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溃疡性结肠炎差异表达基因及中药预测的生物信息学分析

胡宗仁1 郑文江2 严倩2 胡卫维3 孙晓生1

(1.广州中医药大学基础医学院, 广东广州 510006)
(2.广州中医药大学第一临床医学院, 广东广州 510405)
(3.广州中医药大学热带医学研究所, 广东广州 510405)

【摘要】通过生物信息学技术分析比较溃疡性结肠炎(UC)患者与健康人的基因芯片数据,初步筛选UC的差异表达基因,进而预测治疗UC的潜在中药药物。从基因表达数据库(GEO)下载GSE36807基因芯片,使用R语言分析得到上调和下调的差异表达基因,通过String数据库、Cytoscape软件及其插件分析得到差异表达基因的核心基因,对核心基因进行基因本体及京都基因与基因组百科全书分析,通过核心基因与医学本体信息检索平台(Coremine Medical)相互映射,筛选治疗UC的中药。筛选出648个差异表达基因,包括251个下调基因和397个上调基因。上调差异表达基因共得出15个核心基因,包括CXCL8,IL1B,MMP9,CXCL1,CXCL10,CXCL9,CXCL2,CXCL5,TIMP1,CXCL11,STAT1,LCN2,IL1RN,MMP1,IDO1;其生物过程与通路主要富集在白细胞介素、趋化因子配体和细胞因子、趋化因子介导的信号通路,与炎症反应、防御反应、细胞趋化性、分泌颗粒、IL17信号通路、Toll样受体信号通路、NOD样受体信号通路、TNF信号通路等密切相关。治疗UC的潜在中药药物有姜黄、黄连、黄芩、石斛、地榆、黄柏、白及、苍术等。差异表达基因和核心基因的分析促进了对UC发病机制的理解,该研究为UC中药干预的新药开发提供了潜在基因靶标与研发思路。

【关键词】 溃疡性结肠炎;差异表达基因;核心基因;基因本体(GO);京都基因与基因组百科全书(KEGG);蛋白质-蛋白质相互作用;中药预测;

【DOI】

【基金资助】 国家自然科学基金项目(8197151189);

Bioinformatic analysis of differentially expressed genes and Chinese medicine prediction for ulcerative colitis

HU Zong-ren1 ZHENG Wen-jiang2 YAN Qian2 HU Wei-wei3 SUN Xiao-sheng1

(1.School of Basic Medical Science of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China 510006)
(2.the First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China 510405)
(3.Institute of Tropical Medicine of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China 510405)

【Abstract】The aim of this paper was to analyze the microarray data between ulcerative colitis (UC) patients and healthy people by bioinformatics technology, screen the differentially expressed genes of UC, and predict the potential Chinese medicinals for UC. The GSE36807 gene expression profile was downloaded from the gene expression database (GEO) and the differentially expressed (both up-regulated and down-regulated) genes were analyzed by using R language software. The hub genes in the differentially expressed genes were obtained by using String database, Cytoscape software and its plug-in analysis, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the hub genes. Moreover, the hub genes and the medical ontology information retrieval platform (Coremine Medical) were mapped to each other to screen the Chinese medicinals and its active ingredients for treating UC. A total of 648 differentially expressed genes were screened, including 397 up-regulated genes and 251 down-regulated genes. Up-regulation of differentially expressed genes yielded 15 hub genes including CXCL8, IL1 B, MMP9, CXCL1, CXCL10, CXCL9, CXCL2, CXCL5, TIMP1, CXCL11, STAT1, LCN2, IL1RN, MMP1 and IDO1. Their biological processes and pathways were mainly enriched in interleukins, chemokine ligands, and cytokine- and chemokine-mediated signaling pathways, and were closely related to inflammatory responses, defense responses, cell chemotaxis, secretory granules, IL-17 signaling pathways, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, and TNF signaling pathway. Potential Chinese medicinals for the treatment of UC include Rhizoma Curcumae Longae, Rhizoma Coptidis, Radix Scutellariae, Herba Dendrobii, Radix Sanguisorbae, Cortex Phellodendri, Rhizoma Bletillae, and Rhizoma Atractylodis. The analysis of differentially expressed genes and hub genes could promote our understanding on the pathogenesis of UC. This study provides potential gene targets and research ideas for the development of new Chinese medicine in UC intervention .

