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中药有效成分及其复方防治非酒精性脂肪性肝病的现状与展望

潘雨晴 毛傲洁 于楚楚 胡义扬

潘雨晴, 毛傲洁, 于楚楚, 等. 中药有效成分及其复方防治非酒精性脂肪性肝病的现状与展望[J]. 临床肝胆病杂志, 2024, 40(10): 1933-1941. DOI: 10.12449/JCH241002.
引用本文: 潘雨晴, 毛傲洁, 于楚楚, 等. 中药有效成分及其复方防治非酒精性脂肪性肝病的现状与展望[J]. 临床肝胆病杂志, 2024, 40(10): 1933-1941. DOI: 10.12449/JCH241002.
PAN YQ, MAO AJ, YU CC, et al. Active components of traditional Chinese medicine and their compound prescriptions in prevention and treatment of nonalcoholic fatty liver disease: Current status and prospects[J]. J Clin Hepatol, 2024, 40(10): 1933-1941. DOI: 10.12449/JCH241002.
Citation: PAN YQ, MAO AJ, YU CC, et al. Active components of traditional Chinese medicine and their compound prescriptions in prevention and treatment of nonalcoholic fatty liver disease: Current status and prospects[J]. J Clin Hepatol, 2024, 40(10): 1933-1941. DOI: 10.12449/JCH241002.

中药有效成分及其复方防治非酒精性脂肪性肝病的现状与展望

DOI: 10.12449/JCH241002
基金项目: 

国家自然科学基金面上项目 (82174186)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:潘雨晴负责查阅文献,撰写论文;毛傲洁、于楚楚负责查阅文献;胡义扬负责拟定文章思路,修改并最终定稿。
详细信息
    通信作者:

    胡义扬, yyhuliver@163.com (ORCID: 0000-0001-9127-7002)

Active components of traditional Chinese medicine and their compound prescriptions in prevention and treatment of nonalcoholic fatty liver disease: Current status and prospects

Research funding: 

General Project of National Natural Science Foundation of China (82174186)

More Information
    Corresponding author: HU Yiyang, yyhuliver@163.com (ORCID: 0000-0001-9127-7002)
  • 摘要: 非酒精性脂肪性肝病(NAFLD)是目前全球患病率最高的慢性肝病,发病机制复杂,临床治疗手段局限。近20多年来,从中药中发现治疗NAFLD的有效成分以及能发挥多靶点综合作用的成分复方是研究热点之一。本文根据其化学成分,以黄酮类、酚类、萜类、生物碱类、皂苷类分类阐述具有治疗NAFLD前景的中药有效成分,以及具有配伍增效作用的有效成分复方,以期进一步为NAFLD药物治疗策略提供新思路。

     

  • 非酒精性脂肪性肝病(NAFLD)是以肝细胞脂肪过度堆积(肝脏中脂肪含量>5%)为主要特征的进行性疾病,其中约40%的患者会演变为非酒精性脂肪性肝炎(NASH)1,进而发展为进行性纤维化,同时约10%的NAFLD患者在确诊后10~20年内发生肝硬化和肝细胞癌2。如今NAFLD已成为全球最常见的慢性肝病,影响着全球30%的人口,预计2040年NAFLD患病率将高达55.7%3。然而,在治疗学上,目前唯一被美国食品药品监督管理局批准上市,用于治疗伴有肝纤维化的成人NASH患者的新药是甲状腺激素受体-β激动剂Resmetirom4,其临床有效率为29.9%(NASH消退,纤维化未恶化)。由此可见,NAFLD药物研发仍十分迫切。

    NAFLD对世界卫生健康的影响不断扩大,人们对其发病机制的阐述也愈发深刻,从经典的“二次打击”学说5,到认为脂质代谢、氧化应激、内质网应激、脂肪毒性、胰岛素抵抗和肠道微生物众多平行因素相互作用参与NAFLD发展的“多重打击”学说6,提示靶向NAFLD疾病进展中的多个环节可能是未来寻求治疗NAFLD研究方案的关键。

    中医药治疗NAFLD历史悠久且疗效显著7-8。近20多年来,从中药中发现治疗NAFLD的有效成分以及能发挥多靶点综合作用的成分复方是研究热点之一。在NAFLD药物临床试验中,中药有效成分白藜芦醇(NCT02216552)、姜黄素(NCT02908152)已完成临床Ⅲ期研究,而小檗碱(NCT03198572)被批准进入临床Ⅳ期研究9,表明中药有效成分治疗NAFLD具有良好前景。同时,近年来,不少研究以有效成分配伍组成而发挥中药多途径药理作用和配伍增效中药有效成分复方,展示出治疗NAFLD的良好新药研发潜力10-11。本文就治疗NAFLD的中药有效成分及中药有效成分复方进行综述,旨在为中医药防治NAFLD提供研究思路。

