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        中藥復(fù)方逆轉(zhuǎn)肝纖維化及早期肝硬化的作用機(jī)制

        2024-12-31 00:00:00張鵬鄭世豪茍思媛謝金池楊先照葉永安
        臨床肝膽病雜志 2024年9期
        關(guān)鍵詞:肝纖維化中草藥肝硬化

        通信作者:葉永安,yonganye2022@163.com(ORCID:0000-0001-9765-4665);張鵬,zp891223@126.com(ORCID:0000-0003-0215-3572)

        摘要:肝纖維化、肝硬化是多種慢性肝病進(jìn)展后的共同結(jié)局。研究表明,肝纖維化及一定程度的肝硬化是可以逆轉(zhuǎn)的。中藥復(fù)方逆轉(zhuǎn)肝纖維化、早期肝硬化療效確切,但作用機(jī)制尚未完全明確。本文通過梳理國內(nèi)外相關(guān)文獻(xiàn),總結(jié)了中藥復(fù)方起效涉及的6個(gè)主要機(jī)制表型(即抑制肝臟炎癥與調(diào)控免疫,調(diào)控肝星狀細(xì)胞活化及細(xì)胞外基質(zhì)生成,促進(jìn)細(xì)胞外基質(zhì)降解,逆轉(zhuǎn)肝竇毛細(xì)血管化,調(diào)控肝臟細(xì)胞再生以及調(diào)節(jié)腸道菌群),并分析了各個(gè)表型領(lǐng)域研究的進(jìn)展與不足。未來中藥復(fù)方研究可圍繞上述表型進(jìn)行實(shí)驗(yàn)探索和驗(yàn)證,對有確切作用的表型上下游信號進(jìn)一步深入探究。本文旨在幫助厘清中藥復(fù)方療效機(jī)制研究的方向和思路,為闡明中藥復(fù)方科學(xué)實(shí)質(zhì)提供依據(jù)。

        關(guān)鍵詞:肝纖維化;肝硬化;中草藥

        基金項(xiàng)目:國家自然科學(xué)基金青年科學(xué)基金(82104810)

        The mechanism of compound traditional Chinese medicine prescriptions in reversal of liver fibrosis and early livercirrhosis

        ZHANG Peng1,2,ZHENG Shihao3a,GOU Siyuan3a,XIE Jinchi2,YANG Xianzhao1,3b,YE Yongan1,3a.(1.Institute of Liver Disease,Beijing University of Chinese Medicine,Beijing 100007,China;2.Department of Gastroenterology and Hepatology,Dongfang Hospital,Beijing University of Chinese Medicine,Beijing 100078,China;3.a.Department of Gastroenterology,b.Department of Infectious Diseases,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing 100007,China)

        Corresponding authors:YE Yongan,yonganye2022@163.com(ORCID:0000-0001-9765-4665);ZHANG Peng,zp891223@126.com(ORCID:0000-0003-0215-3572)

        Abstract:Liver fibrosis and cirrhosis are the common outcomes of various chronic liver diseases after progression,and studies have shown that liver fibrosis and early liver cirrhosis can be reversed.Compound traditional Chinese medicine prescriptions have a marked therapeutic effect in reversing liver fibrosis and early liver cirrhosis,and their mechanism of action remains unclear.By reviewing related articles in China and globally,this article summarizes the six main phenotypic mechanisms involved in the efficacy of compound traditional Chinese medicine prescriptions,i.e.,inhibiting liver inflammation and regulating liver immune response,regulating hepatic stellate cell activation and extracellular matrix(ECM)generation,promoting ECM degradation,reversing hepatic sinusoidal capillarization,regulating hepatocyte regeneration,and regulating gut microbiota,and in addition,this article also analyzes the advances and shortcomings in current studies on each phenotype.Future studies on compound traditional Chinese medicine prescriptions should focus on experimental exploration and rescue experiments to verify the above phenotypes and further explore the upstream and downstream signaling pathways with a marked effect.This article aims to help clarify the direction and ideas of studies on the therapeutic mechanism of compound traditional Chinese medicine prescriptions,in order to provide abasis for clarifying the scientific essence of compound traditional Chinese medicine prescriptions.