【Keywords】 ulcerative colitis; differentially expressed genes; hub genes; gene ontology (GO); Kyoto encyclopedia of genes and genomes (KEGG); protein-protein interaction; Chinese medicine prediction;

【DOI】

【Funds】 National Natural Science Foundation of China (8197151189);

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    References

    [1] Professional Committee of Digestive System Diseases, Chinese Association of Integrative Medicine. Consensus on diagnosis and treatment of ulcerative colitis with Chinese and Western medicines (2017) [J]. Chinese Journal of Integrated Traditional and Western Medicine on Digestion, 2018, 26 (2): 105 (in Chinese).

    [2] ORDAS I, ECKMANN L, TALAMINI M, et al. Ulcerative colitis [J]. Lancet, 2012, 380 (9853): 1606.

    [3] RUBIN D T, ANANTHAKRISHNAN A N, SIEGEL C A, et al. ACG clinical guideline: ulcerative colitis in adults [J]. Am J Gastroenterol, 2019, 114 (3): 384.

    [4] ZHANG Y J, LIANG J, WU K C. Interpretation of information on ulcerative colitis in the Consensus on Diagnosis and Treatment of Inflammatory Bowel Disease (2018, Beijing) [J]. Chinese Journal of Digestion, 2018, 38 (5): 312 (in Chinese).

    [5] LAHARIE D. Towards therapeutic choices in ulcerative colitis [J]. Lancet, 2017, 390 (10090): 98.

    [6] ZHANG S S, SHEN H, ZHENG K et al. Expert consensus on Chinese medical diagnosis and treatment of ulcerative colitis (2017) [J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2017, 32 (8): 3585 (in Chinese).

    [7] MONTERO-MELENDEZ T, LLOR X, GARCIA-PLANELLA E, et al. Identification of novel predictor classifiers for inflammatory bowel disease by gene expression profiling [J]. PLoS ONE, 2013, 8 (10): e76235.

    [8] SZKLARCZYK D, MORRIS J H, COOK H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible [J]. Nucleic Acids Res, 2017, 45 (D1): D362.

    [9] CHIN C H, CHEN S H, WU H H, et al. CytoHubba: identifying hub objects and sub-networks from complex interactome [J]. BMC Syst Biol, 2014, 8 (Suppl 4): S11.

    [10] BADER G D, HOGUE C W. An automated method for finding molecular complexes in large protein interaction networks [J]. BMC Bioinformatics, 2003, 4: 2.

    [11] YU G, WANG L G, HAN Y, et al. ClusterProfiler: an R package for comparing biological themes among gene clusters [J]. OMICS, 2012, 16 (5): 284.

    [12] ITO K, MURPHY D. Application of ggplot2 to pharmacometric graphics [J]. CPT Pharmacometrics Syst Pharmacol, 2013, 2: e79.

    [13] SAITO Y A. The role of genetics in IBS [J]. Gastroenterol Clin North Am, 2011, 40 (1): 45.

    [14] SARTOR R B. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases [J]. Am J Gastroenterol, 1997, 92 (12 Suppl): 5S.

    [15] RUBIN D T, HUO D, KINNUCAN J A, et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study [J]. Clin Gastroenterol Hepatol, 2013, 11 (12): 1601.

    [16] FISHER R C, BELLAMKONDA K, ALEX M L, et al. Disrupting inflammation-associated CXCL8-CXCR1 signaling inhibits tumorigenicity initiated by sporadic- and colitis-colon cancer stem cells [J]. Neoplasia, 2019, 21 (3): 269.

    [17] DINARELLO C A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases [J]. Blood, 2011, 117 (14): 3720.

    [18] MANICONE A M, MCGUIRE J K. Matrix metalloproteinases as modulators of inflammation [J]. Semin Cell Dev Biol, 2008, 19 (1): 34.

    [19] LAKATOS G, HRITZ I, VARGA M Z, et al. The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases [J]. Dig Dis, 2012, 30 (3): 289.

    [20] JAKUBOWSKA K, PRYCZYNICZ A, JANUSZEWSKA J, et al. Expressions of matrix metalloproteinases 2, 7, and 9 in carcinogenesis of pancreatic ductal adenocarcinoma [J]. Dis Markers, 2016, doi: 10.1155/2016/9895721.

    [21] MAO J W, HE X M, TANG H Y, et al. Protective role of metalloproteinase inhibitor (AE-941) on ulcerative colitis in rats [J]. World J Gastroenterol, 2012, 18 (47): 7063.

