中药方剂与证候的生物学基础

中药方剂与证候的生物学基础

中医学是中华民族疾病理论和实践的结晶。它以一种整体的、联系的、动态的观点来认识复杂的生命现象以及人与自然的相互关系,逐渐形成了整体观、辨证论治、方剂配伍等具有特色的诊疗体系。如何科学地阐释中医药的内涵,理解中药方剂与病证的生物学基础,并与“个体化、可预测、可预防”这一医学新方向协调发展,是中医药现代化的关键问题之一,也是中医药转化研究的重要任务。中医学注重从整体的角度来看待复杂的生命系统,在一定意义上,可以认为其本质上具有系统科学的思想,是一门传统的系统生物医学。随着现代科技的进步,与中医药的整体思维方式相呼应的是,当前医学生命科学研究体现出两个新趋势:一是重视从系统、整体的角度来理解复杂的生命现象;二是强调学科交叉渗透,因为理解生命的复杂性已超出了单一学科的能力范围,需要医学、生命科学、信息科学等各方面的力量进行更为广泛和深入的整合。如何在转化医学思想指导下,以认识机体疾病复杂性为切入点,建立符合中医药特色的预测、预防、诊断和治疗疾病的策略和方法,成为当务之急。当前,以人类基因组计划为发端的“组学”技术产生了海量数据,生物信息学、系统生物学等交叉学科应运而生,特别是生物分子网络概念的提出,被认为是复杂生物系统的分子基础和重要表现方式,它有助于理解生命在系统、整体层次上的规律。通过建立有效的“系统”方法,为解析各种生命的复杂性、生物系统的系统行为及其本质规律,提供了重要的研究工具。在此背景下,国际上相继提出了网络医学、系统医学、网络药理学、系统药理学等新概念。因此,将生物分子网络用于中医药转化医学研究是从系统层面阐释证候的生物学基础、方剂作用机制和病证方关联等问题的一个重要契机。目前,研究人员正致力于上述三个问题的研究,并提出一系列探索性的研究策略和计算工具以解决相关问题。本文对中医药转化医学领域的研究现状、生物分子网络在中医药转化研究中的作用及其应用现状与发展前景进行综述和分析。1中医药转化医学研究转化医学(translationalmedicine)是解决目前基础研究与临床脱节所提出的一种新的医学研究方式。它以患者为核心,从临床诊断和治疗中发现并提出问题,经过基础和实验室研究,将成果高效转向临床应用,在实现个体化诊疗的同时,整体提高临床的诊治水平。其主要特征是基础与临床有效联系和紧密结合,实现“从实验室到病床”(benchtobedside,B2B)的转化,从而形成“临床-基础-临床”的螺旋式上升的解决策略。自1993年提出以来,转化医学研究整合了基因组学、生物信息学、系统生物学、网络生物学以及高通量测序等现代科学技术,在临床风险评估、疾病诊断与分型、疗效及预后评价、治疗方法和新药开发等方面都有突出的进展和贡献。中医药学是在几千年的临床实践经验基础上逐步归纳总结而产生的、有确切疗效的传统医疗体系。近年来,中医基础与临床科研得到了国家的大力支持,在中医药现代化研究中取得了一批重要的研究成果,其中中医证候的生物学基础和方剂配伍规律及其物质基础是两个重要方面。然而,如何将中医基础与临床科研紧密联系,根据中医理论体系进一步指导临床医学实践,从而朝向一种“个体化、可预测、可预防”的新型医学发展方向,成为当前中医药现代化研究的一个重要问题。这一问题的提出,促进了中医药与转化医学的融合。中医药学与转化医学的共同点是强调“人”的因素,以复杂的生物系统作为研究对象,二者皆需要从现代科学的角度进行更为深入的研究。2生物分子网络特点中医药研究的主要任务是科学地阐释整体观、辨证论治等中医药的特色内涵,然而,仿照西医研究思路进行中医药现代研究具有一定的局限性。虽然在一定程度上,从动物、细胞乃至分子层次上获得了对中医药机制的认识,但是中医药临床有效性、中医药的科学证据依然缺乏系统的研究,缺少整体上的突破。因此,加速中医药“源自临床-证于实验-归于临床”的转化过程亟需在研究思路与方法上实现突破与创新。病证的发生发展是一个复杂的动态过程,生物分子是这一过程的结构基础和功能单元,病证的动态发展过程可以归于生物分子的变化过程。然而,单一分子及其构成的单一信号转导通路的确难以反映病证机制和治疗的关键,需要尝试从新的角度整合不同层次的信息达到对病证机制的整体理解和认知。生物分子网络则是该研究策略下的重要切入点,有助于从分子水平综合描述病证发展过程的复杂性及其相互之间的关联关系。生物分子网络主要是指基因、基因产物和代谢物等生物分子之间通过复杂相互作用而形成的网络,也可拓展到以生物分子为基础的信号通路网络、代谢网络、生物过程网络、组织网络等。其特点是:(1)网络分子之间的连接性(connectivity),它们在结构上相互联系、相互影响,在功能上彼此激活与失活或协同与拮抗;(2)中心性(centrality),连接度数高的网络分子往往都发挥重要的生物功能;(3)模块性(modularity),与功能网络中的分子相互作用的分子很可能具有相似的生物功能,这些分子处于同一网络模块中;(4)传递性(propagation),在功能网络中,一个网络分子就是一个节点,每一节点在受到其他节点作用的同时,也对其他节点产生影响,如一个异常基因不仅影响自身介导的效应,而且还可通过网络连接影响其他基因所介导的效应。故生物分子网络不仅刻画了病证的分子本质,而且还为研究多分子之间的复杂调控关系提供了可能,弥补了单纯研究单一分子孤立行为的不足。近年来,生物分子网络在病证相关基因和药物靶点的预测分析上得到了有效的应用。在上述网络特点的基础上,整合病证表型和药物等多层次、多类型信息,提出符合临床医学意义的假设,建立基于网络的预测方法,已经在病证生物学基础和药物开发领域取得了具有临床转化价值的发现。例如,在病证生物学基础研究方面,根据“相似病证表型相关分子在网络上具有模块性”的假设,开发出疾病基因推断方法(correlatingproteininteractionnetworkandphenotypenetworktopredictdiseasegenes,CIPHER),成功预测了乳腺癌等众多疾病的致病基因,并鉴定出对乳腺癌等疾病具有协同作用的基因组合。