基于网络药理学研究补中益气汤治疗盆底功能障碍疾病的分子机制
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摘要
目的:补中益气汤是经典的中药配方,广泛地应用于临床上子宫脱垂等女性盆底功能障碍性疾病,但其药理学作用机制目前仍不清楚。在本研究中,基于网络药理学的策略来阐明其潜在的多成分、多靶点、多途径治疗盆底功能障碍疾病的作用模式。方法:通过中药系统药理学数据库与分析平台(TCMSP)数据库平台获得了补中益气汤的化学成分和作用靶点,同时利用genecard数据库获得与盆底功能障碍疾病治疗相关的靶基因,然后结合两个数据库筛选中药的有效分子和作用靶标。采用Cytoscape3. 6. 0软件构建补中益气汤的中药-活性成分-靶点网络图,根据靶标蛋白构建了补中益气汤的蛋白互作网络。采用R软件对靶基因进行了基因功能注释(Gene Ontology,GO)和京都基因和基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路分析。结果:推测的补中益气汤治疗的核心靶点分别是IL6、MYC、CCL2、ICAM1、PTGS2、SERPINE1、ATF3、CDKN1A和CDKN2A,主要参与AGE-RAGE信号通路在糖尿病并发症、PI3K-Akt信号通路、流体剪切应力与动脉粥样硬化、IL-17信号通路等多种途径。结论:本研究基于网络药理学分析了补中益气汤治疗盆底功能障碍疾病的分子作用机制,有助于进一步理解补中益气汤的药理学作用机制,证实了网络药理学方法可以作为从整体角度揭示中医药作用机制的有效工具。
Objective: Buzhong Yiqi Decoction is a classic Chinese medicine formula widely used in clinical pelvic floor dysfunction( PFD) such as uterine prolapse,but its molecular pharmacological mechanism is still unclear. In this study,basing on a network pharmacology strategy,potential multi-component,multi-target,multi-pathway treatment mode of pelvic floor dysfunction was elucidated. Methods: The chemical active ingredient and putative targets of Buzhong Yiqi Decoction were obtained through the TCMSP database platform. Meanwhile,the genecard database was used to collect target genes related to the treatment of PFD,and then two databases were adopted to screen the effective molecules and putative targets of Chinese herbal medicine. Cytoscape 3. 6. 0 was applied to construct the active ingredient-target interacted network of Buzhong Yiqi Decoction. Based on the screened target protein,the protein interaction network of Buzhong Yiqi Decoction was constructed and analyzed with STRING online database. The gene function annotation( Gene Ontology,GO) and the Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway were analyzed by R software. Results: It is showed that the hub targets of Buzhong Yiqi Decoction were IL6,MYC,CCL2,ICAM1,PTGS2,SERPINE1,ATF3,CDKN1A and CDKN2A,respectively,which mainly participated in various pathways such as AGE-RAGE signaling pathway in diabetic complication,PI3K-Akt signaling pathway,fluid shear stress and atherosclerosis and IL-1 signaling pathway,etc. Conclusion: This study analyzed the molecular mechanism of Buzhong Yiqi Decoction in the treatment of PFD,which helps us to further understand the pharmacological mechanism of Buzhong Yiqi Decoction,implying that the network pharmacology method can be used as an effective tool to reveal the mechanism of TCM effect from a holistic perspective.
Objective: Buzhong Yiqi Decoction is a classic Chinese medicine formula widely used in clinical pelvic floor dysfunction( PFD) such as uterine prolapse,but its molecular pharmacological mechanism is still unclear. In this study,basing on a network pharmacology strategy,potential multi-component,multi-target,multi-pathway treatment mode of pelvic floor dysfunction was elucidated. Methods: The chemical active ingredient and putative targets of Buzhong Yiqi Decoction were obtained through the TCMSP database platform. Meanwhile,the genecard database was used to collect target genes related to the treatment of PFD,and then two databases were adopted to screen the effective molecules and putative targets of Chinese herbal medicine. Cytoscape 3. 6. 0 was applied to construct the active ingredient-target interacted network of Buzhong Yiqi Decoction. Based on the screened target protein,the protein interaction network of Buzhong Yiqi Decoction was constructed and analyzed with STRING online database. The gene function annotation( Gene Ontology,GO) and the Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway were analyzed by R software. Results: It is showed that the hub targets of Buzhong Yiqi Decoction were IL6,MYC,CCL2,ICAM1,PTGS2,SERPINE1,ATF3,CDKN1A and CDKN2A,respectively,which mainly participated in various pathways such as AGE-RAGE signaling pathway in diabetic complication,PI3K-Akt signaling pathway,fluid shear stress and atherosclerosis and IL-1 signaling pathway,etc. Conclusion: This study analyzed the molecular mechanism of Buzhong Yiqi Decoction in the treatment of PFD,which helps us to further understand the pharmacological mechanism of Buzhong Yiqi Decoction,implying that the network pharmacology method can be used as an effective tool to reveal the mechanism of TCM effect from a holistic perspective.