    表  1  治疗NAFLD的中药有效成分
    Table  1.  Effective components of traditional Chinese medicine for the treatment of NAFLD
    分类 有效成分 NAFLD模型构建 剂量 作用机制
    黄酮类 槲皮素12

    db/db小鼠;

    高糖和FFA诱导 HepG2细胞

    体内:50/100/150 mg/kg;

    体外:10/20/40 μmol/L

    mTOR/YY1↓

    CYP7A1↑

    水飞蓟宾13 HFD小鼠 100/300 mg/kg

    产SCFA菌↑:

    Blautia,Bacteroides,Akkermansia

    木犀草素14 HFD大鼠 HFD饮食含0.5%木犀草素

    ZO-1↑

    LPS↓TLR4/NF-κB↓

    葛根素16

    NASH小鼠、斑马鱼模型;

    FFA诱导HepG2细胞;

    LPS+INF-γ诱导RAW 264.7细胞

    小鼠:100 mg/kg;

    斑马鱼:100/200/400 μg/mL;细胞:20/40/80 μmol/L

    AMPK↑—mTOR↓—pULK-1—PAI-1↓—STAT3/HIF1α↓

    PI3K/AKT↑

    二氢杨梅素18

    HFD大鼠;

    PA诱导HepG2细胞

    体内:50/100/200 mg/kg;

    体外:10 μmol/L

    AMPK/PGC-1α↑

    PPARα↑

    山柰酚20

    db/db小鼠;

    油酸诱导HepG2细胞

    体内:50 mg/kg;

    体外:10-6/-7/-8 mol/L

    Sirt1/AMPK/PGC-1α↑

    ACC/FAS/SREBP1↓

    酚类 白藜芦醇21 HFD大鼠 50/100 mg/kg

    产SCFA菌↑:Ruminococcaceae、Lachnospiraceae

    产LPS菌↓:Desulfovibrio

    姜黄素22

    HFD大鼠;

    FFA诱导LSEC细胞、L02细胞

    体内:25/50/100 g/kg;

    体外:1/2/4/8/10 mol/L

    NF-κB↓

    PI3K/Akt/HIF-1α↓

    绿原酸23

    HFD小鼠;

    AML12细胞;THLE-2细胞

    体内:50 mg/kg;

    体外:12.5/25/50/100 μmol/L

    AXL/ERK/LKB1↓

    AMPK/ULK-1↑

    EGCG24

    HFD大鼠;

    LPS诱导Caco-2细胞

    体内:100/200 mg/kg;

    体外:25/50/75/100 μmol/L

    LPS/TLR4/NF-κB↓

    Nrf2—ZO-1/Occludin↑

    和厚朴酚25

    胆碱缺乏的高脂肪饮食小鼠;

    FFA诱导AML12细胞

    体内:2.5/10 mg/kg;

    体外:5/10 μmol/L

    SIRT3/AMPK↑

    维持线粒体功能

    萜类 栀子苷26

    tyloxapol诱导NAFLD模型小鼠;

    FFA诱导HepG2细胞

    体内:50/75/100 g/kg;

    体外:65/130/260 μmol/L

    Nrf2/HO-1/AMPK↑

    mTOR↓

    白术内酯Ⅲ27

    HFD小鼠;

    FFA诱导HepG2细胞

    体内:10 mg/kg灌胃+

    1 mg/mL尾静脉注射;

    体外:25 μg/mL

    AdipoR1/AMPK/SIRT1↑
    白桦脂酸28

    HFD小鼠;

    MCD小鼠;

    HepG2细胞;Hepa1-6细胞

    体内:150 mg/kg;

    体外:10 μmol/L

    YY1/FAS↓
    丹参酮ⅡA29 FFA诱导HepG2细胞、Huh7细胞 5/10 μmol/L LXRα/SREBP1↓
    生物碱 小檗碱34

    HFD小鼠;

    油酸诱导原代肝细胞

    体内:1.4 g/kg;

    体外:4 μmol/L

    SCD1/FABP1/CD36/CPT1A↓
    氧化小檗碱35 HFD大鼠 100 mg/kg IRS-1/PI3K/AKT↑
    甜菜碱36 CDA-HFD小鼠 0.2%/0.5%/1%

    Atg7/LC3Ⅱ/Ⅰ↑

    AMPK↑ ACC↑ Bip/ATF6↓

    氧化苦参碱37

    HFD饮食联合链脲佐菌素注射;

    PA诱导 HepG2细胞

    体内:45/90 mg/kg;

    体外:0.1/0.2 mg/mL

    NLRP3/IL-1β↓
    皂苷 人参皂苷Rb139 HFD小鼠 10 mg/kg PPAR-γ↑
    人参皂苷Re40 HFD小鼠 20/40 mg/kg

    PI3K/AKT↓

    TLR4/NF-κB↓

    人参皂苷RO41 HFD小鼠 45/90 mg/kg

    GLP-1↑

    TGR5↑

    黄芪皂苷Ⅳ42 HFD大鼠 20/40/80 mg/kg TLR4↓、MyD88 ↓、NF-κB↓
    绞股蓝皂苷LXXV43

    MCD小鼠;

    PA诱导HepG2细胞;

    TGF-β诱导LX2细胞;

    LPS+ATP诱导THP-1细胞

    体内:15/30 mg/kg;

    体外:0.001~10 μg/mL

    α-SMA、TGF-β1、TNF-α、MCP-1、IL-1β、NF-κB、GRP78↓
    下载: 导出CSV 
    | 显示表格

    槲皮素是多种植物中广泛存在的类黄酮化合物,研究12表明槲皮素可通过下调哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)/转录因子阴阳-1(Yin-Yang1,YY1)信号通路,激活胆固醇7α-羟化酶(cholesterol 7-alpha hydroxylase,CYP7A1)并增加其转录,使胆固醇转化为胆汁酸恢复肝脏胆固醇稳态,改善肝脏脂质积聚。水飞蓟宾是从水飞蓟果实和种子中分离得到的黄酮木脂素,是应用广泛的天然保肝剂。研究13表明水飞蓟宾可能通过改善肠道微生态,下调厚壁菌门/拟杆菌门比例,增加产短链脂肪酸(short-chain fatty acids,SCFA)菌如BlautiaBacteroidesAkkermansia等,增加肠道乙酸、丙酸和丁酸水平,同时抑制甲酸水平从而达到改善NAFLD的作用。有报道木犀草素抗炎作用也与肠道菌群有关,高脂饮食(high-fat diet,HFD)中补充木犀草素可使细菌种类丰富10%以上,增加闭锁小带蛋白1(zona occludens 1,ZO-1),降低肠道通透性,降低脂多糖(LPS),抑制Toll样受体4(TLR4)/核因子κB(NF-κB)通路,减轻肝脏炎症,防止肝脏单纯脂肪变性向NASH发展14。葛根素是从葛根中分离出的主要活性成分,具有改善脂质代谢、抗炎、恢复线粒体功能等作用15。Fang等16分别在NASH小鼠、斑马鱼模型和及HepG2、RAW 264.7细胞中证明葛根素通过激活单磷酸腺苷活化的蛋白激酶(AMP-activated protein kinase,AMPK),抑制mTOR活性,进而调控自噬相关蛋白激酶1(UNC-51 like autophagy activating kinase 1,ULK-1)磷酸化,产生抑制纤溶酶原激活物抑制物1(plasminogen activator inhibitor-1,PAI-1)活性,抑制信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)/缺氧诱导因子1-α(hypoxia-inducible factor 1-alpha,HIF1α)信号通路串联反应,降低巨噬细胞M1极化,同时激活磷酸肌醇3-激酶(phosphoinositide 3-kinase,PI3K)/蛋白激酶B(protein kinase B,AKT)信号通路,促进巨噬细胞M2极化,以发挥抗NASH活性。在一项纳入60例NAFLD患者的双盲临床试验17中,与安慰剂组相比,3个月内每天2次接受600 mg二氧杨梅素组的患者肝酶、血脂相关指标及胰岛素抵抗都显著改善,同时血清TNF-α、细胞角蛋白-18和成纤维细胞生长因子21水平也显著降低。机制研究18表明二氢杨梅素可能通过AMPK/过氧化物酶体增殖物激活受体γ辅激活子1α(peroxisome proliferator-activated receptor γ coactivator 1-alpha,PGC-1α)和过氧化物酶体增殖物激活受体α(perixisome proliferator-activated receptor alpha,PPARα)介导的自噬途径改善肝脂肪变性和胰岛素抵抗。山柰酚已被报道在多种代谢性疾病中具有良好疗效19,且可能是通过激活沉寂信息调节因子(Sirtuin 1,Sirt1)/AMPK/PGC-1α信号通路,下调脂质合成相关蛋白如乙酰辅酶A羧化酶(acetyl-CoA carboxylase,ACC)、脂肪酸合成酶(fatty acid synthase,FAS)、固醇调节元件结合蛋白1(sterol regulatory element-binding protein 1,SREBP1),降低肝脏脂质积累发挥抗NAFLD作用20