在药物开发方面,网络药理学在全面理解药物的靶点和脱靶点效应、药理作用、毒副作用、药物靶标预测、药物组合预测等方面发挥了重要作用。因此,将基于网络的方法应用于中医药转化医学研究可能成为一种沟通中医基础研究和临床实践的行之有效的手段。3基于分子网络的中医转化医学研究3.1其他生物分子网络的研究机体生物分子网络失衡是导致中医证候发生发展的分子基础,临床上中医“证”的出现则是分子网络失衡的表现形式。不同功能的生物分子失调控决定了失衡网络的不同特征,主要包括网络中分子的变化性质(上调下调、刺激抑制)、强度、时程、关联等因素的组合构成了网络的失衡,这些不同特征进而导致了中医证候表现的不同,例如,寒热证候之不同。“寒、热”是中医辨别疾病性质的两个重要纲领,直接反映了机体阴阳的偏盛与偏衰。近年来,使用生物分子网络已对寒热证的生物学本质进行了多方面的探索性研究。例如,Li等提出一种基于文献挖掘和组学数据融合的病证特定生物分子网络的构建方法,以寒证、热证为对象,构建了寒证、热证生物分子网络,同时将两个网络中的生物分子(基因或化学递质)映射至神经内分泌免疫的分子网络中,并建立了一种“拓扑温度”的网络失衡度量方法,分析发现了寒证、热证的两种生物学特征:寒证网络的分子以激素的功能模块为主,热证网络的分子以细胞因子的功能模块为主,神经递质功能模块共同分布于寒、热证网络,该研究初步给出了寒热证候的分子依据。结果提示,机体生物网络的失衡状态能够较好地反映中医证候的生物学基础。此外,在上述研究基础上,进一步提出证候研究的一种新思路,即以分子网络平衡观点来阐释证候生物学本质,并利用网络关键节点来发现证候的生物标志物。例如,从慢性胃炎典型的寒证、热证患者中,发现了寒证、热证存在能量代谢与免疫调节网络失衡的两种基因表达模式,进而通过验证网络关键节点,发现了寒热证患者的生物标志,且寒热证的生物标志物在浅表性胃炎到萎缩性胃炎过程中基本稳定。同时,还首次开展了中医寒热证候的舌苔微生物组研究,对慢性胃炎寒、热证患者和正常人的舌苔微生物组进行了高通量测序和生物信息学分析,发现舌苔微生物群落是区分寒、热证患者的一种新型生物标志,并构建出了寒、热证相关的舌苔微生物网络。这些结果都表明,寒热证候的形成具有特定的分子网络基础,是分子网络失衡的结果。3.2网络靶标思想中药方剂是一个复杂化学体系,中医证候是一个复杂生物系统。如何考虑这两方面的关联,是理解方剂多靶点、弱干预、整体调节等特点的关键。面对这一问题,我们在病证生物分子网络研究的基础上进一步提出了“网络靶标”的构想,具体而言,即以病证生物分子网络的核心环节为靶标,通过衡量方药成分的靶标谱与病证分子网络关键环节的关系,发现中药方剂的药效物质及其作用机制;通过分析方剂所含成分的靶标在网络上的分布规律,探索药性、君臣佐使、七情合和等方剂特色内涵的网络特征;进一步地利用这种网络特征来预测组方用药的临床生物标志,并利用所发现的规律来进行组方用药的理性设计。目前,网络靶标思想在中药方剂现代研究的多个领域都取得发现。例如,新安医学治疗类风湿性关节炎(rheumatoidarthritis,RA)的代表性方剂清络饮中的抗炎、抗血管新生活性成分及成分组合的确定,首先利用基于网络药理学的靶标推断方法预测清络饮中每个成分的靶标谱,然后对靶标谱进行主成分分析以确定清络饮所含成分在作用机制上的异同,最后利用协同药物组合的预测方法鉴定清络饮中对血管新生、炎性反应、免疫调节等RA不同病理过程发挥协同干预作用的成分组合。此外,还有蔓荆子黄素等中药天然产物靶标的确定、六味地黄丸作用于多种疾病的共同网络靶标揭示异病同治的原理等研究工作,皆表明从生物网络的角度能够较好地理解中药复杂化学体系与病证复杂生物系统的相互作用,从而为解释中药方剂的作用机制提供一定的科学依据。同时,深入发掘中医组方用药的经验与特色,也有助于推动复杂疾病的组合用药、个性化用药研究。4orro-3.3indexhacines网络药理学用于中医药转化医学研究是一个既传统又年轻的领域,这不仅要求该领域的研究思路要符合中医理论与实践,而且在应用过程中还面临诸多挑战。基于生物分子网络的系统分析方法与中医学的思维与实践存在交汇之处,有效弥补了中医基础研究与临床转化的沟壑。我们相信,随着信息学与医学生命科学交叉研究的深入,从网络和信息的整体性视角探索中医药奥秘成为可能。将以“整体”为特点的中医药和以“系统”为朝向的当今医药研究有效地衔接起来,不仅能够为揭示中医药科学原理、加速中医药现代化进程起到重要支撑作用,而且有望为整个医学和药物研究的发展也做出原创性贡献。TraditionalChinesemedicine(TCM)istheculminationoftheChinesemedicaltheoryandpracticalexperience.Understandingthecomplexphenomenonoflifeandtherelationshipbetweenhumanandnatureusinganintegrated,interconnectedanddynamicperspective,TCMhasgraduallyformedadistinctmedicalsystemwithaholisticperspective,syndromedifferentiationandtreatmentaswellasprescriptioncompatibility.HowtoscientificallyexplaintheconnotationsofTCMandmovetowardsanewstepwith“personalized,predictable,andpreventablemedicineresearch”isakeyissueinthemodernizationofTCM.ThesetasksarealsoimportantintranslationalTCMresearch.TCMtreatsthehumanbodyasacomplexsystemusingasystematicandholisticperspective.Inacertainsense,TCMcanbeconsideredtoinherentlyhavethethinkingprocessofasystematicscienceandtobethetraditionalsystematicbiomedicine.TheresearchofTCMcanbecomemorescientificonlywhenthethoughtsandmethodsofinformationandsystemsareapplied.ForboththesystematicandholisticapproachinTCMandtherapidprogressofmodernscienceandtechnology,theresearchstateofmedicallifesciencesreflectstwonewtrends:first,understandingthecomplexbiologicalphenomenausingsystematicandholisticapproaches;andsecond,crossingandinfiltrationamongdisciplines.Thesetrendsreflectawarenessthatanunderstandingofthecomplexityoflifeisbeyondthecapabilitiesofanysingledisciplineandrequiresextensiveandin-depthintegrationamongvariousdisciplines,includingmedicallifesciencesandinformationscience.Inaddition,undertheguidanceoftranslationalmedicineandwithanunderstandingofthecomplexityofagivendiseaseasthestartingpoint,ithasbecomeimperativetoestablishstrategiesandmethodstopredict,prevent,diagnoseandtreatthesediseasesusingTCM.Thecurrent”Omics“technologiesoriginatedwiththeHumanGenomeProject,whichproducedalargeamountofdatathatledtothedevelopmentofbioinformatics,systembiology,andotherinterdisciplinaryefforts.Inparticular,theproposaloftheconceptofbiomolecularnetworksisconsideredtobethemolecularfoundationandmainexpressionofacomplexbiologicalsystem.Biomolecularnetworksprovidewithimportantresearchtoolsforestablishinganeffectivesystematicapproachandunderstandingthenatureoflifeatthesystematicandholisticlevels.Inthiscontext,newconceptssuchasnetworkmedicine,systematicmedicine,networkpharmacologyandsystematicpharmacology,havebeensuccessivelyproposedinternationally.Therefore,theapplicationofbiomolecularnetworksintranslationalresearchinTCMwillbebeneficialtothestudyofthebiologicalfoundationsofZHENG,themechanismsofherbalformulae,andtherelationshipamongdiseases,ZHENGsandformulaeatthesystematiclevel.Currently,researchersareworkingontheabovethreeresearchtopics,andtheyhaveproposedaseriesofexploratoryresearchstrategiesandcomputationaltoolstosolveproblemsrelatedtotheseareas.Inthispaper,thecurrentstateoftranslationalresearchinTCM,theroleofbiomolecularnetworksintranslationalTCMresearch,theirapplicationsanddevelopmentprospectsarereviewedanddiscussed.1clinicarlosso-tracesiphenge+tracesix,算s3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3Translationalmedicineoffersanewmedicalresearchdirectionthatprovidesasolutiontothecurrentseriousgapsbetweenbasicresearchesandclinicalpractices.Byconsideringpatientsoneofthecentralsubjectsofinvestigation,translationalmedicinediscoversandraisesquestionsduringclinicaldiagnosisandtreatment.Throughbasicexperimentalandlaboratorystudies,theresultsareefficientlyconvertedintoclinicalapplications.Byprovidingindividualizedtreatment,theoveralllevelofclinicaldiagnosisandtherapyisimproved.Themainfeatureoftranslationalmedicineistheeffectiveandclosecooperationbetweenfundamentalandclinicalresearchtoachieveatransformationfromue130benchtobedsideue132(B2B),thusformingthecyclicalsolutionstrategyofue130clinical-basicclinical.ue132Sinceitwasproposedin1993,thefieldoftranslationalmedicinehasintegratedmodernscientifictechniques,suchasgenomics,bioinformatics,systemsbiology,networkbiologyandhigh-throughputsequencingintoclinicalpractices.Translationalmedicinehasalreadyledtooutstandingprogressandcontributionsinclinicalriskassessment,diseasediagnosisandclassification,theassessmentoftreatmentefficacyandprognosis,treatmentmethodsandnewdrugdevelopmentsincethen.TCMisaneffectivetraditionalmedicalsystemthathasbeengraduallygeneratedandintegratedbasedonthousandsofyearsofexperienceinclinicalpractice.Inrecentyears,basicandclinicalresearchintoTCMhasreceivedstrongsupportfromtheChinesegovernmentandhasproducedanumberofimportantresearchachievementsrelatedtothemodernizationofTCM.Oftheseachievements,thebiologicalbasisoftheZHENG/syndromesofTCM,theruleofprescriptioncompatibilityandtheeffectivesubstancebasisofTCMarethethreeimportantparts.However,howtocloselyconnectthebasicandclinicalresearchonTCMandmovetowardsanewstageof“personalized,predictable,andpreventablemedicine”withfurtherguidancefromTCMtheoryhasbecomeanimportantissueinthemodernizedstudyofTCM.AwarenessofthisproblemhaspromotedintegrationbetweenTCMandtranslationalmedicine.ThemostprevalentconcernofTCMandtranslationalmedicineishumanerrors.Thus,itisnecessarytolegitimizethecomplexsystemofTCMthroughfurtherin-depthstudyfromtheperspectiveofmodernscience.2thievega和tratrebcopThemaintaskoftranslationalmedicalresearchinTCMistoscientificallyexplainthecharacteristiccontentofTCM,includingitsholisticconceptandsyndromedifferentiation.However,currentresearchinTCM,especiallyChineseherbalformulae,hadsomelimitationsbecauseresearcheffortsfocusedonlyontheideasofWesternmedicalresearch.Althoughthemechanismsofherbalformulaehavetosomeextentbeenunderstoodattheanimal,cell,orevenmolecularlevel,systematicresearchintothescientificevidenceofTCM'sclinicalefficacyisstillpoor;consequentlymodernclinicalmedicineremainsconfinedtotraditionaltheory,anditisverydifficultforTCMtomakeabreakthrough.Therefore,breakthroughsandinnovationsinresearchideasandmethodsareurgentlyneededtoacceleratetheue130basicexperimentalresearchtoclinicalpracticeue132conversionprocessforTCM.Theoccurrenceanddevelopmentofadisease/ZHENGisacomplexanddynamicprocess,andbiologicalmoleculesarethestructuralbasisandthefunctionalunitofthisprocess.Thedynamicdevelopmentprocessofadisease/ZHENGcanbeattributedtochangesinbiologicalmolecules.However,asinglemoleculeanditssinglesignaltransductionpathwaycannotreflectthemolecularmechanismofthedisease/ZHENGandtreatment.Theintegrationofdifferentlevelsofinformationinanewperspectiveisneededtoachieveacomprehensiveunderstandingofthedisease/ZHENGmechanism.Biomolecularnetworksareanimportantstartingpointinthisresearchstrategy;thesenetworkshelptocomprehensivelydescribethecomplexityofthedevelopmentalprocessesofdiseases/ZHENGsandtheirassociationatthemolecularlevel.Biomolecularnetworksmainlyrefertothenetworksformedthroughthecomplexinteractionsamonggenes,geneproducts,metabolitesandotherbiologicalmolecules.Theseinteractionscanbeextendedtoothertypesofnetworksbasedonbiologicalmolecules,suchassignalpathwaynetworks,metabolicnetworks,biologicalprocessnetworksandtissuenetworks.Thecharacteristicsofbiomolecularnetworksareasfollows:a)Connectivitybetweenthemoleculesinthenetwork,whichmeansthatthemoleculesinteractwitheachotherinstructureandareactivatedanddeactivatedoraresynergisticorantagonisticinfunction;b)Centrality,whichmeansthattheelementswithahighdegreeofconnectivityinanetworkoftenplayanimportantbiologicalfunction;c)Modularity,meaningthatthemoleculesthatinteractwitheachotherinafunctionnetworkarelikelytosharesimilarbiologicalfunctionsandmaybeinthesamenetworkmodule;d)Propagation,whichmeansthatinafunctionalnetwork,onetypeofnetworkelementisanode,andeachnodeisaffectedbyothernodesandaffectsothernodesinturn.Forexample,anabnormalgenenotonlyaffectsthefunctionitdirectlymediates,butitalsoaffectsotherfunctionsmediatedbyothergenesthroughnetworkconnections.Therefore,thebiomolecularnetworknotonlycharacterizesthemolecularnatureofadisease/ZHENGbutalsooffersthepossibilitytostudythemorecomplexregulatoryrelationshipsamongmultiplemolecules,whichcompensatesforthelimitedstudiesontheisolatedbehaviorofasinglemolecule.Inrecentyears,thebiomolecularnetworkshavebeenefficientlyappliedinpredictionanalysesfordisease/ZHENG-relatedgenesanddrugtargets.Basedonthecharacteristicsofthenetworkandthroughtheintegrationofvarioussourcesofinformationaboutthedisease/ZHENG'sphenotypeanddrugtargets,hypothesesbasedonclinicalsignificancehavebeenproposed,andanetwork-basedpredictionmethodhasbeenestablished;together,thesefactorshaveachievedvariousvaluablediscoveriesintheclinicaltransformationofthebiologicalfoundationsofdisease/ZHENGanddrugdiscovery.Infundamentalresearchondisease/ZHENGbiology,theinferencemethodofhumandiseasegenes(Correlatingproteininteractionnetworkandphenotypenetworktopredictdiseasegenes,CIPHER)wasdevelopedaccordingtothehypothesisthatmoleculesrelatedtoasimilarsyndromephenotypehaveamodularnature.Thismethodhasbeenabletosuccessfullypredictmanydiseasegenessuchasbreastcancerrelatedgenesandidentifymolecularcompositionsthathaveasynergisticeffectonthedisease.Indrugdevelopment,networkpharmacologyhasplayedanimportantroleinthecomprehensiveunderstandingofthetargetedandoff-targetedeffectsofadrug,itspharmacologicalroles,toxicsideeffects,targetpredictionsforadrug,andpredictionsaboutdrugcombinations.Therefore,theapplicationofnetwork-basedmethodsintranslationalresearchonChinesemedicineislikelytobeaneffectivemeansoflinkingfundamentalresearchandclinicalpractice.3内科医学专业素质分析二级内科医学植根基质可靠射击3.1u2004范围Imbalancesinbio-molecularnetworksinahumanbodyarethemolecularbasisforthedevelopmentofTCMZHENG.Inanotherword,theemergenceofaclinicalZHENGinTCMistherepresentationofanimbalanceinamolecularnetwork.Thedysregulationofbiomoleculeswithdifferentfunctionsdeterminesthecharacteristicsoftheimbalanceinthenetworkandthusthedisease.Networkimbalancecanarisethroughthechangesinnetworkelements,includingup-regulationordown-regulation,stimulationorinhibition,andchangesinintensity,durationofassociationsCombinationsofthesecharacteristicsfurthercausethedifferentmanifestationsofTCMZHENG(forexample,ColdZHENGandHotZHENG)inTCM.“Cold”and“hot”arethetwoimportantprinciplesusedtodistinguishthenatureofadiseaseinTCM,andtheydirectlyreflecttheexcessordeficiencyofYinandYanginahumanbody.Inrecentyears,manyexploratorystudieshavebeenconductedonthebiologicalnatureofcoldandhotZHENGusingbiomolecularnetworks.Forexample,Lietalproposedamethodforconstructingaspecificbiomolecularnetworkbasedonthecombinationofliteraturereviewandomicsdata.TakingcoldandhotZHENGastheresearchobjects,thebiomolecularnetworksforcoldandhotZHENGwereconstructed.Thebiologicalmoleculesinthetwonetworks(geneticorchemicaltransmitters)weresimultaneouslymappedintoneuroendocrine-immunemolecularnetworks,andthemethodof“topologicaltemperature”wasestablishedtomeasurethenetworkimbalancestatus.AnanalysisrevealedtwobiologicalcharacteristicsforthecoldandhotZHENG:themoleculesinthecoldZHENGnetworkweremainlyinthehormone-functionmodule,whilethemoleculesinthehotZHENGnetworkweremainlyinthecytokine-functionmodule.ThemoduleofneurotransmitterfunctionwascommonlydistributedinbothcoldandhotZHENGnetworks.ThisstudypreliminarilyprovidedamolecularbasisforcoldandhotZHENG.TheseresultssuggestthatimbalancesinbiologicalnetworkscouldwellreflectthebiologicalbasisofaTCMZHENG.Inaddition,basedontheabovestudies,anewhypothesiswasfurtherproposedforthestudyoftheseZHENGstoexplainthebiologicalnatureofaZHENGfromtheperspectiveofabalancedmolecularnetworkandtodiscoverthebiomarkersofaZHENGusingthekeynodeofthenetwork.Forexample,inchronicgastritispatientswithatypicalcoldandhotZHENG,twogeneexpressionpatternswithimbalancednetworksofenergymetabolismandimmuneregulationwerefoundforthecoldandhotZHENG,andthekeynodesinthenetworkwerethenverifiedtorevealthebiomarkersforthecoldandhotZHENG.ThebiomarkersforpatientswithcoldandhotZHENGwereidentified;thesebiomarkerswerebasicallystablethroughouttheprogressionfromsuperficialgastritistoatrophicgastritis.Similarly,tonguemicrobiomeresearchwasfirstconductedforcoldandhotZHENGinTCM.High-throughputsequencingandbioinformaticsanalysiswereperformedontonguemicrobegroupsfromchronicgastritispatientswithcoldorhotZHENGandthosefromhealthyindividuals.ThetonguemicrobegroupwasfoundtobeanovelbiomarkertodistinguishthepatientswithcoldorhotZHENG,andtonguemicrobialnetworkswereconstructedthatcorrespondedtocoldandhotZHENG.TheseresultsindicatedthattheformationofcoldandhotZHENGwasbasedonspecificmolecularnetworksandwascausedbyimbalancesinthemolecularnetworks.3.2通过转色规划可部分天气形貌保证toreinvi生物c.n.案例toTCMherbalformulaearecomplexchemicalsystems,andTCMZHENGsarecomplexbiologicalsystems.Anunderstandingoftheassociationbetweenthesetwoaspectsisthekeytounderstandingthecharacteristicsofmultipletargets,weakinterventionsandtheintegratedregulationofherbalformulae.Tosolvethisproblem,Liproposedaue130networktargetue132conceptbasedonthestudyofthebiomolecularnetworksofadisease/ZHENG.Specifically,bytakingthecorepartofthebiomolecularnetworkofadisease/ZHENGasthetargetandmeasuringtherelationshipofthetargetprofilesoftheingredientsintheherbalformulaeandthekeynodeinthemolecularnetworkofthedisease/ZHENG,theeffectivesubstancesoftheTCMherbalformulaeandtheirfunctionalmechanismscanbefound.Byanalyzingthetargetdistributionoftheingredientsintheherbalformulae,thenetworkcharacteristicsoftheherbalpropertiesandcombinatorialprinciplescanbeinvestigated.Furthermore,suchnetworkcharacteristicscanbeusedtopredicttheclinicalbiomarkersintheherbalformulae,andtheidentifiedpatternscanbeusedfortherationaldesignofdrugprescriptions.Todate,thetheoryofnetworktargetinghasresultedindiscoveriesinvariousfieldsoftranslationalresearchinTCMherbalformulae.Forexample,theingredientsandtheingredientcombinationswithanti-inflammatoryandanti-angiogenicactivitywereidentifiedinthetypicalprescriptionQing-Luo-Yin(QLY)usedinXin'anmedicinetotreatrheumatoidarthritis(RA).Firstly,thenetwork-basedinf