        Key words:Liver Fibrosis;Liver Cirrhosis;Drugs,Chinese Herbal

        Research funding:Youth Science Foundation of National Natural Science Foundation of China(82104810)

        肝纖維化、肝硬化是不同原因慢性肝病在走向終末結(jié)局過程中共同經(jīng)歷的疾病階段。研究[1]表明,肝纖維化及一定程度的肝硬化是可以逆轉(zhuǎn)的,但現(xiàn)代醫(yī)學(xué)缺少抗肝纖維化、肝硬化的特效治療方案。在長期臨床實(shí)踐中,中醫(yī)藥逆轉(zhuǎn)肝硬化、肝纖維化具有良好療效[2-4],值得深入挖掘與研究。與當(dāng)前中藥單體研究方興未艾相比,中藥復(fù)方由于其組成、機(jī)制的復(fù)雜性,相關(guān)機(jī)制研究處于瓶頸階段。為了更好地開展未來研究,本文梳理了中藥復(fù)方抗肝纖維化、早期肝硬化機(jī)制研究的現(xiàn)狀,總結(jié)了6個(gè)主要機(jī)制表型,旨在為未來探索中藥復(fù)方療效機(jī)制提供思路與借鑒。

        1抑制肝臟炎癥與調(diào)控免疫

        肝臟炎癥的發(fā)生是炎癥感受細(xì)胞識別炎癥誘導(dǎo)物并釋放炎癥介質(zhì)的結(jié)果,包括巨噬細(xì)胞、中性粒細(xì)胞等在內(nèi)的免疫細(xì)胞是最常見的炎癥感受細(xì)胞,而免疫細(xì)胞釋放的細(xì)胞因子也是最主要的炎癥介質(zhì)?,F(xiàn)代醫(yī)學(xué)通過病因治療及保肝藥的應(yīng)用對肝臟炎癥有較好的治療作用,最新研究也針對靶向調(diào)控免疫細(xì)胞及免疫因子等進(jìn)行了諸多探索。研究[5-8]表明,包括肝臟內(nèi)駐留和募集的巨噬細(xì)胞、中性粒細(xì)胞、T淋巴細(xì)胞、固有淋巴細(xì)胞、樹突狀細(xì)胞(DC)、自然殺傷細(xì)胞(NK細(xì)胞)等在內(nèi)的多種免疫細(xì)胞,在不同疾病狀態(tài)和不同位置的肝組織中其功能活動(dòng)存在較大的異質(zhì)性。通過靶向已發(fā)現(xiàn)的信號通路及靶點(diǎn)調(diào)控免疫細(xì)胞表型,或嘗試將特定表型的免疫細(xì)胞過繼轉(zhuǎn)移,都是現(xiàn)代醫(yī)學(xué)研究逆轉(zhuǎn)早期肝硬化、肝纖維化的熱點(diǎn),但上述治療尚未實(shí)現(xiàn)臨床應(yīng)用[9-11]。

        中藥復(fù)方在抑制肝臟炎癥和調(diào)控免疫方面具有確切的作用。上海中醫(yī)藥大學(xué)研發(fā)的扶正化瘀方經(jīng)過多次臨床研究[12]證實(shí),對于不同病因引起的肝纖維化、肝硬化,具有降低轉(zhuǎn)氨酶水平、抑制肝損傷的作用。多項(xiàng)體內(nèi)及體外實(shí)驗(yàn)[13-18]表明,扶正化瘀膠囊及其主要成分可以通過保護(hù)肝細(xì)胞免受脂質(zhì)過氧化損傷,減少炎癥小體活化和肝細(xì)胞凋亡等實(shí)現(xiàn)緩解肝臟炎癥的作用,同時(shí)也可以通過調(diào)控肝內(nèi)巨噬細(xì)胞極化,上調(diào)NK細(xì)胞數(shù)量及活化程度等方式調(diào)節(jié)肝臟免疫微環(huán)境,逆轉(zhuǎn)肝纖維化。同樣對巨噬細(xì)胞極化有影響的還有經(jīng)典名方四物湯[19]、經(jīng)驗(yàn)方芪甲柔肝方等[20],后者可能通過調(diào)節(jié)JAK1/STAT6-microRNA-23a負(fù)反饋抑制M2型巨噬細(xì)胞極化,逆轉(zhuǎn)肝纖維化。莫嬋等[21]觀察中藥復(fù)方保肝寧逆轉(zhuǎn)肝纖維化的作用可能與促進(jìn)肝臟中DC表型成熟,刺激T淋巴細(xì)胞增殖能力增強(qiáng)有關(guān)。臨床研究、基礎(chǔ)研究[3,22-23]同樣證明,復(fù)方鱉甲軟肝片、安絡(luò)化纖丸等為代表的上市中藥復(fù)方也能夠通過減輕肝臟炎癥逆轉(zhuǎn)肝纖維化、肝硬化,但其調(diào)控肝臟炎癥及免疫的機(jī)制尚待進(jìn)一步探索。