    白藜芦醇(resveratrol,RSV)是一种天然多酚,Chen等21发现RSV的含量在盲肠中远远大于血浆,提示生物利用度差的RSV很可能通过重塑肠菌结构发挥抗NAFLD作用,RSV上调HFD大鼠肠道中产SCFA菌属RuminococcaceaeLachnospiraceae和下调产LPS菌属Desulfovibrio的相对丰度,进而调节内源性大麻素系统,改善肠屏障。姜黄素(curcumin,Cur)在肠道被微生物主要代谢为四氢姜黄素(tetrahydrocurcumin,THC),Cur和THC都可通过NF-κB和PI3K/AKT/HIF-1α信号通路改善肝窦内皮细胞功能,间接减轻L02细胞的脂肪变性和损伤,且THC在恢复肝窦内皮细胞功能方面优于Cur22。研究23表明绿原酸可直接结合RNA去甲基化酶AlkB同源物5并抑制其m6A脱甲基酶活性,从而降低受体酪氨酸激酶(AXL) mRNA稳定性,进一步抑制细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)/肝激酶B1(liver kinase B1,LKB1)并激活AMPK/ULK-1信号通路,恢复HFD小鼠肝脏中的自噬通量减少脂质积累。表没食子儿茶素没食子酸酯(epigallocatechin-3-gallate,EGCG)是绿茶中含量最丰富、活性最强的多酚,EGCG显著下调了结肠白细胞介素-1β(IL-1β)、IL-6和单核细胞趋化因子-1(monocytechemoattractantprotein-1,MCP-1)的mRNA水平,改善了肠道炎症,下调了产LPS革兰阴性菌门ProteobacteriaSpirochaetae,通过抑制LPS/TLR4/NF-κB途径改善肠道氧化应激和炎症反应,上调基于核转录因子红系2相关因子2(nuclear factor-erythroid 2-related factor 2,Nrf2)途径激活肠道紧密连接蛋白表达,维持肠道屏障功能24。和厚朴酚是一种具有多效生物活性的天然木脂素,可通过促进SIRT3/AMPK增强脂滴上的自噬来减少脂质积累,并使长链酰基辅酶A脱氢酶脱乙酰化以增加线粒体中的脂肪酸氧化,从而减弱肝细胞中的脂毒性发挥抗NAFLD作用25

    栀子苷是栀子中提取的环烯醚萜苷类化合物,其对NAFLD模型小鼠和细胞的氧化应激和炎症具有保护作用,可能通过上调Nrf2/血红素加氧酶1(heme oxygenase 1,HO-1)和AMPK信号通路的蛋白表达,从而抑制mTOR及其相关蛋白的磷酸化,达到增强肝细胞的抗氧化应激能力和抗炎疗效26。白术内酯Ⅲ(atractylenolide Ⅲ,ATL Ⅲ)是苍术中发现的主要生物活性成分,是一种倍半萜内酯,Li等27通过计算机辅助药物设计试验发现脂联素受体蛋白1(adiponectin receptor 1,AdipoR1)是与ATL Ⅲ潜在的结合受体,进一步机制研究发现ATL Ⅲ通过调节AdipoR1介导的AMPK-SIRT1信号通路发挥抗NAFLD作用。白桦脂酸是一种天然存在的植物来源的五环三萜类化合物,Mu等28通过体内外试验均验证白桦脂酸通过负向调节YY1的表达和YY1与FAS启动子的结合效率,延缓肝细胞脂质积累,发挥抗NAFLD作用。丹参酮ⅡA是丹参中提取出的二萜类化合物,研究29表明丹参酮ⅡA可能是通过抑制肝X受体α(liver X receptor α,LXRα),并下调SREBP1的mRNA和蛋白表达,抑制脂质合成蛋白ACC1、FAS表达,进而减弱游离脂肪酸(free fatty acid,FFA)诱导的HepG2细胞、Huh7细胞中脂质积累。

    小檗碱(berberine,BBR)是黄连中提取出的一种苄基异喹啉类生物碱,先前研究30-33已广泛报道BBR具有改善肠菌结构,调节巨噬细胞活化,促进自噬和改善脂质代谢等多种生物活性。Yu等34发现BBR抑制了肠道和肝脏的线粒体电子传递链复合体Ⅰ,刺激肝脏线粒体融合,进而下调硬脂酰辅酶A去饱和酶1(stearoyl-CoA desaturase 1,SCD1)、脂肪酸结合蛋白1(fatty acid binding protein 1,FABP1)、白细胞分化抗原36(cluster of differentiation 36,CD36)和肉毒碱棕榈酰基转移酶1A(carnitine palmitoyltransferase 1A,CPT1A)的蛋白表达,逆转了HFD喂养小鼠的肥胖、肝脏脂质沉积和胰岛素抵抗。氧化小檗碱是BBR的肠道菌群代谢产物35,并展示出更佳的AMPK磷酸化性能,能显著抑制胰岛素受体底物1(insulin receptor substrate 1,IRS-1)的异常磷酸化,上调下游PI3K、p-AKT/AKT蛋白表达和磷酸化,改善肝脏胰岛素信号转导35。甜菜碱增加AMPK、ACC磷酸化水平,且增加了自噬相关基因7(autophagy-related 7,Atg7)和自噬标志物LC3Ⅱ/Ⅰ比值,下调了免疫球蛋白重链结合蛋白(immunoglobulin heavy chain binding protein,Bip)和激活转录因子6(activated transcription factor 6,ATF6)水平,减轻了内质网应激,缓解缺乏胆碱、L-氨基酸限定的高脂肪饮食(CDA-HFD)小鼠疾病特征36。氧化苦参碱能够降低NAFLD合并2型糖尿病小鼠血糖和血脂水平,增强抗氧化能力,抑制NLRP3/IL-1β炎症途径,下调在棕榈酸(palmitic acid,PA)诱导的HepG2细胞中NOD受体蛋白3(NOD-like receptor protein 3,NLRP3)和IL-1β的表达37

