枸杞子促进虹膜色素上皮细胞定向分化治疗视网膜色素变性的分子网络调控机制研究

doi:10.12092/j.issn.1009-2501.2019.12.013

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (12): 1402-1414.doi: 10.12092/j.issn.1009-2501.2019.12.013

枸杞子促进虹膜色素上皮细胞定向分化治疗视网膜色素变性的分子网络调控机制研究

宋厚盼^1,2，曾梅艳²，陈小娟^1,2，陈新怡^1,2，彭俊³，周亚莎³，杨毅敬³，杨焘³，蔡雄¹，彭清华^1,3

¹湖南中医药大学中医诊断学湖南省重点实验室，长沙 410208，湖南； ²湖南中医药大学中医学院，长沙 410208，湖南；³湖南中医药大学医学院，长沙 410208，湖南

收稿日期:2019-10-08 修回日期:2019-11-28 出版日期:2019-12-26 发布日期:2020-01-07
通讯作者: 彭清华，男，博士，教授，博士生导师，主要从事中西医结合防治青光眼、眼底病和中医局部诊法的研究。 Tel:0731-88458010 E-mail:pqh410007@126.com
作者简介:宋厚盼，男，博士，副教授，从事中西医结合治疗消化系统疾病和眼底病研究。 Tel:0731-88459435 E-mail:hpsong2015@126.com
基金资助:
国家自然科学基金项目（81804150,81703920）；中国博士后科学基金资助项目（2019M662790）；湖南省自然科学基金项目（2019JJ50442,2019JJ40226）；中医药防治眼耳鼻咽喉疾病湖南省重点实验室开放基金项目（2018YZD05）；湖南中医药大学中医学一流学科开放基金项目（2018ZYX26,2018ZYX20）

Molecular network regulation mechanism of Lycii Fructus in promoting directional differentiation of iris pigment epithelial cells to treat retinitis pigmentosa

SONG Houpan ^1,2, ZENG Meiyan ², CHEN Xiaojuan ^1,2, CHEN Xinyi ^1,2, PENG Jun ³, ZHOU Yasha ³, YANG Yijing ³, YANG Tao ³, CAI Xiong ¹, PENG Qinghua ^1,3

¹ Hunan Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha 410208, Hunan,China; ²College of TCM, Hunan University of Chinese Medicine, Changsha 410208, Hunan,China; ³Medical College, Hunan University of Chinese Medicine, Changsha 410208, Hunan,China

Received:2019-10-08 Revised:2019-11-28 Online:2019-12-26 Published:2020-01-07

摘要/Abstract

摘要：

目的:基于生物信息学和网络药理学方法探究枸杞子（LF）促进虹膜色素上皮细胞定向分化治疗视网膜色素变性（RP）的分子网络调控机制。方法:在中药系统药理学数据库和分析平台（TCMSP）检索LF的主要活性成分及其可能的作用靶点；从GEO数据库下载GSE81058基因表达谱数据，采用R软件构建虹膜色素上皮细胞（IPE）和视网膜色素上皮细胞（RPE）差异表达基因火山图和聚类热图；采用STRING数据库构建LF成分-靶点和IPE-RPE差异表达基因的蛋白质-蛋白质交互网络（PPI），运用Cytoscape提取交集网络基因；通过DAVID数据库对交集基因进行基因本体和信号通路分析；采用cytoHubba分析LF作用于IPE的关键靶点。结果:共获得LF的化学成分188个，其中主要的入血活性成分36个，这些活性成分可能作用的靶点201个；IPE与RPE主要的差异表达基因有142个，其中上、下调基因各71个；发掘得到105个与LF促进IPE分化以治疗RP的相关基因靶点；LF作用于这些靶点涉及的生物学过程包括调节细胞分化、调节视网膜层形成等，相关的分子功能主要涉及转录共激活剂活性、离子通道活性等，主要富集于细胞质、高尔基体、细胞核等区域；LF作用于IPE涉及的分子机制包括调控PI3K-Akt信号通路、神经活性配体-受体相互作用通路等；LF促进IPE分化主要作用于SPP1、MMP9等十个关键靶点。结论:IPE与RPE具有明显差异的基因表达谱，LF的有效活性成分可作用于这些差异表达基因，促进IPE细胞分化为RPE，从而治疗RP。本研究可为细胞移植与中医药联合的中西医结合疗法应用于RP的临床治疗提供科学依据。

