily showed that the treatment of HUA with mulberry twig had the characteristics of multi-component, multi-target and multi-signal pathway, which provided a scientific basis for further study on the molecular mechanism of the treatment of HUA with the potential active components of mulberry twig.
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Keywords:
- hyperuricemia /
- mulberry twig /
- molecular docking /
- network pharmacology
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高尿酸血症（Hyperuricemia，HUA）作为一种常见的代谢性疾病，主要是由于嘌呤在代谢过程中发生异常所致，体外嘌呤摄入过多、内源性嘌呤生产过剩以及嘌呤排泄不及时等都是诱发高尿酸血症的关键因素[1]。根据发病过程中机制的差异性，可将其划分为原发性HUA和继发性HUA两大类型，由基因突变引起的多为原发性HUA，为遗传性类；由药物使用或肾脏等疾病诱导的多为继发性HUA[2]。许多研究证明血清尿酸（UA）的升高已成为与疾病密切相关的独立危险因子，如痛风[3]、糖尿病[4]、心血管方面疾病[5]、高血压[6]和肾脏方面慢性疾病[7]等。临床上，降低血清尿酸常作为防治HUA的措施[8]，目前常用抑制尿酸生成药、改善尿酸排泄药、尿酸酶合成剂和碱化尿液药等4类药物治疗HUA[9]，但治疗过程中副作用较为明显，临床应用受到了限制。近年来传统中药成为研究热点，主要由于其在疗效突出的同时，兼具安全性高及多靶点治疗的特性，所以在调节尿酸水平及发挥抗炎作用方面的优势是西医无法替代的。
桑枝（Morus alba L.）又名桑条，通常为桑树干燥嫩枝的统称，其药性平和，味略苦涩，归于肝经，具有祛除风湿、改善关节等功效，常用于治疗关节炎及风湿病等[10-11]。据2022年发布的药食同源最新目录，桑枝被收录于可用于保健食品的物品名单中，表明桑枝可作为保健食品的原料，具有较大的开发及应用前景。此外，桑枝治疗痛风痹证历史悠久，《苍生司命》中已有记载[12]；陈宝刚等[13]及高忠恩等[14]在整理及论述总结传统医籍治疗名方时，该功效也被论证。此外，研究表明，桑枝提取物能有效控制黄嘌呤氧化酶（XOD）的活性[15-16]，从而降低HUA模型小鼠的血清尿酸水平。近年来中药研究领域，网络药理学被广泛应用，作为建立在系统生物学理论基础上的一门新技术，网络药理学主要阐述药物相互作用机制，特性主要包括“整体性”与“系统性”，通过从整体角度揭示药物的作用机制，与中药治疗具有一致性[17]，同时中医的整体观念也是如此，两者之间不谋而合[18]。结合现有研究报道及实验室前期工作基础，可知桑枝具有抗HUA作用，但发挥防治作用的药效物质及作用方式缺少整体认识。因此，本实验采取网络药理学这一新技术来探讨桑枝治疗HUA的药效组分及作用靶点，以期为桑枝后续开发及临床研究给予方向及思路。
1. 实验方法
1.1 桑枝组分及靶点建立
以“桑枝”、“Sangzhi”、“mulberry twig”为检索词，于TCMSP（http://tcmspw.com/tcmsp.php/）、Batman-TCM（http://bionet.ncpsb.org.cn/batman-tcm/）、PubMed（https://pubmed.ncbi.nlm.nih.gov/）、CNKI（https://www.cnki.net/）等数据库平台进行检索，获取桑枝组分群，TCMSP平台中口服生物利用度（Oral bioavailability）和类药性（Drug-like）及SwissTargetPrediction（http://www.swisstargetprediction.ch/）数据库中的Pharmacokinetics和Druglikeness等中药体内ADME相关指标参考程欢欢等[19]进行，借助SwissTargetPrediction及PharmMapper（http://www.lilab-ecust.cn/pharmmapper/）在线平台检索组分靶点，去除重复值，建立桑枝组分靶点库。
1.2 HUA靶点获取
于GeneCards（https://www.genecards.org/）和OMIM（https://omim.org/）平台，以“Hyperuricemia”、“Gout”等为检索关键词，获取HUA靶点；借助UniProt（https://www.uniprot.org/）数据库，设定物种类型为“Homo sapiens”，得到靶点名称并去重，建立疾病靶点库。