    人参皂苷是人参最主要的活性成分,按照苷元结构可分为人参皂苷二醇型(A型)、人参皂苷三醇型(B型)和齐墩果酸型(C型)三种类型32。A型代表有人参皂苷Rb1(ginsenoside Rb1,GRb1),具有调节脂质代谢、改善胰岛素抵抗和氧化应激等多种生物活性38,研究39表明可通过上调PPAR-γ减轻HFD小鼠中高迁移率族蛋白B1(high-mobility group box 1 protein,HMGB1)诱导的肝细胞凋亡。人参皂苷Re(ginsenoside Re,GRe)属于B型,Zhang等40指出GRe通过下调PI3K/AKT介导的脂质生成和TLR4/NF-κB介导的炎症相关蛋白表达,改善NAFLD疾病进展;人参皂苷RO(ginsenoside Ro,GRo)为C型,GRo可促进肠道胰高血糖素样肽1(glucagon-like peptide 1,GLP-1)分泌,并上调了血清和肝脏鹅去氧胆酸、熊去氧胆酸含量,激活胆汁酸G蛋白偶联受体5(G protein-coupled bile acid receptor 5,TGR5)增加能量消耗,改善HFD小鼠肥胖和胰岛素抵抗41。黄芪皂苷Ⅳ(astragaloside Ⅳ,AS-Ⅳ)显著降低NAFLD大鼠血清AST、ALT、TG、TNF-α、IL-6和IL-8水平,下调肝组织中TLR4、髓样分化因子88(Myeloid differentiation primary response gene 88,MyD88)、NF-κB mRNA和蛋白质的表达42。绞股蓝皂苷LXXV(gypenoside LXXV,Gyp LXXV)通过下调肝纤维化标志物α-平滑肌肌动蛋白(α-smooth muscle actin,α- SMA)、胶原蛋白1、TGF-β1、TNF-α、MCP-1、IL-1β、NF-κB和GRP78,明显减轻蛋氨酸-胆碱缺乏饮食(MCD)所致的小鼠肝损伤、炎症和纤维化43

    表  2  治疗NAFLD的中药有效成分复方
    Table  2.  Effective component compound of traditional Chinese medicine for the treatment of NAFLD
    中药有效成分复方 比例及剂量 作用机制
    栀子苷+绿原酸46-48

    67.16∶1;

    90 mg/kg+1.34 mg/kg

    SCD-1↓ LPS/TLR-4、TNF-α、

    IL-1β↓ MAPK↓

    花生皮提取物+栀子苷+异槲皮素49

    16∶10∶1;

    80 mg/kg+50 mg/kg+5 mg/kg

    TLR4/NF-κB↓ AMPK/ACC/CPT1↑

    AMPK/UKL-1/LC3B↑

    葛根素+小檗碱51 10∶1~40∶1 PPARγ
    葛根素+小檗碱+黄芩苷52 10∶1∶1~10∶1∶2 PPARγ
    小檗碱+姜黄素53-54 50 mg/kg+50 mg/kg

    PPARγ↑ caveolin-1↑

    SREBP-1c↓ SCD-1↓

    NF-κB↓TNF-α↓

    小檗碱+生育三烯酚+绿原酸56

    小鼠:87.84 mg/kg+5.27 mg/kg+5.28 mg/kg;

    人:500 mg+30 mg+30 mg

    miR-122↑ miR-34a↓
    丹酚酸B+苦杏仁苷+五味子酯甲1057 16 mg/kg+0.5 mg/kg+2 mg/kg

    CK7、CK19、EpCAM、OV6↓

    Notch↓

    水飞蓟宾+丹酚酸B+葛根素58 总质量100.3 g,干预饲料含:0.101 g+0.046 g+0.042 g

    益生菌↑:Akkermansia、Blautia

    次生胆汁酸合成相关的属↓:Clostridium、Bacteroides

    原人参二醇+丹参酮ⅡA+大黄素60 10∶10∶1 血清ALT、TC、HDL-c、LDL-c ↓
    阿魏酸+香豆酸61 1∶1.3

    HDAC1↓

    PPARγ/FABP/CD36↓

    木犀草素+番茄红素62

    体内:20 mg/kg+20 mg/kg;