        現(xiàn)有研究初步證實(shí)了中藥復(fù)方調(diào)控肝臟炎癥與免疫的作用,但研究結(jié)果缺乏挽救實(shí)驗(yàn)驗(yàn)證?,F(xiàn)代醫(yī)學(xué)通過免疫細(xì)胞過繼轉(zhuǎn)移的治療思路也可以借鑒用于中藥復(fù)方調(diào)控免疫細(xì)胞表型的作用驗(yàn)證。未來同樣需要在分子、細(xì)胞等層面,結(jié)合現(xiàn)代醫(yī)學(xué)最新成果,對中藥復(fù)方調(diào)控免疫細(xì)胞、免疫因子水平的上游機(jī)制進(jìn)行更深入的探索。

        2調(diào)控肝星狀細(xì)胞(HSC)活化及細(xì)胞外基質(zhì)(ECM)生成

        以HSC為代表的肝臟成纖維細(xì)胞持續(xù)活化以及ECM的過度生成是肝纖維化、肝硬化發(fā)展的關(guān)鍵環(huán)節(jié)。現(xiàn)代醫(yī)學(xué)研究表明,HSC的活化與受損的肝細(xì)胞、肝竇內(nèi)皮細(xì)胞(liver sinusoidal endothelial cell,LSEC)、巨噬細(xì)胞等釋放的旁分泌信號直接相關(guān),HSC也是肝纖維化、肝硬化階段ECM生成的主要來源。近年來,研究[24-28]發(fā)現(xiàn)了很多參與HSC激活和維持活化狀態(tài)的靶蛋白和靶通路,并開展了借助于納米多肽等載體靶向抑制HSC活化、增殖,促使HSC表型轉(zhuǎn)化,促進(jìn)HSC壞死、衰老、凋亡的諸多研究,但尚未研發(fā)出有效的治療藥物。

        研究表明,調(diào)控HSC的活化狀態(tài)并減少ECM的生成同樣是中藥復(fù)方起效的機(jī)制之一。上海中醫(yī)藥大學(xué)團(tuán)隊(duì)針對扶正化瘀方逆轉(zhuǎn)肝纖維化的多項(xiàng)機(jī)制研究[29-32]發(fā)現(xiàn),該復(fù)方能在體內(nèi)及體外減少α平滑肌肌動(dòng)蛋白的表達(dá),抑制HSC的活化,其機(jī)制可能與調(diào)節(jié)過氧化物酶體增殖物激活受體γ、CYP4A12等靶蛋白,調(diào)控TGF-β1/Smads、表皮生長因子受體等通路,以及影響NK細(xì)胞殺傷功能有關(guān)。安絡(luò)化纖丸、復(fù)方鱉甲軟肝片、經(jīng)驗(yàn)方金三莪同樣被發(fā)現(xiàn)可能通過調(diào)節(jié)TGF-β1/Smads通路抑制HSC激活[22,24,33]。Shao等[34]體外實(shí)驗(yàn)發(fā)現(xiàn)加味桃核承氣湯可能抑制肝巨噬細(xì)胞Notch通路的表達(dá)從而引起巨噬細(xì)胞代謝重編程,進(jìn)而抑制HSC活化。筆者團(tuán)隊(duì)的經(jīng)驗(yàn)方抗纖抑癌方同樣表現(xiàn)出能減少α-平滑肌肌動(dòng)蛋白表達(dá),抑制HSC活化,并減少膠原合成的作用[35-36]。

