中藥方劑與證候的生物學(xué)基礎(chǔ)

中藥方劑與證候的生物學(xué)基礎(chǔ)

中醫(yī)學(xué)是中華民族疾病理論和實(shí)踐的結(jié)晶。它以一種整體的、聯(lián)系的、動(dòng)態(tài)的觀點(diǎn)來認(rèn)識復(fù)雜的生命現(xiàn)象以及人與自然的相互關(guān)系,逐漸形成了整體觀、辨證論治、方劑配伍等具有特色的診療體系。如何科學(xué)地闡釋中醫(yī)藥的內(nèi)涵,理解中藥方劑與病證的生物學(xué)基礎(chǔ),并與“個(gè)體化、可預(yù)測、可預(yù)防”這一醫(yī)學(xué)新方向協(xié)調(diào)發(fā)展,是中醫(yī)藥現(xiàn)代化的關(guān)鍵問題之一,也是中醫(yī)藥轉(zhuǎn)化研究的重要任務(wù)。中醫(yī)學(xué)注重從整體的角度來看待復(fù)雜的生命系統(tǒng),在一定意義上,可以認(rèn)為其本質(zhì)上具有系統(tǒng)科學(xué)的思想,是一門傳統(tǒng)的系統(tǒng)生物醫(yī)學(xué)。隨著現(xiàn)代科技的進(jìn)步,與中醫(yī)藥的整體思維方式相呼應(yīng)的是,當(dāng)前醫(yī)學(xué)生命科學(xué)研究體現(xiàn)出兩個(gè)新趨勢:一是重視從系統(tǒng)、整體的角度來理解復(fù)雜的生命現(xiàn)象;二是強(qiáng)調(diào)學(xué)科交叉滲透,因?yàn)槔斫馍膹?fù)雜性已超出了單一學(xué)科的能力范圍,需要醫(yī)學(xué)、生命科學(xué)、信息科學(xué)等各方面的力量進(jìn)行更為廣泛和深入的整合。如何在轉(zhuǎn)化醫(yī)學(xué)思想指導(dǎo)下,以認(rèn)識機(jī)體疾病復(fù)雜性為切入點(diǎn),建立符合中醫(yī)藥特色的預(yù)測、預(yù)防、診斷和治療疾病的策略和方法,成為當(dāng)務(wù)之急。當(dāng)前,以人類基因組計(jì)劃為發(fā)端的“組學(xué)”技術(shù)產(chǎn)生了海量數(shù)據(jù),生物信息學(xué)、系統(tǒng)生物學(xué)等交叉學(xué)科應(yīng)運(yùn)而生,特別是生物分子網(wǎng)絡(luò)概念的提出,被認(rèn)為是復(fù)雜生物系統(tǒng)的分子基礎(chǔ)和重要表現(xiàn)方式,它有助于理解生命在系統(tǒng)、整體層次上的規(guī)律。通過建立有效的“系統(tǒng)”方法,為解析各種生命的復(fù)雜性、生物系統(tǒng)的系統(tǒng)行為及其本質(zhì)規(guī)律,提供了重要的研究工具。在此背景下,國際上相繼提出了網(wǎng)絡(luò)醫(yī)學(xué)、系統(tǒng)醫(yī)學(xué)、網(wǎng)絡(luò)藥理學(xué)、系統(tǒng)藥理學(xué)等新概念。因此,將生物分子網(wǎng)絡(luò)用于中醫(yī)藥轉(zhuǎn)化醫(yī)學(xué)研究是從系統(tǒng)層面闡釋證候的生物學(xué)基礎(chǔ)、方劑作用機(jī)制和病證方關(guān)聯(lián)等問題的一個(gè)重要契機(jī)。目前,研究人員正致力于上述三個(gè)問題的研究,并提出一系列探索性的研究策略和計(jì)算工具以解決相關(guān)問題。本文對中醫(yī)藥轉(zhuǎn)化醫(yī)學(xué)領(lǐng)域的研究現(xiàn)狀、生物分子網(wǎng)絡(luò)在中醫(yī)藥轉(zhuǎn)化研究中的作用及其應(yīng)用現(xiàn)狀與發(fā)展前景進(jìn)行綜述和分析。1中醫(yī)藥轉(zhuǎn)化醫(yī)學(xué)研究轉(zhuǎn)化醫(yī)學(xué)(translationalmedicine)是解決目前基礎(chǔ)研究與臨床脫節(jié)所提出的一種新的醫(yī)學(xué)研究方式。