    体外:20 μmol/L+10 μmol/L

    Sirt1/AMPK/β氧化↑

    NF-κB/IL-6、IL-1β、TNF-α↓

    毛冬青皂苷A1+海南冬青苷D63 41.6∶54.4,60/120/240 mg/kg ZO-1、Occludin↑ Akkermansia↑ Desulfovibrio↓
    EGCG+咖啡因64 40 mg/kg+20 mg/kg TNF-α、IL-6、MCP-1↓
    姜黄素+白藜芦醇65 8∶2,150 mg/kg

    PI3K/AKT/mTOR/STAT3/

    HIF-1α/VEGF↓

    下载: 导出CSV 
    | 显示表格

    祛湿化瘀方是经过多年临床和实验研究认证的治疗NAFLD有效经验方44-45,临床随机对照试验研究7表明相较于阳性对照药,祛湿化瘀方可显著改善患者血清ALT、AST水平,同时有46.2%患者肝脏相对脂肪含量下降30%。以祛湿化瘀方中5种已知的有效单体(绿原酸、栀子苷、姜黄素、虎杖苷、白术多糖)为研究对象,利用均匀设计回归分析,得到对肝脏甘油三酯抑制效果最佳的有效成分复方,栀子苷+绿原酸(GC方),比例为66.17∶146。GC可通过抑制硬脂酰辅酶A去饱和酶1(stearoyl coenzyme A desaturase 1,SCD-1)改善肝脏脂质沉积47,同时可通过下调肠源性LPS信号传导,下降TLR-4、TNF-α、IL-1β,抑制肠道MAPK信号通路恢复肠屏障功能发挥抗NAFLD效应48

    异槲皮素是罗布麻中提取的一种黄酮类物质,花生皮是花生外面的一种红色薄皮,有研究49报道按照16∶10∶1混合花生皮提取物(80 mg/kg)+栀子苷(50 mg/kg)+异槲皮素(5 mg/kg),通过调节肠道微生物区系的稳态,修正TLR4/NF-κB,激活AMPK/ACC/CPT1和AMPK/UKL-1/LC3B信号通路而有效地改善HFD小鼠的肝脏脂肪变性和肝功能,且优于单一成分疗效。

    葛根芩连汤对NASH大鼠模型药效学疗效显著50,通过FFA诱导HepG2细胞建立体外NASH细胞模型进一步研究葛根芩连汤主要单体成分葛根素、小檗碱、黄芩苷联合用药干预NASH的疗效,得出结论在改善细胞病理及TNF-α、IL-8和葡萄糖转运蛋白4方面,葛根素和小檗碱存在协同增效,且葛根素和小檗碱组合比例在10∶1~40∶1为佳51;而在减少细胞内脂滴方面,葛根素、小檗碱、黄芩苷联合用药比例在10∶1∶1~10∶1∶2最佳52

    姜黄素联合小檗碱(各50 mg/kg)在改善NAFLD大鼠模型的肝脏脂肪变性、肝脏病理结构方面显著优于双倍剂量的姜黄素和小檗碱单独给药,血清ALT、AST、TG、TC与单独给药组相比都具有显著差异,联合给药后肝组织PPARγ基因表达上调,SREBP-1c基因及蛋白、SCD-1、NF-κB基因表达下调,caveolin-1蛋白表达上调53-54

    在一项纳入49例脂肪变性程度为S1~S2的NAFLD患者的临床随机对照试验55中,给予患者小檗碱(500 mg)、生育三烯酚(30 mg)、绿原酸(30 mg)混合物6个月后,与安慰剂相比,接受混合物治疗的患者血清葡萄糖、胰岛素水平、HOMA-IR指数和肝脏CAP值均显著降低。进一步机制研究中,接受混合物的HFD小鼠体质量、胰岛素抵抗均明显改善,恢复肠道微环境,通过上调肝脏脂质代谢调控基因miR-122和下调miR-34a表达发挥抗NAFLD作用56

    扶正化瘀方具有良好的改善肝功能,逆转肝纤维化作用,通过对扶正化瘀方原方提取液、原方入血后门静脉、肝脏、周围血暴露量位居前列的丹酚酸B、苦杏仁苷、五味子酯甲进行均匀设计实验,在四氯化碳和胆管结扎诱导大鼠肝纤维化模型中,以肝组织羟脯氨酸含量和天狼星红染色胶原半定量为筛选指标,筛选出丹酚酸B(16 mg/kg)+苦杏仁苷(0.5 mg/kg)+五味子酯甲(2 mg/kg)为改善肝纤维化最佳组合JY5,疗效与原方相当57。机制研究中JY5干预后,肝纤维化模型大鼠肝组织中胆管细胞标志物CK7、CK19和肝祖细胞标志物EpCAM、OV6的表达明显降低,提示JY5可抑制肝祖细胞向胆管细胞分化的胆管反应,并且JY5可能通过抑制Notch信号通路,调控胆汁性肝纤维化10

