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[1]梁博程,史曉林,許超,等.基于中藥系統(tǒng)藥理學方法研究六味地黃丸治療骨質疏松癥的藥效成分、作用靶點及作用特點[J].中醫(yī)正骨,2019,31(04):1-7.
　LIANG Bocheng,SHI Xiaolin,XU Chao,et al.A study of pharmacodynamic components,action targets and characteristics of Liuwei Dihuang Wan(六味地黃丸)in treatment of osteoporosis using traditional chinese medicine systems pharmacology approach[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2019,31(04):1-7.
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基于中藥系統(tǒng)藥理學方法研究六味地黃丸治療骨質疏松癥的藥效成分、作用靶點及作用特點()
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《中醫(yī)正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第31卷
期數(shù):
2019年04期
頁碼:
1-7
欄目:
基礎研究
出版日期:
2019-04-30

文章信息/Info

Title:
A study of pharmacodynamic components,action targets and characteristics of Liuwei Dihuang Wan(六味地黃丸)in treatment of osteoporosis using traditional chinese medicine systems pharmacology approach
作者:
梁博程; 史曉林; 許超; 吳連國; 何濱; 李琰華; 李敏
(浙江中醫(yī)藥大學附屬第二醫(yī)院,浙江 杭州 310005)
Author(s):
LIANG Bocheng; SHI Xiaolin; XU Chao; WU Lianguo; HE Bin; LI Yanhua; LI Min
The Second Affiliated Hospital of Zhejiang Chinese Medical University,Hangzhou 310005,Zhejiang,China
關鍵詞:
骨質疏松;  六味地黃丸;  藥理作用;  基因本體論;  信號通路
Keywords:
osteoporosis;  Liuwei Dihuang Wan;  pharmacologic actions;  gene ontology;  signaling pathway
摘要:
目的:基于中藥系統(tǒng)藥理學方法探討六味地黃丸治療骨質疏松癥(osteoporosis,OP)的藥效成分、作用靶點及作用特點。方法:在中藥綜合數(shù)據(jù)庫中檢索六味地黃丸中的已知化學成分,然后使用中醫(yī)藥分子機制生物信息學分析工具預測六味地黃丸已知化學成分的作用靶點。通過檢索DisGeNET數(shù)據(jù)庫和人工閱讀文獻,查找OP相關靶基因和蛋白,通過與預測得到的作用靶點進行交疊,篩選六味地黃丸治療OP的作用靶點。利用Cytoscape 3.7軟件自帶的BiNGO和ClueGO插件,分別對篩選出的靶點進行基因注釋和信號通路富集分析。最后選取前期構建的絕經后OP疾病模型中的87個差異表達蛋白(基于血清蛋白質組學篩選的絕經后OP女性與絕經后骨量正常女性的血清差異表達蛋白),與篩選出的六味地黃丸治療OP的作用靶點進行交疊,篩選六味地黃丸治療OP的關鍵靶點,通過分析原始數(shù)據(jù),確定相應的中藥及其藥效成分。結果:通過檢索發(fā)現(xiàn)六味地黃丸化學成分130個,其中熟地黃化學成分8個、山藥化學成分20個、山茱萸化學成分46個、澤瀉化學成分21個、牡丹皮化學成分18個、茯苓化學成分21個; 茯苓與山茱萸、山茱萸與牡丹皮各含有1個相同化學成分,澤瀉與山茱萸含有2個相同化學成分。根據(jù)六味地黃丸化學成分共預測到1169個作用靶點,其中君藥熟地黃作用靶點42個,臣藥山茱萸和山藥作用靶點997個,佐藥澤瀉、牡丹皮和茯苓作用靶點共622個; 君藥與臣藥共有12個共同作用靶點,君藥與佐藥有14個共同作用靶點,臣藥與佐藥有472個共同作用靶點,君藥、臣藥、佐藥共有6個共同作用靶點。經檢索DisGeNET數(shù)據(jù)庫和人工閱讀文獻,共檢索到OP相關靶點687個,通過與預測到的六味地黃丸作用靶點交疊,共篩選出六味地黃丸治療OP的作用靶點142個。靶點基因注釋發(fā)現(xiàn),六味地黃丸治療OP的142個作用靶點主要參與了20種生物學過程,分布于8種細胞成分中,具有10種分子功能,其作用涉及骨重建、骨化、血管重塑、軟骨發(fā)育、肌肉發(fā)育、骨骼發(fā)育、維生素D代謝、維生素應答、雌激素刺激應答、破骨細胞分化、成骨細胞分化、骨礦化、Wnt信號通路和Samd信號通路等生物學行為的調控。信號通路富集分析發(fā)現(xiàn),119個信號通路被顯著富集,破骨細胞分化、NF-κB信號通路和卵巢類固醇生成等24個功能組被顯著富集,其中Wnt信號通路和與絕經后OP密切相關的雌激素調控信號通路等在24個功能組中廣泛分布。通過將87個差異表達蛋白與篩選出的六味地黃丸治療OP的作用靶點交疊,篩選出血管緊張素原、載脂蛋白E、Dickkopf相關蛋白3、RAS相關蛋白7a和蛋白質二硫鍵異構酶共5個關鍵靶點,對應山茱萸、山藥、茯苓的6個藥效成分,包括馬兜鈴酮、α-考繞咖烯、豆甾醇、尿囊素、鞘氨醇A及齒孔醇。結論:六味地黃丸治療OP的藥效成分包括山藥、山茱萸和茯苓所含化合物馬兜鈴酮、α-考繞咖烯、豆甾醇、尿囊素、鞘氨醇A及齒孔醇,主要作用靶點包括血管緊張素原、載脂蛋白E、Dickkopf相關蛋白3、RAS相關蛋白7a和蛋白質二硫鍵異構酶。六味地黃丸治療OP具有多靶點、多系統(tǒng)協(xié)同作用的特點。
Abstract:
Objective:To explore the pharmacodynamic components,action targets and characteristics of Liuwei Dihuang Wan(六味地黃丸,LWDHW)in treatment of osteoporosis(OP)using traditional Chinese medicine(TCM)systems pharmacology approach.Methods:The known chemical components of LWDHW were searched out from traditional Chinese medicine integrative database(TCMID),and the action targets of known chemical components of LWDHW were predicted by using a bioinformatics analysis tool for molecular mechanism of raditional Chinese medicine(BATMAN-TCM).The OP-related target genes and proteins were searched out through retrieving DisGeNET database and reading the articles,and the action targets of LWDHW for treatment of OP were selected out through overlapping the OP-related target genes and proteins with the predicted action targets.Gene annotation and signal pathway enrichment analysis were performed on the selected targets respectively by using BiNGO and ClueGO plug-ins in Cytoscape 3.7 software.Eighty-seven proteins,which differentially expressed in