        現(xiàn)有研究初步證實(shí)了中藥復(fù)方能通過調(diào)控TGF-β1/Smads等上游經(jīng)典信號通路抑制HSC活化并減少ECM生成的作用,但研究結(jié)果缺少對關(guān)鍵蛋白、通路過表達(dá)和沉默的驗(yàn)證,科學(xué)依據(jù)不足。未來研究應(yīng)立足于經(jīng)典通路和研究熱點(diǎn),通過結(jié)合單細(xì)胞測序、多組學(xué)檢測等先進(jìn)技術(shù),在表觀遺傳修飾、不同細(xì)胞死亡方式調(diào)控、HSC與不同細(xì)胞串?dāng)_等方面進(jìn)一步探索該表型的機(jī)制。

        3促進(jìn)肝臟ECM降解

        ECM主要由膠原以及蛋白多糖、糖蛋白等組成,其降解依賴基質(zhì)金屬蛋白酶(MMP)、絲氨酸蛋白酶類及半胱氨酸蛋白酶類等,其中MMP起關(guān)鍵作用。MMP一旦被激活就會(huì)受到基質(zhì)金屬蛋白酶組織抑制因子(tissue inhibitor of metalloproteinase,TIMP)的抑制,以保持二者的動(dòng)態(tài)平衡。HSC、LSEC、巨噬細(xì)胞等均可能參與了在肝纖維化、肝硬化中MMP/TIMP的表達(dá)失衡[37-38]。此外,ECM中不同成分的交聯(lián),尤其是膠原纖維和彈性纖維等之間的交聯(lián),與纖維化逆轉(zhuǎn)的難度密切相關(guān)。賴氨酰氧化酶(lysyl oxidase,LOX)家族成員在ECM交聯(lián)中起關(guān)鍵作用[39],靶向LOX家族成員也可能是促進(jìn)ECM降解的重要環(huán)節(jié)。

        體內(nèi)外實(shí)驗(yàn)[31,35,40-42]表明,包括扶正化瘀方、復(fù)方鱉甲軟肝片、安絡(luò)化纖丸、六味五靈片、復(fù)方861合劑等在內(nèi)的中藥復(fù)方能夠?qū)MP/TIMP平衡起到調(diào)節(jié)作用,從而促進(jìn)ECM降解。其中,上調(diào)MMP-9、MMP-13,下調(diào)TIMP-1、TIMP-2水平是上述實(shí)驗(yàn)中最常見的作用機(jī)制,而關(guān)于MMP-2的調(diào)節(jié)作用則不盡相同。筆者團(tuán)隊(duì)[43]也發(fā)現(xiàn)經(jīng)驗(yàn)方抗纖抑癌方能促進(jìn)膠原纖維、彈性纖維等ECM降解,上調(diào)MMP-1表達(dá),下調(diào)MMP-2、TIMP-1表達(dá),部分結(jié)果尚未發(fā)表。盡管上述研究表明中藥復(fù)方對MMP/TIMP的平衡可能存在調(diào)節(jié)作用,但目前研究均缺少挽救實(shí)驗(yàn)驗(yàn)證,也沒有從分子、細(xì)胞等不同層次對影響MMP/TIMP平衡的上游機(jī)制深入探究。未來研究也可以聚焦中藥復(fù)方調(diào)節(jié)LOX家族成員影響ECM交聯(lián)的機(jī)制進(jìn)行探索。

        4逆轉(zhuǎn)肝竇毛細(xì)血管化

        在肝纖維化、肝硬化發(fā)生發(fā)展過程中,ECM在竇周周隙的沉積導(dǎo)致LSEC連續(xù)的基底膜形成,窗孔喪失,阻礙了肝細(xì)胞與血液的物質(zhì)交換。LSEC的毛細(xì)血管化在肝損傷早期即可發(fā)生,并先于HSC激活以及肝纖維化形成出現(xiàn)。血管內(nèi)皮生長因子(VEGF)通過一氧化氮依賴和非依賴的方式影響LSEC表型是肝竇毛細(xì)血管化的關(guān)鍵機(jī)制之一,其他機(jī)制可能還包括熱休克蛋白90乙酰化、Hedgehog信號通路、Notch信號通路、LSEC自噬等[44]。

        扶正化瘀方、復(fù)方861合劑、下瘀血湯、血府逐瘀湯等具有活血化瘀作用的中藥復(fù)方干預(yù)肝纖維化動(dòng)物模型后,通過透射電鏡等方法可以觀察到具有改善肝竇內(nèi)皮細(xì)胞失窗孔化、恢復(fù)肝血竇結(jié)構(gòu)的作用[45-47]。中藥復(fù)方逆轉(zhuǎn)肝竇毛細(xì)血管化的作用機(jī)制可能與抑制VEGF通路、Notch通路有關(guān)。未來研究可結(jié)合現(xiàn)代醫(yī)學(xué)先進(jìn)的微血管活體成像技術(shù),進(jìn)一步對中藥復(fù)方改善肝竇毛細(xì)血管化的過程進(jìn)行深入探索。