    丹参酚酸B联合水飞蓟素、葛根素改善HFD小鼠肝脏脂肪变性,恢复了肝功能,与微生物群改变、AkkermansiaBlautia等益生菌增加、次生胆汁酸合成相关的属如ClostridiumBacteroides下降有关58

    中药复方降脂颗粒治疗脂肪肝具有较好的临床疗效59,应用权重配伍法对原方中3种有效成分原人参二醇、丹参酮ⅡA和大黄素进行剂量配伍,通过体内、体外实验筛选出10∶10∶1为优效配比,该配比显著改善了细胞内脂滴积聚及HFD小鼠ALT、血脂和肝组织病理变化60

    研究61表明阿魏酸、香豆酸以1∶1.3的配伍显著抑制FFA诱导的体外脂质积累,同时改善HFD小鼠中肝损伤和脂质积累,组方与组蛋白去乙酰化酶1(histone deacetylase 1,HDAC1)结合抑制其表达,同时抑制PPARγ的表达,进而抑制脂质合成及转运相关蛋白、FABP、CD36的表达。

    木犀草素、番茄红素配伍以上调烟酰胺磷酸核糖转移酶表达,提高Sirt1的共底物NAD+的水平,间接激活Sirt1/AMPK通路,增加β-氧化,抑制脂质积累,同时降低NF-κB诱导IL-6、IL-1β和TNF-α水平,减轻炎症62

    毛冬青皂苷A1、海南冬青苷D以41.6∶54.4比例联用,调节了HFD小鼠肠菌结构,降低了厚壁菌门/拟杆菌门之比,降低了Desulfovibrio的相对丰度,提高了Akkermansia的相对丰度,回肠ZO-1和occludin表达上调,肠道屏障改善,因而减少了菌源性LPS进入循环,降低了促炎细胞因子的肝脏基因表达水平63

    大剂量的EGCG和咖啡因会造成有害影响,甚至产生肝毒性,Yang等64采用低剂量EGCG(40 mg/kg)、咖啡因(20 mg/kg)联用能有效抑制HFD大鼠体质量增加,白色脂肪组织质量上升,血清TNF-α、IL-6和MCP-1水平下降,且与EGCG最大剂量(160 mg/kg)疗效相当。

    姜黄素、白藜芦醇(8∶2)以协同作用降低了PA诱导的HepG2细胞的脂质水平,在进一步的NAFLD模型大鼠中联合用药降低了血脂,减轻肝脂肪变性,潜在机制可能是通过下调PI3K/AKT/mTOR/STAT3信号通路,抑制HIF-1α的表达从而抑制血管内皮生长因子的表达65

    随着生活方式和生活水平的变化,NAFLD已逐渐成为临床医学重大问题。由于代谢性疾病病理机制复杂,聚焦于某一单一环节来防治多环节的复杂病变,有其局限性,这也可能是迄今缺乏理想临床治疗药物的原因之一。因此,在不断发现治疗NAFLD有效且理想的中药有效成分基础上,研发有多途径药理作用、“配伍增效”的中药有效成分复方,是未来NAFLD新药研究的发展趋向之一。

    中药传统复方有多成分、多途径的药理作用是其优势特点,临床实践证明中药复方治疗代谢性疾病有一定的特色优势。但另一方面,中药传统复方成分复杂,存在很多的未知,也影响制剂可控性、稳定性的提高;而单一组分或成分治疗可能失去中医整体观治疗复杂疾病的特色和优势。因此,探索由明确的物质成分组成并有中药复方多途径药理作用内涵的中药有效成分复方,是一重要的科学问题。

    在方法学上,如何获得配伍增效的有效成分复方,是一关键问题。目前来看,常见思路如运用数学模型、均匀设计等进行筛选,筛选的范围多选择临床实践有效的传统复方中所含的有效成分,从笔者长期研究实践来看,此方法有效可行;再如根据NAFLD的发生发展机制及已知药物成分的作用靶点进行组合研究来发现,其研究需要更深入的前期研究发现为基础。其他方法也在不断探索中,相信未来新的研究方法会不断出现。

    总之,治疗NAFLD有效且理想的中药有效成分的不断发现,以及其作用机制和靶点的不断阐明,将为中药新药研发奠定重要基础。而中药有效成分复方,对开发疗效能进一步提高的中药新药来说,是一重要思路与策略。目前防治NAFLD中药有效成分及其复方的研究成果,已为进一步的新药研发储备了良好条件。