1.3 关键靶点获取
分别将“1.1”和“1.2”项下的靶点输入在线平台（https://bioinfogp.cnb.csic.es/tools /venny/index.html）制作靶点韦恩图，获取关键靶点。
1.4 蛋白互作网络图（PPI）建立
参照王佰灵等[20]将“1.3”项下靶点导入到STRING（https://string-db.org/）在线平台分析，并将结果导入到Cytoscape 3.8.2平台展开网络拓扑学过程分析，筛选桑枝核心靶点。
1.5 关键靶点富集分析
将关键靶点借助DAVID（https://david.abcc.ncifcrf.gov/）平台进行GO功能注释及KEGG富集分析（P<0.01），限定物种类型为“Homo sapiens”，并将结果可视化。
1.6 “化合物-靶点-通路”网络图建立
利用Cytoscape软件平台获取“化合物-靶点-通路”关系网络图，图中节点代表化合物、靶点、通路，边表示彼此之间的交互关系。
1.7 核心靶点晶体结构获取及处理
于PDB（https://www1.rcsb.org/）平台获取核心靶点对应的晶体结构，借助Discovery Studio 3.5平台去除受体原配体和水分子、添加氢原子、检测扭转中心和扭转键等，并寻找活性口袋。
1.8 分子对接
采用AutoDock Vina 1.1.2软件平台将核心靶点分别与活性组分及对照药（非布司他）进行分子对接验证，对网络分析可靠性加以评价，并将结果可视化。
2. 结果与分析
2.1 桑枝组分及靶点
从数据库及文献挖掘共检索到桑枝化合物156个，首先依次将156个化合物按“1.1”项进行ADME筛选，其次采取SwissTargetPrediction及PharmMapper在线平台对符合ADME筛选条件的化合物进行靶点预测，其中PharmMapper平台以Normalized Fit Score≥0.7为遴选条件，SwissTargetPrediction平台以Probability≥0为遴选条件，然后将每个化合物分别在两个平台中预测所得的靶点进行汇总并去重，得到每个化合物对应的靶点，通过UniProt在线平台核对校正。最终共获得符合条件的潜在活性组分45个以及汇总去重靶点共620个，组分详情见表1。
表 1 桑枝潜在活性组分Table 1. Potential active components of mulberry twig编号 CAS号 成分 中文名 1 520-18-3 Kaempferol 山奈酚 2 480-16-0 Morin 桑色素 3 548-30-1 Oxysanguinarine 氧化血根碱 4 53846-50-7 8-Prenylnaringenin 8-异戊烯基柚皮素 5 73343-42-7 Albanin A — 6 73343-43-8 Albanin C — 7 552-58-9 Eriodictyol 圣草酚 8 — Euchrenone-a7 — 9 480-19-3 Isorhamnetin 异鼠李素 10 137832-27-0 Kenusanone A — 11 62949-77-3 Kuwanon A 桑黄酮A 12 67172-84-3 Kuwanon D 桑黄酮D 13 68401-05-8 Kuwanon E 桑黄酮E 14 71344-07-5 Kuwanon F 桑黄酮F 15 56317-21-6 Moracin M 桑辛素M 16 123702-97-6 Moracin O 桑辛素O 17 — Morusignin L — 18 62949-93-3 Morusinol 桑根皮醇 19 62393-99-1 Mulberranol 环桑色醇 20 480-41-1 Naringenin 柚皮素 21 29700-22-9 Oxyresveratrol 氧化白藜芦醇 22 99-50-3 Protocatechuic acid 原儿茶酸 23 202526-51-0 Sanggenol F 桑根醇F 24 480-18-2 Taxifolin 花旗松素 25 480-20-6 Aromadendrin 香树素 26 69065-16-3 4'-Prenyloxyresveratrol 4-异戊烯基氧基白藜芦醇 27 73-24-5 Adenine 腺嘌呤 28 2271-08-1 Cularicine 苦来西碱 29 19275-51-5 Cyclomulberrin 环桑素 30 62596-34-3 Cyclomulberrochromene 环桑色烯 31 480-20-6 Dihydrokaempferol 香橙素（二氢山奈酚） 32 18422-83-8 