        5調(diào)控肝臟細(xì)胞再生

        肝臟實(shí)質(zhì)細(xì)胞具有再生能力,肝再生的正常與否對肝臟疾病預(yù)后具有重要作用。在肝纖維化、肝硬化進(jìn)程中,肝臟實(shí)質(zhì)細(xì)胞正常再生的過程會(huì)受到干擾。研究[48]表明,端粒酶高表達(dá)的肝細(xì)胞、混合肝細(xì)胞、源自肝細(xì)胞的Sox9+肝祖細(xì)胞樣細(xì)胞、肝卵圓細(xì)胞和膽管上皮細(xì)胞均可發(fā)生肝細(xì)胞再生,HSC也存在通過間質(zhì)-上皮轉(zhuǎn)型轉(zhuǎn)化為肝細(xì)胞、膽管細(xì)胞、血管細(xì)胞等的可能,再生細(xì)胞來源可能取決于損傷的類型。血管緊張素2、TGF-β、血管內(nèi)皮細(xì)胞生長因子受體2、人血管生成素受體酪氨酸激酶2、趨化因子受體7、IL-6、肝細(xì)胞生長因子、成纖維細(xì)胞生長因子、Notch信號通路、Wnt信號通路和Hippo信號通路等均可能在調(diào)控肝再生過程中起到調(diào)控作用[48]?,F(xiàn)代醫(yī)學(xué)已探索通過外源性補(bǔ)充可促進(jìn)再生細(xì)胞改善肝纖維化、肝硬化,并利用多孔微球等載體提高干細(xì)胞回輸肝臟比例[49-50],但由于調(diào)控肝再生的機(jī)制復(fù)雜,單一靶點(diǎn)或單一細(xì)胞治療難以兼顧整個(gè)微環(huán)境的網(wǎng)絡(luò)信號。中藥復(fù)方具有多靶點(diǎn)、網(wǎng)絡(luò)化調(diào)節(jié)的特點(diǎn)和優(yōu)勢,可能是調(diào)控肝實(shí)質(zhì)細(xì)胞再生的有效方法。

        目前中藥復(fù)方調(diào)控肝再生的研究較少,結(jié)果初步表明了中藥復(fù)方具有輔助干細(xì)胞向肝臟歸巢、向肝細(xì)胞分化等作用。扶正化瘀方可能通過調(diào)節(jié)p38 MAPK信號通路,上調(diào)體外培養(yǎng)的HSC表達(dá)骨形態(tài)發(fā)生蛋白7,下調(diào)TGF-β1,促進(jìn)間質(zhì)-上皮轉(zhuǎn)型發(fā)生,也有研究報(bào)道該方在體外能促進(jìn)人胚胎干細(xì)胞向肝細(xì)胞分化[51-52]。復(fù)方861合劑在體外也具有促使大鼠肝臟卵圓細(xì)胞系WB-F344向肝細(xì)胞分化的作用[53]。鱉甲煎丸、一貫煎聯(lián)合骨髓間充質(zhì)干細(xì)胞(BMSC)移植治療肝纖維化大鼠后均有可能幫助BMSC歸巢至肝臟起到增效作用[54-55],鱉甲煎丸的作用可能與調(diào)控SDF-1/CRCX4(基質(zhì)細(xì)胞衍生因子-1/特異性受體CXC趨化因子受體4)軸有關(guān)。未來研究可進(jìn)一步重點(diǎn)探索中藥復(fù)方在肝再生過程中可發(fā)揮作用的幾個(gè)環(huán)節(jié),如調(diào)控非實(shí)質(zhì)細(xì)胞表達(dá)相關(guān)再生信號,肝細(xì)胞、祖細(xì)胞、卵圓細(xì)胞等接受、傳導(dǎo)信號,肝再生信號終止等。