    [22] WANG X D, DONG E Y. The expression of interleukin-17 in patients with ulcerative colitis [J]. Chinese Journal of Digestion, 2001, 21 (11): 29 (in Chinese).

    [23] BAUMGART D C, CARDING S R. Inflammatory bowel disease: cause and immunobiology [J]. Lancet, 2007, 369 (9573): 1627.

    [24] SANCHEZ-MUNOZ F, FONSECA-CAMARILLO G, VILLEDA-RAMIREZ M A, et al. Transcript levels of Toll-like receptors 5,8 and 9 correlate with inflammatory activity in ulcerative colitis [J]. BMC Gastroenterol, 2011, 11: 138.

    [25] WANG Y, TANG Q, DUAN P, et al. Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis [J]. Immunopharmacol Immunotoxicol, 2018, 40 (6): 476.

    [26] ZHU L W, ZHU D J. Research progress of curcumin in the treatment of ulcerative colitis [J]. The Journal of Medical Theory and Practice, 2019, 32 (5): 657 (in Chinese).

    [27] ZHU L, GU P, SHEN H. Protective effects of berberine hydrochloride on DSS-induced ulcerative colitis in rats [J]. Int Immunopharmacol, 2019, 68: 242.

    [28] XIE S Z, SHANG Z Z, LI Q M, et al. Dendrobium huoshanense polysaccharide regulates intestinal lamina propria immune response by stimulation of intestinal epithelial cells via Toll-like receptor 4 [J]. Carbohydr Polym, 2019, 222: 115028.

    [29] GENG L, YANG G T, ZHANG X Q, et al. The Effect of extracts from Geranium strictipes R. Knuth on the chronic ulcerative colitis in rats [J]. Traditional Chinese Drug Research and Clinical Pharmacology, 2019, 30 (6): 653 (in Chinese).

    [30] ZHENG Z C, SHEN H, ZHU X X, et al. Effects of Cortex Philodendra, Radix Sanguisorbae and Rhizoma Bletillae on the expression of cytokines and NF-κB in ulcerative colitis rats [J]. Journal of Emergency in Traditional Chinese Medicine, 2010, 19 (3): 469 (in Chinese).

    [31] NING H R, CHEN J W, LIU W H et al. Effect of Atractylodis Rhizoma mixture on ulcerative colitis in rats and antioxidant mechanism [J]. Journal of Sun Yat-sen University (Medical Sciences), 2008, 29 (S1): 169 (in Chinese).

    [32] MA X R, WANG Y L, ZOU D X, et al. The effects of Huangqin Tang on oxidative stress and ulcerative colitis in rats through the Nrf2 signal pathway [J]. Acta Pharmaceutica Sinica, 2019, 54 (4): 653 (in Chinese).

    [33] ZHONG Y, ZHENG X B, YE H, et al. Effect of Shaoyao Tang on ulcerative colitis in rats via regulation of TLR4/NF-κB signal pathway [J]. China Journal of Chinese Materia Medica, 2019, 44 (7): 1450 (in Chinese).

    [34] WANG F Y, ZHAO D S, PU X W, et al. Effect of Shaoyaotang on expressions of AP-1 and TNF-α in colon of rats with hygrothermal ulcerative colitis [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2019, 25 (16): 7 (in Chinese).

    [35] WANG X M, TIAN G, DUAN Q J, et al. Therapeutic potential of n-butanol extract of Pulsatilla decoction in a murine model of ulcerative colitis induced by DSS combined with Candida albicans colonization [J]. China Journal of Chinese Materia Medica, 2018, 43 (14): 2979 (in Chinese).

    [36] ZHONG Y, ZHENG X B, YE H, et al. Efficacy and immune mechanism of Baitouweng Tang on ulcerative colitis in rats [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2019, 25 (12): 15 (in Chinese).

    [37] XU Y Y, CAI H, DUAN Y, et al. Research progress of Baizhu Shaoyao powder in treating ulcerative colitis [J]. China Journal of Chinese Materia Medica, 2017, 42 (5): 856 (in Chinese).

This Article

ISSN:1001-5302

CN: 11-2272/R

Vol 45, No. 07, Pages 1684-1690

April 2020

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Article Outline

Abstract

  • 1 Materials and methods
  • 2 Results
  • 3 Discussion
  • References