引文
[1]Haylen BT,Maher CF,Barber MD,et al.An International Urogynecological Association(IUGA)/International Continence Society(ICS)joint report on the terminology for female pelvic organ prolapse(POP)[J].Int Urogynecol J,2016,27(4):655-684.
[2]Dieter AA,Wilkins MF,Wu JM.Epidemiological trends and future care needs for pelvic floor disorders[J].Curr Opin Obstet Gynecol,2015,27(5):380-384.
[3]陈聪,鲁意,彭继文,等.温州女性盆底功能障碍性疾病流行病学研究[J].温州医科大学学报,2016,46(3):194-198.
[4]杜亚飞,房桂英,陈然,等.石家庄地区女性盆底功能障碍性疾病患病情况调查[J].检验医学与临床,2016,22(13):3 141-3145.
[5]Arnouk A,De E,Rehfuss A,et al.Physical,Complementary,andAlternative Medicine in the Treatment of Pelvic Floor Disorders[J].Curr Urol Rep,2017,18(6):47.
[6]陈舟,黄和,陈其余.补中益气汤加味联合盆底肌肉锻炼-生物反馈-电刺激治疗产后早期盆底功能障碍性疾病的疗效研究[J].中国中药杂志,2018,43(11):2 391-2 395.
[7]侯秀红,丁岩,夏和霞,等.补中益气汤辅助治疗盆底功能障碍性疾病的疗效及对患者生活质量的影响[J].中国妇幼保健,2017,43(11):2 391-2 395.
[8]Jiang X,Chen G,Huang J,et al.Modified Buzhong Yiqi decoction for myasthenia gravis:A systematic review protocol[J].Medicine(Baltimore),2018,97(50):e13 677.
[9]王媛.孟鲁司特片联合补中益气汤治疗对支气管哮喘缓解期患儿炎症指标、免疫功能的影响[J].亚太传统医药,2017,13(24):146-148.
[10]王娜,张建平,徐华洲,等.补中益气汤治疗慢性心衰的临床观察.补中益气汤对阿霉素诱导心衰大鼠的保护作用[J].中国中药杂志,2011,36(4):508-510.
[11]龙红萍,蔺晓源,王宇红,等.基于网络药理学研究复方钩藤降压片治疗高血压的作用机制[J].中国中药杂志,2018,43(7):1360-1 365.
[12]Yu G,Zhang Y,Ren W,et al.Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis[J].Int J Chron Obstruct Pulmon Dis,2017,12:85.
[13]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(3):13-17.
[14]Yu G,Wang LG,Han Y,He QY.clusterProfiler:an R package for comparing biological themes among gene clusters[J].OMICS,2012,16(5):284-287.
[15]杨静,梁嘉丽,秦佳佳.中医调理气机对女性盆底功能障碍性疾病的康复意义[J].中国中医药信息杂志,2017,24(3):111-113.
[16]ZHU Lan,LANG Jinhe,LIU Chunyan,et al.The epidemiological study of women with urinary incontinence and risk factors for stress urinary incontinence in China[J].Menopause,2009,16(4):831-836.
[17]Cecati M,Corradetti A,Sartini D,et al.Expression of extracellular matrix and adhesion proteins in pelvic organ prolapse[J].Cell Mol Biol(Noisy-le-grand),2018,64(5):142-148.
[18]Wang H,Kira Y,Hamuro A,et al.Differential gene expression of extracellular-matrix-related proteins in the vaginal apical compartment of women with pelvic organ prolapse[J].Int Urogynecol J,2019,30(3):439-446.
[19]Alarab M,Kufaishi H,Lye S,et al.Expression of extracellular matrix-remodeling proteins is altered in vaginal tissue of premenopausal women with severe pelvic organ prolapse.Reprod Sci[J].2014,21(6):704-715.
[20]Liang CC,Huang HY,Chang SD.Gene expression and immunoreactivity of elastolytic enzymes in the uterosacral ligaments from women with uterine prolapse.Reprod Sci[J].2012,19(4):354-359.
[21]冷冰洁,周全,佐满珍.盆腔器官脱垂分子及遗传流行病学研究进展[J].实用医学杂志,2016,32(10):1 716-1 718.
[22]艾阳,薛丽霞,陈滢,等.补中益气汤对转化生长因子β3及ⅠⅢ型胶原蛋白的影响及其治疗盆腔脏器脱垂的机制研究[J].中国药物与临床,2017,17(1):41-43.
[23]Dong Feng,Chen,Xican Li,et al.Hexadecanoic Acid from Buzhong Yiqi Decoction Induced Proliferation of Bone Marrow Mesenchymal Stem Cells[J].J Med Food,2010,13(4):967-975.