Dihydromorin 二氢桑色素 33 5289-74-7 Ecdysterone 蜕皮甾酮 34 491-70-3 Luteolin 木犀草素 35 519-34-6 Maclurin 2,3',4,4',6-五羟基二苯甲酮 36 67259-16-9 Moracin B 桑辛素B 37 62596-29-6 Mulberrochromene 桑辛素 38 68978-04-1 Mulberrofuran A 桑呋喃A 39 552-41-0 Paeonol 丹皮酚 40 109-52-4 Pentanic Acid 戊酸 41 65914-17-2 Piceid 白藜芦醇苷 42 117-39-5 Quercetin 槲皮素 43 92-61-5 Scopoletin 东莨菪内酯 44 535-83-1 Trigonelline 葫芦巴碱 45 93-35-6 Umbelliferone 7-羟基香豆素 2.2 HUA及共同靶点
以“Hyperuricemia”、“Gout”等为检索关键词，从Genecards和OMIM在线平台获取疾病作用靶点，共1277个。将“2.1”项下的成分靶点与HUA相关的1277个靶点取交集，获取共同靶点，共128个，结果见图1。
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图 1 HUA靶点与活性组分靶点交集韦恩图Figure 1. Venn diagram of the intersection of HUA target and active component target2.3 蛋白互作网路（PPI）结果
将128个关键靶点导入到STRING平台分析并用Cytoscape软件平台建立PPI图，结果见图2。节点代表不同靶点，交互作用强弱以节点连线数量表示，节点颜色由外到内变化代表相应的degree值由小到大。Degree值均大于中位数12的靶点共有56个，其中靶点STAT3、MAPK8、VEGFA、SRC、PIK3CA、MAPK1、PIK3R1、IL6、FYN、HSP90AA1、TNF、ALB、XDH的Degree值大于中位数的3倍，表明以上靶点可能为桑枝治疗HUA的核心靶点，对发挥治疗作用具有重要意义。
2.4 交集靶点富集分析
于DAVID平台进行GO功能注释及KEGG富集分析（P<0.01）[21]。GO分析共获取295个条目，将前10结果可视化，结果见图3。生物过程（BP）共212个，主要包括细胞增殖正相调控、凋亡过程负相调控等；细胞组成（CC）共31个，靶点主要存在于质膜及细胞质等；分子功能（MF）共52个，主要涉及蛋白质结合、ATP结合等。
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图 3 桑枝靶点GO功能富集分析Figure 3. GO function enrichment analysis of the targets of mulberry twigKEGG富集分析结果表明，128个交集靶点总共涉及78条通路（P<0.01），信号通路排名前25的结果见图4，主要包括PI3K-Akt、TNF、Ras、Rap1、HIF-1、TRP、Cancer、Toll-like receptor等信号通路。
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图 4 桑枝靶点KEGG通路富集分析Figure 4. KEGG pathway enrichment analysis of the targets of mulberry twig2.5 “化合物-靶点-通路”网络作用图
将成分、靶点及通路预测结果处理后，导入到Cytoscape平台，搭建三者之间交互作用图，结果见图5。其中，环桑色烯（Cyclomulberrochromene）、槲皮素（Quercetin）、柚皮素（Naringenin）、异鼠李素（Isorhamnetin）、圣草酚（Eriodictyol）、山奈酚（Kaempferol）、桑色素（Morin）、桑辛素M（Moracin M）、木犀草素（Luteolin）、桑黄酮E（Kuwanon E）等的degree值较高（图中蓝色圆点），degree值分别为32、28、25、28、23、27、27、27、27、26，均能与多个靶点相互作用，推测上述组分可能是桑枝治疗HUA的主要活性组分。
2.6 分子对接结果
将“2.3”项下靶点蛋白分别与“2.5”项下活性组分及对照药（非布司他）进行分子对接验证，结果见图6。当配体与受体相互作用时，一般认为结合能小于−5.0 kcal/mol，则表明两者结合良好，并且该值越小代表结合越良好，相互作用越强[20]。结果显示，95%组分与靶点蛋白之间均具有较好的结合，且部分结合性优于对照药，揭示预测结果较为可靠。