它以患者為核心,從臨床診斷和治療中發(fā)現(xiàn)并提出問題,經(jīng)過基礎(chǔ)和實(shí)驗(yàn)室研究,將成果高效轉(zhuǎn)向臨床應(yīng)用,在實(shí)現(xiàn)個(gè)體化診療的同時(shí),整體提高臨床的診治水平。其主要特征是基礎(chǔ)與臨床有效聯(lián)系和緊密結(jié)合,實(shí)現(xiàn)“從實(shí)驗(yàn)室到病床”(benchtobedside,B2B)的轉(zhuǎn)化,從而形成“臨床-基礎(chǔ)-臨床”的螺旋式上升的解決策略。自1993年提出以來,轉(zhuǎn)化醫(yī)學(xué)研究整合了基因組學(xué)、生物信息學(xué)、系統(tǒng)生物學(xué)、網(wǎng)絡(luò)生物學(xué)以及高通量測序等現(xiàn)代科學(xué)技術(shù),在臨床風(fēng)險(xiǎn)評估、疾病診斷與分型、療效及預(yù)后評價(jià)、治療方法和新藥開發(fā)等方面都有突出的進(jìn)展和貢獻(xiàn)。中醫(yī)藥學(xué)是在幾千年的臨床實(shí)踐經(jīng)驗(yàn)基礎(chǔ)上逐步歸納總結(jié)而產(chǎn)生的、有確切療效的傳統(tǒng)醫(yī)療體系。近年來,中醫(yī)基礎(chǔ)與臨床科研得到了國家的大力支持,在中醫(yī)藥現(xiàn)代化研究中取得了一批重要的研究成果,其中中醫(yī)證候的生物學(xué)基礎(chǔ)和方劑配伍規(guī)律及其物質(zhì)基礎(chǔ)是兩個(gè)重要方面。然而,如何將中醫(yī)基礎(chǔ)與臨床科研緊密聯(lián)系,根據(jù)中醫(yī)理論體系進(jìn)一步指導(dǎo)臨床醫(yī)學(xué)實(shí)踐,從而朝向一種“個(gè)體化、可預(yù)測、可預(yù)防”的新型醫(yī)學(xué)發(fā)展方向,成為當(dāng)前中醫(yī)藥現(xiàn)代化研究的一個(gè)重要問題。這一問題的提出,促進(jìn)了中醫(yī)藥與轉(zhuǎn)化醫(yī)學(xué)的融合。中醫(yī)藥學(xué)與轉(zhuǎn)化醫(yī)學(xué)的共同點(diǎn)是強(qiáng)調(diào)“人”的因素,以復(fù)雜的生物系統(tǒng)作為研究對象,二者皆需要從現(xiàn)代科學(xué)的角度進(jìn)行更為深入的研究。2生物分子網(wǎng)絡(luò)特點(diǎn)中醫(yī)藥研究的主要任務(wù)是科學(xué)地闡釋整體觀、辨證論治等中醫(yī)藥的特色內(nèi)涵,然而,仿照西醫(yī)研究思路進(jìn)行中醫(yī)藥現(xiàn)代研究具有一定的局限性。雖然在一定程度上,從動(dòng)物、細(xì)胞乃至分子層次上獲得了對中醫(yī)藥機(jī)制的認(rèn)識,但是中醫(yī)藥臨床有效性、中醫(yī)藥的科學(xué)證據(jù)依然缺乏系統(tǒng)的研究,缺少整體上的突破。因此,加速中醫(yī)藥“源自臨床-證于實(shí)驗(yàn)-歸于臨床”的轉(zhuǎn)化過程亟需在研究思路與方法上實(shí)現(xiàn)突破與創(chuàng)新。病證的發(fā)生發(fā)展是一個(gè)復(fù)雜的動(dòng)態(tài)過程,生物分子是這一過程的結(jié)構(gòu)基礎(chǔ)和功能單元,病證的動(dòng)態(tài)發(fā)展過程可以歸于生物分子的變化過程。然而,單一分子及其構(gòu)成的單一信號轉(zhuǎn)導(dǎo)通路的確難以反映病證機(jī)制和治療的關(guān)鍵,需要嘗試從新的角度整合不同層次的信息達(dá)到對病證機(jī)制的整體理解和認(rèn)知。生物分子網(wǎng)絡(luò)則是該研究策略下的重要切入點(diǎn),有助于從分子水平綜合描述病證發(fā)展過程的復(fù)雜性及其相互之間的關(guān)聯(lián)關(guān)系。