[24]Zhou Q,Hong L,Wang J.Identification of key genes and pathways in pelvic organ prolapse based on gene expression profiling by bioinformatics analysis[J].Arch Gynecol Obstet,2018,297(5):1 323-1 332.
[2]Dieter AA,Wilkins MF,Wu JM.Epidemiological trends and future care needs for pelvic floor disorders[J].Curr Opin Obstet Gynecol,2015,27(5):380-384.
[3]陈聪,鲁意,彭继文,等.温州女性盆底功能障碍性疾病流行病学研究[J].温州医科大学学报,2016,46(3):194-198.
[4]杜亚飞,房桂英,陈然,等.石家庄地区女性盆底功能障碍性疾病患病情况调查[J].检验医学与临床,2016,22(13):3 141-3145.
[5]Arnouk A,De E,Rehfuss A,et al.Physical,Complementary,andAlternative Medicine in the Treatment of Pelvic Floor Disorders[J].Curr Urol Rep,2017,18(6):47.
[6]陈舟,黄和,陈其余.补中益气汤加味联合盆底肌肉锻炼-生物反馈-电刺激治疗产后早期盆底功能障碍性疾病的疗效研究[J].中国中药杂志,2018,43(11):2 391-2 395.
[7]侯秀红,丁岩,夏和霞,等.补中益气汤辅助治疗盆底功能障碍性疾病的疗效及对患者生活质量的影响[J].中国妇幼保健,2017,43(11):2 391-2 395.
[8]Jiang X,Chen G,Huang J,et al.Modified Buzhong Yiqi decoction for myasthenia gravis:A systematic review protocol[J].Medicine(Baltimore),2018,97(50):e13 677.
[9]王媛.孟鲁司特片联合补中益气汤治疗对支气管哮喘缓解期患儿炎症指标、免疫功能的影响[J].亚太传统医药,2017,13(24):146-148.
[10]王娜,张建平,徐华洲,等.补中益气汤治疗慢性心衰的临床观察.补中益气汤对阿霉素诱导心衰大鼠的保护作用[J].中国中药杂志,2011,36(4):508-510.
[11]龙红萍,蔺晓源,王宇红,等.基于网络药理学研究复方钩藤降压片治疗高血压的作用机制[J].中国中药杂志,2018,43(7):1360-1 365.
[12]Yu G,Zhang Y,Ren W,et al.Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis[J].Int J Chron Obstruct Pulmon Dis,2017,12:85.
[13]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(3):13-17.
[14]Yu G,Wang LG,Han Y,He QY.clusterProfiler:an R package for comparing biological themes among gene clusters[J].OMICS,2012,16(5):284-287.
[15]杨静,梁嘉丽,秦佳佳.中医调理气机对女性盆底功能障碍性疾病的康复意义[J].中国中医药信息杂志,2017,24(3):111-113.
[16]ZHU Lan,LANG Jinhe,LIU Chunyan,et al.The epidemiological study of women with urinary incontinence and risk factors for stress urinary incontinence in China[J].Menopause,2009,16(4):831-836.
[17]Cecati M,Corradetti A,Sartini D,et al.Expression of extracellular matrix and adhesion proteins in pelvic organ prolapse[J].Cell Mol Biol(Noisy-le-grand),2018,64(5):142-148.
[18]Wang H,Kira Y,Hamuro A,et al.Differential gene expression of extracellular-matrix-related proteins in the vaginal apical compartment of women with pelvic organ prolapse[J].Int Urogynecol J,2019,30(3):439-446.
[19]Alarab M,Kufaishi H,Lye S,et al.Expression of extracellular matrix-remodeling proteins is altered in vaginal tissue of premenopausal women with severe pelvic organ prolapse.Reprod Sci[J].2014,21(6):704-715.
[20]Liang CC,Huang HY,Chang SD.Gene expression and immunoreactivity of elastolytic enzymes in the uterosacral ligaments from women with uterine prolapse.Reprod Sci[J].2012,19(4):354-359.
[21]冷冰洁,周全,佐满珍.盆腔器官脱垂分子及遗传流行病学研究进展[J].实用医学杂志,2016,32(10):1 716-1 718.
[22]艾阳,薛丽霞,陈滢,等.补中益气汤对转化生长因子β3及ⅠⅢ型胶原蛋白的影响及其治疗盆腔脏器脱垂的机制研究[J].中国药物与临床,2017,17(1):41-43.
[23]Dong Feng,Chen,Xican Li,et al.Hexadecanoic Acid from Buzhong Yiqi Decoction Induced Proliferation of Bone Marrow Mesenchymal Stem Cells[J].J Med Food,2010,13(4):967-975.
[24]Zhou Q,Hong L,Wang J.Identification of key genes and pathways in pelvic organ prolapse based on gene expression profiling by bioinformatics analysis[J].Arch Gynecol Obstet,2018,297(5):1 323-1 332.