选取结合能较小的结果进行可视化分析，结果见图7。结果表明，Kuwanon E与SRC中的Pro-249、Tyr-152形成氢键，与Phe-153产生π-π共轭，与Lys-206、Phe-153形成疏水作用，使体系能量降低，结构趋于稳定（图7A）；Luteolin分别与SRC中的His-204、Glu-181、Thr-182形成氢键，与Lys-206产生疏水作用，使体系能量降低，形成稳定结构（图7B）；与TNF中的Gln-51、Tyr-224、Asp-228形成氢键，与Trp-52产生疏水作用，降低体系能量，形成稳定结构（图7C）；与PIK3CA中的Gln-661、Pro-168、Pro-757残基形成氢键，与Arg-662产生疏水作用，形成稳定结构（图7D）；结果表明几者之间均结合良好。
3. 讨论与结论
“化合物-靶点-通路”网络拓扑分析表明，桑色素、槲皮素、异鼠李素、山奈酚、木犀草素、柚皮素、环桑色烯、桑辛素M等为桑枝治疗HUA的主要活性组分。研究表明：桑色素是一种具有抑制和促进尿酸排泄双重作用的天然产物黄酮成分[22]；槲皮素可降低XOD活性[23]，并减少葡萄糖转运蛋白9在肝脏及肠道中的表达量，从而使血清尿酸（UA）表达水平降低[24]；异鼠李素能够抑制XOD在肝脏中的活性，从而使UA的产生量减少[25]；山奈酚能抑制XOD的活性且具有显著性，当底物与XOD活性位点中心结合时，其能够占据该位点，从而使尿酸生成量减少[26]；柚皮素能清除XOD活性[27-29]；木犀草素能够降低血清IL-1β和TNF-α表达水平，还能通过降低肾脏mURAT1，并在一定程度上抑制XO活性，对高尿酸血症小鼠具有有效的尿酸排泄作用[30]。上述结果表明本研究筛选具有一定的理论依据，可为桑枝治疗HUA的药效成分研究提供方向，综上初步推测加强尿酸排泄、抑制尿酸生成以及改善炎症3个方面可能是桑枝中主要活性组分发挥治疗HUA的作用方式。分子对接结果表明，桑枝活性组分与核心靶点结合良好（结合能小于−5.0 kcal/mol），其中对接结合能最好的活性化合物Luteolin与关键的TNF、SRC核心靶点蛋白，研究证明Luteolin可以浓度依赖性地抑制TNF靶点蛋白的表达量[31]；Luteolin可作为SRC靶点蛋白的直接抑制剂，从而在NF-κB的激活中起核心作用，证实了Luteolin具有较强的抗炎活性，其能够直接阻断SRC激酶活性[32]。综上可知活性组分可对关键核心靶点加以调控从而发挥治疗HUA作用，另一方面也对网络药理学分析预测结果的可靠性进行了验证。高尿酸血症（HUA）是一种代谢性疾病，与氧化应激和炎症反应密切相关。在桑枝治疗HUA的分子机制中，GO功能注释及KEGG通路分析结果表明，128个核心靶点在功能注释方面，主要参与细胞增殖的正调控、凋亡过程的负调控、信号转导、蛋白质自磷酸化、血管生成、炎症反应、先天免疫反应等发挥关键治疗作用的生物过程；在分子功能方面，发挥蛋白酪氨酸激酶活性、ATP结合、受体结合、丝氨酸型内肽酶活性、蛋白质结合、磷脂酰肌醇-4,5-二磷酸3-激酶活性等关键功能作用，提示桑枝可能通过体内的多种生物学过程发挥治疗HUA的作用。KEGG通路富集分析方面，桑枝活性主要涉及调控TNF、HIF-1、Cancer、PI3K-Akt、Ras、Rap1、TRP、Toll-like receptor等信号通路，结合PPI拓扑分析筛选桑枝防治HUA的核心靶点，推测桑枝可能通过调控如IL-6、VEGFA、TNF、MAPK1、STAT3等靶点，参与细胞增殖、细胞凋亡、炎症反应、免疫反应、蛋白质ATP结合的过程，从而抑制炎症反应、改善免疫功能及调节尿酸代谢转运来发挥治疗HUA作用。大量研究证明，TNF信号通路在痛风性关节炎的发病机制中意义重大，其机制包括诱导IL-1活化、增强IL-6介导的炎症反应、激活NF-κB炎症信号通路，该过程与慢性痛风性关节炎密切相关；并且TNF-α水平在痛风患者血清中表达会升高，当NF-κB的表达被TNF-α上调后会引起一系列效应，从而使机体炎症反应程度受到影响，与HUA的发生密切相关[33-36]。TRP通路属离子通道类，与炎症和疼痛发生息息相关，研究揭示，类风湿性关节炎、痛风、骨关节炎等病症和该通路密切相关[37-38]。Toll-like receptor通路与炎性疾病关系紧密，其能够识别内源性的尿酸盐结晶信号分子，从而激活NF-κB，进而诱导IL-1、IL-6、IFN-α、TNF-α、IFN-β等炎症因子释放表达，促进痛风性炎症发作[20,39-40]。PI3K-Akt 信号通路和细胞凋亡及细胞增殖两方面紧密相关，调控该信号通路，可以使造血和血小板生成率增加，发挥补血活血的作用，从而促进血管新生，加快生物过程转化[41-42]，推测调控该通路可以促进代谢转运，从而加快尿酸排泄。综上，本研究采取网络药理学对桑枝治疗HUA的活性组分、核心靶点及信号通路作了初步探索，并借助分子对接将活性组分及核心靶点加以进一步验证，从系统层面阐释了桑枝治疗HUA中多组分、多通路、多靶点的作用特点。但由于中药成分具有复杂性，基于网络药理学对桑枝的初步探索仍具有不足，针对预测结果中桑枝治疗HUA的作用靶点及通路，后期将进一步予以实验验证，以期为桑枝治疗HUA的药效组分研究提供理论依据及参考，也为后期加强实验设计优化及进一步探讨提供依据。