生物分子網(wǎng)絡(luò)主要是指基因、基因產(chǎn)物和代謝物等生物分子之間通過復(fù)雜相互作用而形成的網(wǎng)絡(luò),也可拓展到以生物分子為基礎(chǔ)的信號通路網(wǎng)絡(luò)、代謝網(wǎng)絡(luò)、生物過程網(wǎng)絡(luò)、組織網(wǎng)絡(luò)等。其特點(diǎn)是:(1)網(wǎng)絡(luò)分子之間的連接性(connectivity),它們在結(jié)構(gòu)上相互聯(lián)系、相互影響,在功能上彼此激活與失活或協(xié)同與拮抗;(2)中心性(centrality),連接度數(shù)高的網(wǎng)絡(luò)分子往往都發(fā)揮重要的生物功能;(3)模塊性(modularity),與功能網(wǎng)絡(luò)中的分子相互作用的分子很可能具有相似的生物功能,這些分子處于同一網(wǎng)絡(luò)模塊中;(4)傳遞性(propagation),在功能網(wǎng)絡(luò)中,一個(gè)網(wǎng)絡(luò)分子就是一個(gè)節(jié)點(diǎn),每一節(jié)點(diǎn)在受到其他節(jié)點(diǎn)作用的同時(shí),也對其他節(jié)點(diǎn)產(chǎn)生影響,如一個(gè)異?；虿粌H影響自身介導(dǎo)的效應(yīng),而且還可通過網(wǎng)絡(luò)連接影響其他基因所介導(dǎo)的效應(yīng)。故生物分子網(wǎng)絡(luò)不僅刻畫了病證的分子本質(zhì),而且還為研究多分子之間的復(fù)雜調(diào)控關(guān)系提供了可能,彌補(bǔ)了單純研究單一分子孤立行為的不足。近年來,生物分子網(wǎng)絡(luò)在病證相關(guān)基因和藥物靶點(diǎn)的預(yù)測分析上得到了有效的應(yīng)用。在上述網(wǎng)絡(luò)特點(diǎn)的基礎(chǔ)上,整合病證表型和藥物等多層次、多類型信息,提出符合臨床醫(yī)學(xué)意義的假設(shè),建立基于網(wǎng)絡(luò)的預(yù)測方法,已經(jīng)在病證生物學(xué)基礎(chǔ)和藥物開發(fā)領(lǐng)域取得了具有臨床轉(zhuǎn)化價(jià)值的發(fā)現(xiàn)。例如,在病證生物學(xué)基礎(chǔ)研究方面,根據(jù)“相似病證表型相關(guān)分子在網(wǎng)絡(luò)上具有模塊性”的假設(shè),開發(fā)出疾病基因推斷方法(correlatingproteininteractionnetworkandphenotypenetworktopredictdiseasegenes,CIPHER),成功預(yù)測了乳腺癌等眾多疾病的致病基因,并鑒定出對乳腺癌等疾病具有協(xié)同作用的基因組合。在藥物開發(fā)方面,網(wǎng)絡(luò)藥理學(xué)在全面理解藥物的靶點(diǎn)和脫靶點(diǎn)效應(yīng)、藥理作用、毒副作用、藥物靶標(biāo)預(yù)測、藥物組合預(yù)測等方面發(fā)揮了重要作用。因此,將基于網(wǎng)絡(luò)的方法應(yīng)用于中醫(yī)藥轉(zhuǎn)化醫(yī)學(xué)研究可能成為一種溝通中醫(yī)基礎(chǔ)研究和臨床實(shí)踐的行之有效的手段。3基于分子網(wǎng)絡(luò)的中醫(yī)轉(zhuǎn)化醫(yī)學(xué)研究3.1其他生物分子網(wǎng)絡(luò)的研究機(jī)體生物分子網(wǎng)絡(luò)失衡是導(dǎo)致中醫(yī)證候發(fā)生發(fā)展的分子基礎(chǔ),臨床上中醫(yī)“證”的出現(xiàn)則是分子網(wǎng)絡(luò)失衡的表現(xiàn)形式。