关键词: 视网膜色素变性, 生物信息学, 网络药理学, 虹膜色素上皮细胞, 视网膜色素上皮细胞, 枸杞子

Abstract:

AIM: To investigate the molecular network regulation mechanism of Lycii Fructus (LF) in promoting directional differentiation of iris pigment epithelial cells in the treatment of retinitis pigmentosa(RP) based on the methods of bioinformatics and network pharmacology. METHODS: The main active ingredients and potential targets of LF were retrieved from TCMSP database and analysis platform. The data of GSE81058 gene expression profile was downloaded from GEO database. Volcanic maps and clustering thermal maps of differentially expressed genes between IPE and RPE were plotted by ggplot2 and Pheatmap packages, respectively. Protein-protein interaction (PPI) networks of LF component-target and IPE-RPE differentially expressed genes were constructed by STRING database. Cytoscape software was used to extract genes of the intersection network. Gene ontology and signaling pathway analysis of intersection genes were carried out through DAVID online database. CytoHubba was used to analyze the key targets of LF. RESULTS:A total of 188 chemical constituents of LF were obtained, of which 36 were the main active ingredients in blood. There were 201 possible targets for these active ingredients. 142 differentially expressed genes of IPE and RPE were obtained, of which 71 were up-regulated and 71 were down-regulated. 105 gene targets related to LF promoting IPE differentiation and treating RP were identified. The biological processes involved in LF acting on these targets included regulating cell differentiation and retinal layer formation. The related molecular functions mainly involved transcriptional co-activator activity, ion channel activity, etc. They were mainly concentrated in cytoplasm, Golgi apparatus, and other areas. The molecular mechanisms involved the regulation of PI3K-Akt signaling pathway, neuroactive ligand-receptor interaction pathway, etc. The key targets of LF for IPE differentiation include SPP1, MMP9, SNAI2, etc.CONCLUSION: The gene expression profiles are of significant differences between IPE and RPE. The active ingredients of LF can act on these differentially expressed genes, promote IPE cells to differentiate into RPE, and thus treat RP. This study provides a scientific basis for the combination of cell transplantation and traditional Chinese medicine in the treatment of RP.

Key words: retinitis pigmentosa, bioinformatics, network pharmacology, iris pigment epithelial cells, retinal pigment epithelial cells, Lycii Fructus

中图分类号:

R965.2

宋厚盼，曾梅艳，陈小娟，陈新怡，彭俊，周亚莎，杨毅敬，杨焘，蔡雄，彭清华. 枸杞子促进虹膜色素上皮细胞定向分化治疗视网膜色素变性的分子网络调控机制研究[J]. 中国临床药理学与治疗学, 2019, 24(12): 1402-1414.

SONG Houpan, ZENG Meiyan, CHEN Xiaojuan, CHEN Xinyi, PENG Jun, ZHOU Yasha, YANG Yijing, YANG Tao, CAI Xiong, PENG Qinghua. Molecular network regulation mechanism of Lycii Fructus in promoting directional differentiation of iris pigment epithelial cells to treat retinitis pigmentosa[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(12): 1402-1414.