        6調(diào)控腸道菌群

        近年來隨著腸-肝軸的提出,腸道微生態(tài)在肝纖維化、肝硬化中的作用逐漸得到重視。腸道微生物及其代謝產(chǎn)物可通過門靜脈循環(huán)及淋巴系統(tǒng)進(jìn)入肝臟,對肝內(nèi)免疫細(xì)胞等產(chǎn)生影響,肝臟可以通過合成膽汁酸并排入腸道,對腸道微生態(tài)產(chǎn)生調(diào)控作用。研究[56-59]發(fā)現(xiàn),肝纖維化、肝硬化患者腸道菌群豐度下降,伴有小腸細(xì)菌過度生長,有益菌比例減少,有害菌比例升高,且這種改變與肝硬化的病因無關(guān)。有害菌及脂多糖等代謝產(chǎn)物進(jìn)入肝臟,由于肝竇毛細(xì)血管化、肝臟巨噬細(xì)胞等免疫屏障功能下降,加劇了肝內(nèi)的促炎環(huán)境。另一方面,肝纖維化、肝硬化患者膽汁酸分泌及排泄減少,影響法尼酯X受體軸,加劇腸道菌群移位[60]。但腸道微生態(tài)改變與肝纖維化、肝硬化進(jìn)展的因果關(guān)系目前尚無定論。

        中藥復(fù)方口服后會(huì)對腸道菌群產(chǎn)生影響,調(diào)節(jié)腸道微生態(tài)在中藥復(fù)方逆轉(zhuǎn)肝纖維化、肝硬化中起到的作用也受到了關(guān)注。多項(xiàng)研究[61-63]表明,大黃蟄蟲丸、當(dāng)歸芍藥散、茵陳五苓散等經(jīng)典方劑均可能改善肝纖維化動(dòng)物模型的腸道屏障功能,恢復(fù)腸道菌群豐度,部分有益菌的豐度升高,部分有害菌的豐度下降,并伴有膽汁酸等多種代謝物水平的變化。未來,相關(guān)研究可通過菌群移植實(shí)驗(yàn)驗(yàn)證腸道微生態(tài)改變在中藥復(fù)方療效中的必要性,并結(jié)合現(xiàn)代醫(yī)學(xué)最新提出的腸-肝-免疫軸理論[64],將腸道微生態(tài)改變與肝臟炎癥、肝內(nèi)免疫調(diào)控等機(jī)制進(jìn)行整合探索。

        7不足與展望

        一直以來,闡明中藥復(fù)方機(jī)制研究被認(rèn)為是中醫(yī)藥領(lǐng)域重大科學(xué)問題之一,中藥復(fù)方成分和機(jī)制的復(fù)雜性猶如黑箱困擾著科研工作者。本文在現(xiàn)代醫(yī)學(xué)對肝纖維化、肝硬化發(fā)生發(fā)展機(jī)制認(rèn)識的基礎(chǔ)上,系統(tǒng)總結(jié)了中藥復(fù)方逆轉(zhuǎn)肝纖維化、早期肝硬化可能涉及到的6個(gè)機(jī)制表型(圖1),即抑制肝臟炎癥及調(diào)控免疫反應(yīng),調(diào)控HSC活化和ECM生成,促進(jìn)ECM降解,逆轉(zhuǎn)肝竇毛細(xì)血管化,恢復(fù)肝再生能力與調(diào)控腸道微生態(tài)。表型之間可相互聯(lián)系、相互影響,如肝臟免疫細(xì)胞可識別肝細(xì)胞損傷及腸道菌群釋放的信號,調(diào)節(jié)HSC的狀態(tài),參與ECM的降解調(diào)控;LSEC毛細(xì)血管化也會(huì)影響肝臟免疫細(xì)胞、HSC等狀態(tài)和功能;上述細(xì)胞也均參與了肝再生信號的調(diào)控。未來研究可針對上述表型機(jī)制進(jìn)行實(shí)驗(yàn)驗(yàn)證,并對有確切作用的表型上下游信號進(jìn)一步深入探索。