serum of females with PMOP and postmenopausal females with normal bone mass,were selected out from the PMOP models to overlap with the selected action targets of LWDHW for treatment of OP,and the key targets of LWDHW for treatment of OP were selected out finally.The corresponding TCMs and their pharmacodynamic components were determined through analyzing the original data.Results:One hundred and thirty chemical components of LWDHW were found out through retrieving TCMID,including the chemical components of radix rehmanniae praeparata(8),rhizoma dioscoreae(20),fructus corni(46),rhizoma alismatis(21),cortex moutan radicis(18)and poria cocos(21).One identical chemical component was found in poria cocos and fructus corni and in fructus corni and cortex moutan radicis respectively,and two identical chemical components were found in rhizoma alismatis and fructus corni.One thousand one hundred and sixty-nine action targets were predicted according to the chemical components of LWDHW,including the action targets of radix rehmanniae praeparata(sovereign drug,42),fructus corni and rhizoma dioscoreae(minister drug,997)and rhizoma alismatis,cortex moutan radicis and poria cocos(assistant drug,622).The common action targets were found in sovereign drug and minister drug(12),sovereign drug and assistant drug(14),minister drug and assistant drug(472)and sovereign drug,minister drug and assistant drug(6).Six hundred and eighty-seven OP-related targets were searched out through retrieving DisGeNET database and reading the articles,and 142 action targets of LWDHW for treatment of OP were selected out by overlapping the OP-related targets with the predicted action targets of LWDHW.The results of gene annotation for the targets demonstrated that the 142 action targets of LWDHW for treatment of OP were mainly involved in 20 kinds of biological processes,distributed in 8 kinds of cell components and had 10 kinds of molecular functions,and played a role in the regulation of biological behaviors such as bone reconstruction,ossification,vascular remodeling,cartilage development,muscle development,bone development,vitamin D metabolism,response to vitamin,response to estrogen stimulation,osteoclast differentiation,osteoblast differentiation,bone mineralization,Wnt signaling pathway and Samd signaling pathway.The results of signal pathway enrichment analysis of the targets demonstrated that 119 signaling pathways were significantly enriched,and 24 functional groups including osteoclast differentiation,NF-κB signaling pathway and ovarian steroidogenesis were significantly enriched,and Wnt signaling pathway and PMOP-related estrogen regulation signaling pathway were widely distributed in the 24 functional groups.Five key targets,including angiotensinogen(AGT),apolipoprotein E(APOE),Dickkopf-related protein 3(DKK3),RAB7A and protein disulfide isomerase(PDI),were selected out through overlapping the 87 differentially expressed proteins with the selected action targets of LWDHW for treatment of OP,and they corresponded to the 6 pharmacodynamic components of fructus corni,rhizoma dioscoreae and poria cocos,including aristolone,alpha-corocalene,stigmasterol,allantoin,sphingosine A and eburicol.Conclusion:The pharmacodynamic components of LWDHW for treatment of OP include aristolone,alpha-corocalene,stigmasterol,allantoin,sphingosine A and eburicol,which are contained in rhizoma dioscoreae,fructus corni and poria cocos,and their main action targets include AGT,APOE,DKK3,RAB7A and PDI.LWDHW is characterized by synergistic effect of multiple targets and multiple systems in treatment of OP.

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備注/Memo

備注/Memo:
基金項目:國家自然科學基金項目(81803902) 通訊作者:李敏 E-mail:[email protected](收稿日期:2018-12-28 本文編輯:李曉樂)
更新日期/Last Update: 2019-10-08