参考文献

［1］Son G, Lee S, Kim YJ, et al. Correlation between visual function and structural characteristics of the macula in advanced retinitis pigmentosa［J］. Ophthalmologica, 2019, 242 (1): 22-30.
［2］Zafar S, Ahmad K, Ali A, et al. Retinitis pigmentosa genes implicated in South Asian populations: a systematic review ［J］. J Pak Med Assoc, 2017, 67 (11): 1734-1739.
［3］Kharitonov AE, Surdina AV, Lebedeva OS, et al. Possibilities for using pluripotent stem cells for restoring damaged eye retinal pigment epithelium ［J］. Acta Natural, 2018, 10 (3): 30-39.
［4］McGill TJ, Wilson DJ, Stoddard J, et al. Cell transplantation for retinal degeneration: transition from rodent to nonhuman primate models ［J］. Adv Exp Med Biol, 2018, 1074 (1): 641-647.
［5］宋厚盼, 曾梅艳, 彭俊, 等. 枸杞子-丹参药对治疗视网膜色素变性的分子机制探讨［J］. 中国实验方剂学杂志, 2019, 25 (14): 199-206.
［6］Ru J, Li P, Wang J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines ［J］. J Cheminform, 2014, 6 (1): 13.
［7］蔡淑珍, 李建良, 陈圆, 等. 基于网络药理学的荜茇降血脂作用机制研究［J］. 医药导报, 2019, 38 (11): 1398-1402.
［8］Zhu W, Nan Y, Wang S, et al. Bioinformatics analysis of gene expression profiles of sex differences in ischemic stroke ［J］. Biomed Res Int, 2019, 2019 (1): 2478453.
［9］Wu Y, Zhang J, Wang M, et al. Proteomics analysis indicated the protein expression pattern related to the development of fetal conotruncal defects ［J］. J Cell Physiol, 2019, 234 (8): 13544-13556.
［10］郑丽, 莫娟芬, 吴加元, 等. 基于网络药理学的虎杖抗高血脂作用及信号通路研究［J］. 中国临床药理学与治疗学, 2019, 24 (10): 1107-1119.
［11］Wan Y, Xu L, Liu Z, et al. Utilising network pharmacology to explore the underlying mechanism of Wumei Pill in treating pancreatic neoplasms ［J］. BMC Complement Altern Med, 2019, 19 (1): 158.
［12］肖剑寒, 刘守胜, 赵真真, 等. TM6SF2 在肝细胞癌组织中的表达及其生物信息学功能分析［J］. 临床肝胆病杂志, 2019, 35 (8): 1734-1739.
［13］Wang H, Zhang M, Xie Q, et al. Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples ［J］. Peer J, 2019, 7 (1): e7171.
［14］Xiang Q, Guo Y, Cao Y, et al. Identification of a CNGB1 frameshift mutation in a han Chinese family with retinitis pigmentosa ［J］. Optom Vis Sci, 2018, 95 (12): 1155-1161.
［15］Gouras P, Flood MT, Kjedbye H, et al. Transplantation of cultured human retinal epithelium to Bruch's membrane of the owl monkey's eye ［J］. Curr Eye Res, 1985, 4 (3): 253-265.
［16］McGill TJ, Osborne L, Lu B, et al. Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium ［J］. Transl Vis Sci Technol, 2019, 8 (3): 43.
［17］Borras T. The cellular and molecular biology of the iris, an overlooked tissue: the iris and pseudoexfoliation glaucoma ［J］. J Glaucoma, 2014, 23 (8): S39-S42.
［18］Bennis A, Ten Brink JB, Moerland PD, et al. Comparative gene expression study and pathway analysis of the human iris- and the retinal pigment epithelium ［J］. PLoS One, 2017, 12 (8): e0182983.
［19］宋厚盼, 曾梅艳, 彭俊, 等. 丹参对视网膜色素变性病理过程Müller细胞特征性基因变化及关键蛋白表达的影响［J］. 中草药, 2019, 50 (8): 1863-1872.
［20］Wang J, Chen X, Wang F, et al. OFD1, as a ciliary protein, exhibits neuroprotective function in photoreceptor degeneration models ［J］. PLoS One, 2016, 11 (5): e0155860.
［21］Zheng S, Xiao L, Liu Y, et al. DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice ［J］. Cell Death Dis, 2018, 9 (3): 310.
［22］Shin JA, Kim HS, Vargas A, et al. Inhibition of matrix metalloproteinase 9 enhances rod survival in the s334ter-line3 retinitis pigmentosa model ［J］. PLoS One, 2016, 11 (11): e0167102.
［23］Zhen YB, Chen XF, Yan T, et al. Expression of TAG1/APP signaling pathway in the proliferation and differentiation of glioma stem cells ［J］. Oncol Lett, 2017, 14 (2): 2137-2140.
［24］Borkowska P, Kowalska J, Fila-Danilow A, et al. Affect of antidepressants on the in vitro differentiation of rat bone marrow mesenchymal stem cells into neuronal cells ［J］. Eur J Pharm Sci, 2015, 73 (1): 81-87.
［25］Choudhary M, Ding JD, Qi X, et al. PPARbeta/delta selectively regulates phenotypic features of age-related macular degeneration ［J］. Aging (Albany NY), 2016, 8 (9): 1952-1978.
［26］Genini S, Zangerl B, Slavik J, et al. Transcriptional profile analysis of RPGRORF15 frameshift mutation identifies novel genes associated with retinal degeneration ［J］. Invest Ophthalmol Vis Sci, 2010, 51 (11): 6038-6050.
［27］Hu XL, Chen G, Zhang S, et al. Persistent expression of VCAM1 in radial glial cells is required for the embryonic origin of postnatal neural stem cells ［J］. Neuron, 2017, 95 (2): 309-325.