        目前研究表明,中藥復(fù)方對上述6個(gè)機(jī)制表型均可能起到一定作用,但相關(guān)研究還存在以下問題:(1)調(diào)控腸道菌群、逆轉(zhuǎn)肝竇毛細(xì)血管化、調(diào)控肝再生等表型的研究較少,相關(guān)研究在確認(rèn)中藥復(fù)方調(diào)控表型有效時(shí)缺少挽救實(shí)驗(yàn)驗(yàn)證,也有很多研究在表型有效基礎(chǔ)上缺少對上下游機(jī)制的探索;(2)中藥復(fù)方常以多靶點(diǎn)、多環(huán)節(jié)、多維度方式起效,但目前研究多局限于一個(gè)或兩個(gè)表型、機(jī)制和通路,桎梏了研究方向,缺少對不同表型、機(jī)制、細(xì)胞、分子通路互作、串?dāng)_的探索;(3)目前研究局限于經(jīng)驗(yàn)方劑或經(jīng)典方劑的機(jī)制研究,對中醫(yī)理論結(jié)合不足,忽視了對中醫(yī)理論實(shí)質(zhì)的闡釋;(4)在臨床前研究的基礎(chǔ)上缺少結(jié)合臨床樣本進(jìn)行驗(yàn)證。

        針對上述存在的問題,筆者提出以下建議:(1)未來研究可利用過表達(dá)、基因敲除、基因沉默、加入阻斷劑或激動(dòng)劑、細(xì)胞過繼轉(zhuǎn)移、糞菌移植等方法驗(yàn)證表型及機(jī)制,并在表型實(shí)驗(yàn)的基礎(chǔ)上,結(jié)合多組學(xué)、單細(xì)胞測序、類器官、3D打印及微流控芯片模型等先進(jìn)實(shí)驗(yàn)技術(shù),篩選、探索調(diào)控該表型的上下游機(jī)制。(2)未來研究可基于系統(tǒng)生物學(xué)理論,整合不同層次、不同方法、不同學(xué)科,從“系統(tǒng)-系統(tǒng)”的層次認(rèn)識中藥復(fù)方的作用機(jī)制。具體而言,在研究中整合多組學(xué)測序、生物信息學(xué)、中藥化學(xué)物質(zhì)組學(xué)以及代謝動(dòng)力學(xué)等方法,揭示復(fù)方對不同表型、機(jī)制、細(xì)胞、分子通路互作、串?dāng)_的網(wǎng)絡(luò)機(jī)制。(3)研究可探索中醫(yī)治法與表型的相關(guān)性,如活血化痰作用與促進(jìn)ECM降解的關(guān)系,活血通絡(luò)治法與逆轉(zhuǎn)肝竇毛細(xì)血管化的相關(guān)性等。這需要在復(fù)方有效的基礎(chǔ)上進(jìn)行不同治法的拆方驗(yàn)證,有助于闡釋中醫(yī)治法理論的科學(xué)實(shí)質(zhì)。(4)利用中醫(yī)藥臨床病例資源,建立前瞻性肝纖維化、肝硬化患者隊(duì)列數(shù)據(jù)庫,獲得患者知情同意前提下,利用患者肝穿刺樣本及相關(guān)檢驗(yàn)結(jié)果驗(yàn)證臨床前研究的結(jié)果。

        綜上所述,本文總結(jié)了中藥復(fù)方逆轉(zhuǎn)肝纖維化、肝硬化可能涉及到的6個(gè)機(jī)制表型,針對相關(guān)表型進(jìn)行研究將有助于厘清中藥復(fù)方機(jī)制研究的方向和思路,為闡明中藥復(fù)方科學(xué)實(shí)質(zhì)提供依據(jù)。

        利益沖突聲明:本文不存在任何利益沖突。

        作者貢獻(xiàn)聲明:張鵬負(fù)責(zé)課題設(shè)計(jì),資料分析,撰寫論文;鄭世豪、茍思媛、謝金池、楊先照參與檢索文獻(xiàn)、修改論文;張鵬、葉永安擬定寫作思路并最后定稿。

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        收稿日期:2024-01-22;錄用日期:2024-02-21

        本文編輯:王瑩

        引 證 本 文 : ZHANG P, ZHENG SH, GOU SY, et al. The mechanism of compound traditional Chinese medicine prescriptions in reversal of liver fibrosis and early liver cirrhosis[J]. J Clin Hepatol, 2024, 40(9): 1873-1879.

        張鵬, 鄭世豪, 茍思媛, 等 . 中藥復(fù)方逆轉(zhuǎn)肝纖維化及早期肝硬化 的作用機(jī)制[J]. 臨床肝膽病雜志, 2024, 40(9): 1873-1879.

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