不同功能的生物分子失調(diào)控決定了失衡網(wǎng)絡(luò)的不同特征,主要包括網(wǎng)絡(luò)中分子的變化性質(zhì)(上調(diào)下調(diào)、刺激抑制)、強(qiáng)度、時(shí)程、關(guān)聯(lián)等因素的組合構(gòu)成了網(wǎng)絡(luò)的失衡,這些不同特征進(jìn)而導(dǎo)致了中醫(yī)證候表現(xiàn)的不同,例如,寒熱證候之不同?！昂?、熱”是中醫(yī)辨別疾病性質(zhì)的兩個(gè)重要綱領(lǐng),直接反映了機(jī)體陰陽的偏盛與偏衰。近年來,使用生物分子網(wǎng)絡(luò)已對寒熱證的生物學(xué)本質(zhì)進(jìn)行了多方面的探索性研究。例如,Li等提出一種基于文獻(xiàn)挖掘和組學(xué)數(shù)據(jù)融合的病證特定生物分子網(wǎng)絡(luò)的構(gòu)建方法,以寒證、熱證為對象,構(gòu)建了寒證、熱證生物分子網(wǎng)絡(luò),同時(shí)將兩個(gè)網(wǎng)絡(luò)中的生物分子(基因或化學(xué)遞質(zhì))映射至神經(jīng)內(nèi)分泌免疫的分子網(wǎng)絡(luò)中,并建立了一種“拓?fù)錅囟取钡木W(wǎng)絡(luò)失衡度量方法,分析發(fā)現(xiàn)了寒證、熱證的兩種生物學(xué)特征:寒證網(wǎng)絡(luò)的分子以激素的功能模塊為主,熱證網(wǎng)絡(luò)的分子以細(xì)胞因子的功能模塊為主,神經(jīng)遞質(zhì)功能模塊共同分布于寒、熱證網(wǎng)絡(luò),該研究初步給出了寒熱證候的分子依據(jù)。結(jié)果提示,機(jī)體生物網(wǎng)絡(luò)的失衡狀態(tài)能夠較好地反映中醫(yī)證候的生物學(xué)基礎(chǔ)。此外,在上述研究基礎(chǔ)上,進(jìn)一步提出證候研究的一種新思路,即以分子網(wǎng)絡(luò)平衡觀點(diǎn)來闡釋證候生物學(xué)本質(zhì),并利用網(wǎng)絡(luò)關(guān)鍵節(jié)點(diǎn)來發(fā)現(xiàn)證候的生物標(biāo)志物。例如,從慢性胃炎典型的寒證、熱證患者中,發(fā)現(xiàn)了寒證、熱證存在能量代謝與免疫調(diào)節(jié)網(wǎng)絡(luò)失衡的兩種基因表達(dá)模式,進(jìn)而通過驗(yàn)證網(wǎng)絡(luò)關(guān)鍵節(jié)點(diǎn),發(fā)現(xiàn)了寒熱證患者的生物標(biāo)志,且寒熱證的生物標(biāo)志物在淺表性胃炎到萎縮性胃炎過程中基本穩(wěn)定。同時(shí),還首次開展了中醫(yī)寒熱證候的舌苔微生物組研究,對慢性胃炎寒、熱證患者和正常人的舌苔微生物組進(jìn)行了高通量測序和生物信息學(xué)分析,發(fā)現(xiàn)舌苔微生物群落是區(qū)分寒、熱證患者的一種新型生物標(biāo)志,并構(gòu)建出了寒、熱證相關(guān)的舌苔微生物網(wǎng)絡(luò)。這些結(jié)果都表明,寒熱證候的形成具有特定的分子網(wǎng)絡(luò)基礎(chǔ),是分子網(wǎng)絡(luò)失衡的結(jié)果。3.2網(wǎng)絡(luò)靶標(biāo)思想中藥方劑是一個(gè)復(fù)雜化學(xué)體系,中醫(yī)證候是一個(gè)復(fù)雜生物系統(tǒng)。如何考慮這兩方面的關(guān)聯(lián),是理解方劑多靶點(diǎn)、弱干預(yù)、整體調(diào)節(jié)等特點(diǎn)的關(guān)鍵。面對這一問題,我們在病證生物分子網(wǎng)絡(luò)研究的基礎(chǔ)上進(jìn)一步提出了“網(wǎng)絡(luò)靶標(biāo)”的構(gòu)想,具體而言,即以病證生物分子網(wǎng)絡(luò)的核心環(huán)節(jié)為靶標(biāo),通過衡量方藥成分的靶標(biāo)譜與病證分子網(wǎng)絡(luò)關(guān)鍵環(huán)節(jié)的關(guān)系,發(fā)現(xiàn)中藥方劑的藥效物質(zhì)及其作用機(jī)制;通過分析方劑所含成分的靶標(biāo)在網(wǎng)絡(luò)上的分布規(guī)律,探索藥性、君臣佐使、七情合和等方劑特色內(nèi)涵的網(wǎng)絡(luò)特征;進(jìn)一步地利用這種網(wǎng)絡(luò)特征來預(yù)測組方用藥的臨床生物標(biāo)志,并利用所發(fā)現(xiàn)的規(guī)律來進(jìn)行組方用藥的理性設(shè)計(jì)。