[1]	游蓉丽, 黄玉荣, 毛睿, 海丽娜, 王颖莉, 王艳. 基于血清代谢组学与网络药理学探究复方苦参注射液治疗肺癌的作用机制[J]. 中国临床药理学与治疗学, 2023, 28(9): 988-999.
[2]	曹放, 覃开蓉, 郑国爽, 赵德伟. 基于网络药理学探讨银杏叶干预激素性股骨头坏死的作用机制[J]. 中国临床药理学与治疗学, 2023, 28(3): 266-275.
[3]	侯小煜, 冷玉芳, 曹雪芬, 吕兴娇, 韩晓霞, Janvier NIBARUTA, 刘永强. 五味子乙素减轻小鼠肠缺血再灌注损伤的网络药理学分析及实验验证[J]. 中国临床药理学与治疗学, 2023, 28(2): 147-154.
[4]	陈玉林, 蒋虎刚, 王新强, 刘凯, 李应东, 安涛, 赵信科. 基于网络药理学和分子对接探讨芪参益心颗粒治疗射血分数保留型心力衰竭的作用机制[J]. 中国临床药理学与治疗学, 2023, 28(10): 1081-1092.
[5]	刘艳之, 王艳, 刘凯丽, 周文华, 朱平, 王颖莉, 杜守颖. 西黄丸对H22荷瘤小鼠的抑瘤作用及其机制研究[J]. 中国临床药理学与治疗学, 2022, 27(7): 754-761.
[6]	姚倩, 陈赟, 商娟, 袭晓昀, 陈影, 顾潇, 居文政, 邹建东, 卢苏, 许美娟. 基于HPLC-Q-TOF/MS和网络药理学的清心滋肾方防治绝经综合征潜在药效物质基础和作用机制研究[J]. 中国临床药理学与治疗学, 2022, 27(5): 481-497.
[7]	谢梦蝶, 王衬衬, 李冰涛, 欧阳长生, 邱雨美, 李洪铭, 涂珺, 尚广彬, 汤喜兰. 基于体外细胞实验和网络药理学研究乳香挥发油抗心脏肥大的作用机制[J]. 中国临床药理学与治疗学, 2022, 27(3): 241-252.
[8]	陈宇罡, 屠艳琼, 王聪庆, 陈娟, 张博宏. 应用网络药理学和分子对接技术探讨金虎通胆汤治疗胆石症的作用机制及实验验证[J]. 中国临床药理学与治疗学, 2022, 27(10): 1090-1098.
[9]	李梦颖, 司明东, 温子帅, 石欢, 李新蕊, 张园园, 王红芳, 马东来, 楚立. 基于网络药理学的西红花治疗动脉粥样硬化作用机制探讨[J]. 中国临床药理学与治疗学, 2020, 25(6): 649-657.
[10]	周海艳，王开玲. 白藜芦醇通过上调miR-26a改善高糖诱导的人视网膜色素上皮细胞损伤[J]. 中国临床药理学与治疗学, 2020, 25(3): 285-292.
[11]	刘建辉, 周根鸿, 李春林, 鲍美华, 刘方怡. 生物信息学筛选骨髓增生异常综合征相关长链非编码RNA[J]. 中国临床药理学与治疗学, 2020, 25(12): 1351-1356.
[12]	刘宇佳，李莉，胡晓平，钟里科，李晶晶，黄萍，张轶雯. 基于生物信息学的胃癌特征基因网络关键节点及预后关联分析[J]. 中国临床药理学与治疗学, 2019, 24(8): 852-859.
[13]	范文斌，汪春荣，陈开林，罗经文. 网络药理学方法探讨苦丁茶防治食管鳞癌的活性成分及分子机制的研究[J]. 中国临床药理学与治疗学, 2019, 24(8): 880-888.
[14]	余静，赵海岚，程凯尧，沈平宇，金黄林. 黄芪皂苷通过调控蛋白激酶R样内质网激酶途径抑制高糖诱导的人视网膜色素上皮细胞自噬的研究[J]. 中国临床药理学与治疗学, 2019, 24(4): 361-368.
[15]	张轶雯，楼倩雯，钟里科，潘宗富，方罗，黄萍. 基于GEO数据库的近端与远端结肠癌特征基因生物信息学研究[J]. 中国临床药理学与治疗学, 2018, 23(4): 422-427.

枸杞子促进虹膜色素上皮细胞定向分化治疗视网膜色素变性的分子网络调控机制研究

Molecular network regulation mechanism of Lycii Fructus in promoting directional differentiation of iris pigment epithelial cells to treat retinitis pigmentosa

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价