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图 1 HUA靶点与活性组分靶点交集韦恩图
Figure 1. Venn diagram of the intersection of HUA target and active component target
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图 3 桑枝靶点GO功能富集分析
Figure 3. GO function enrichment analysis of the targets of mulberry twig
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图 4 桑枝靶点KEGG通路富集分析
Figure 4. KEGG pathway enrichment analysis of the targets of mulberry twig
表 1 桑枝潜在活性组分
Table 1 Potential active components of mulberry twig
编号 CAS号 成分 中文名 1 520-18-3 Kaempferol 山奈酚 2 480-16-0 Morin 桑色素 3 548-30-1 Oxysanguinarine 氧化血根碱 4 53846-50-7 8-Prenylnaringenin 8-异戊烯基柚皮素 5 73343-42-7 Albanin A — 6 73343-43-8 Albanin C — 7 552-58-9 Eriodictyol 圣草酚 8 — Euchrenone-a7 — 9 480-19-3 Isorhamnetin 异鼠李素 10 137832-27-0 Kenusanone A — 11 62949-77-3 Kuwanon A 桑黄酮A 12 67172-84-3 Kuwanon D 桑黄酮D 13 68401-05-8 Kuwanon E 桑黄酮E 14 71344-07-5 Kuwanon F 桑黄酮F 15 56317-21-6 Moracin M 桑辛素M 16 123702-97-6 Moracin O 桑辛素O 17 — Morusignin L — 18 62949-93-3 Morusinol 桑根皮醇 19 62393-99-1 Mulberranol 环桑色醇 20 480-41-1 Naringenin 柚皮素 21 29700-22-9 Oxyresveratrol 氧化白藜芦醇 22 99-50-3 Protocatechuic acid 原儿茶酸 23 202526-51-0 Sanggenol F 桑根醇F 24 480-18-2 Taxifolin 花旗松素 25 480-20-6 Aromadendrin 香树素 26 69065-16-3 4'-Prenyloxyresveratrol 4-异戊烯基氧基白藜芦醇 27 73-24-5 Adenine 腺嘌呤 28 2271-08-1 Cularicine 苦来西碱 29 19275-51-5 Cyclomulberrin 环桑素 30 62596-34-3 Cyclomulberrochromene 环桑色烯 31 480-20-6 Dihydrokaempferol 香橙素（二氢山奈酚） 32 18422-83-8 Dihydromorin 二氢桑色素 33 5289-74-7 Ecdysterone 蜕皮甾酮 34 491-70-3 Luteolin 木犀草素 35 519-34-6 Maclurin 2,3',4,4',6-五羟基二苯甲酮 36 67259-16-9 Moracin B 桑辛素B 37 62596-29-6 Mulberrochromene 桑辛素 38 68978-04-1 Mulberrofuran A 桑呋喃A 39 552-41-0 Paeonol 丹皮酚 40 109-52-4 Pentanic Acid 戊酸 41 65914-17-2 Piceid 白藜芦醇苷 42 117-39-5 Quercetin 槲皮素 43 92-61-5 Scopoletin 东莨菪内酯 44 535-83-1 Trigonelline 葫芦巴碱 45 93-35-6 Umbelliferone 7-羟基香豆素 
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