目前,網(wǎng)絡(luò)靶標(biāo)思想在中藥方劑現(xiàn)代研究的多個(gè)領(lǐng)域都取得發(fā)現(xiàn)。例如,新安醫(yī)學(xué)治療類風(fēng)濕性關(guān)節(jié)炎(rheumatoidarthritis,RA)的代表性方劑清絡(luò)飲中的抗炎、抗血管新生活性成分及成分組合的確定,首先利用基于網(wǎng)絡(luò)藥理學(xué)的靶標(biāo)推斷方法預(yù)測清絡(luò)飲中每個(gè)成分的靶標(biāo)譜,然后對靶標(biāo)譜進(jìn)行主成分分析以確定清絡(luò)飲所含成分在作用機(jī)制上的異同,最后利用協(xié)同藥物組合的預(yù)測方法鑒定清絡(luò)飲中對血管新生、炎性反應(yīng)、免疫調(diào)節(jié)等RA不同病理過程發(fā)揮協(xié)同干預(yù)作用的成分組合。此外,還有蔓荊子黃素等中藥天然產(chǎn)物靶標(biāo)的確定、六味地黃丸作用于多種疾病的共同網(wǎng)絡(luò)靶標(biāo)揭示異病同治的原理等研究工作,皆表明從生物網(wǎng)絡(luò)的角度能夠較好地理解中藥復(fù)雜化學(xué)體系與病證復(fù)雜生物系統(tǒng)的相互作用,從而為解釋中藥方劑的作用機(jī)制提供一定的科學(xué)依據(jù)。同時(shí),深入發(fā)掘中醫(yī)組方用藥的經(jīng)驗(yàn)與特色,也有助于推動(dòng)復(fù)雜疾病的組合用藥、個(gè)性化用藥研究。4orro-3.3indexhacines網(wǎng)絡(luò)藥理學(xué)用于中醫(yī)藥轉(zhuǎn)化醫(yī)學(xué)研究是一個(gè)既傳統(tǒng)又年輕的領(lǐng)域,這不僅要求該領(lǐng)域的研究思路要符合中醫(yī)理論與實(shí)踐,而且在應(yīng)用過程中還面臨諸多挑戰(zhàn)?；谏锓肿泳W(wǎng)絡(luò)的系統(tǒng)分析方法與中醫(yī)學(xué)的思維與實(shí)踐存在交匯之處,有效彌補(bǔ)了中醫(yī)基礎(chǔ)研究與臨床轉(zhuǎn)化的溝壑。我們相信,隨著信息學(xué)與醫(yī)學(xué)生命科學(xué)交叉研究的深入,從網(wǎng)絡(luò)和信息的整體性視角探索中醫(yī)藥奧秘成為可能。將以“整體”為特點(diǎn)的中醫(yī)藥和以“系統(tǒng)”為朝向的當(dāng)今醫(yī)藥研究有效地銜接起來,不僅能夠?yàn)榻沂局嗅t(yī)藥科學(xué)原理、加速中醫(yī)藥現(xiàn)代化進(jìn)程起到重要支撐作用,而且有望為整個(gè)醫(yī)學(xué)和藥物研究的發(fā)展也做出原創(chuàng)性貢獻(xiàn)。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”O(jiān)mics“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內(nèi)科醫(yī)學(xué)專業(yè)素質(zhì)分析二級內(nèi)科醫(yī)學(xué)植根基質(zhì)可靠射擊3.1u2004范圍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通過轉(zhuǎn)色規(guī)劃可部分天氣形貌保證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