  • 表  1  治疗NAFLD的中药有效成分

    Table  1.   Effective components of traditional Chinese medicine for the treatment of NAFLD

    分类 有效成分 NAFLD模型构建 剂量 作用机制
    黄酮类 槲皮素12

    db/db小鼠;

    高糖和FFA诱导 HepG2细胞

    体内:50/100/150 mg/kg;

    体外:10/20/40 μmol/L

    mTOR/YY1↓

    CYP7A1↑

    水飞蓟宾13 HFD小鼠 100/300 mg/kg

    产SCFA菌↑:

    Blautia,Bacteroides,Akkermansia

    木犀草素14 HFD大鼠 HFD饮食含0.5%木犀草素

    ZO-1↑

    LPS↓TLR4/NF-κB↓

    葛根素16

    NASH小鼠、斑马鱼模型;

    FFA诱导HepG2细胞;

    LPS+INF-γ诱导RAW 264.7细胞

    小鼠:100 mg/kg;

    斑马鱼:100/200/400 μg/mL;细胞:20/40/80 μmol/L

    AMPK↑—mTOR↓—pULK-1—PAI-1↓—STAT3/HIF1α↓

    PI3K/AKT↑

    二氢杨梅素18

    HFD大鼠;

    PA诱导HepG2细胞

    体内:50/100/200 mg/kg;

    体外:10 μmol/L

    AMPK/PGC-1α↑

    PPARα↑

    山柰酚20

    db/db小鼠;

    油酸诱导HepG2细胞

    体内:50 mg/kg;

    体外:10-6/-7/-8 mol/L

    Sirt1/AMPK/PGC-1α↑

    ACC/FAS/SREBP1↓

    酚类 白藜芦醇21 HFD大鼠 50/100 mg/kg

    产SCFA菌↑:Ruminococcaceae、Lachnospiraceae

    产LPS菌↓:Desulfovibrio

    姜黄素22

    HFD大鼠;

    FFA诱导LSEC细胞、L02细胞

    体内:25/50/100 g/kg;

    体外:1/2/4/8/10 mol/L

    NF-κB↓

    PI3K/Akt/HIF-1α↓

    绿原酸23

    HFD小鼠;

    AML12细胞;THLE-2细胞

    体内:50 mg/kg;

    体外:12.5/25/50/100 μmol/L

    AXL/ERK/LKB1↓

    AMPK/ULK-1↑

    EGCG24

    HFD大鼠;

    LPS诱导Caco-2细胞

    体内:100/200 mg/kg;

    体外:25/50/75/100 μmol/L

    LPS/TLR4/NF-κB↓

    Nrf2—ZO-1/Occludin↑

    和厚朴酚25

    胆碱缺乏的高脂肪饮食小鼠;

    FFA诱导AML12细胞

    体内:2.5/10 mg/kg;

    体外:5/10 μmol/L

    SIRT3/AMPK↑

    维持线粒体功能

    萜类 栀子苷26

    tyloxapol诱导NAFLD模型小鼠;

    FFA诱导HepG2细胞

    体内:50/75/100 g/kg;

    体外:65/130/260 μmol/L

    Nrf2/HO-1/AMPK↑

    mTOR↓

    白术内酯Ⅲ27

    HFD小鼠;

    FFA诱导HepG2细胞

    体内:10 mg/kg灌胃+

    1 mg/mL尾静脉注射;

    体外:25 μg/mL

    AdipoR1/AMPK/SIRT1↑
    白桦脂酸28

    HFD小鼠;

    MCD小鼠;

    HepG2细胞;Hepa1-6细胞

    体内:150 mg/kg;

    体外:10 μmol/L

    YY1/FAS↓
    丹参酮ⅡA29 FFA诱导HepG2细胞、Huh7细胞 5/10 μmol/L LXRα/SREBP1↓
    生物碱 小檗碱34

    HFD小鼠;

    油酸诱导原代肝细胞

    体内:1.4 g/kg;

    体外:4 μmol/L

    SCD1/FABP1/CD36/CPT1A↓
    氧化小檗碱35 HFD大鼠 100 mg/kg IRS-1/PI3K/AKT↑
    甜菜碱36 CDA-HFD小鼠 0.2%/0.5%/1%

    Atg7/LC3Ⅱ/Ⅰ↑

    AMPK↑ ACC↑ Bip/ATF6↓

    氧化苦参碱37

    HFD饮食联合链脲佐菌素注射;

    PA诱导 HepG2细胞

    体内:45/90 mg/kg;

    体外:0.1/0.2 mg/mL

    NLRP3/IL-1β↓
    皂苷 人参皂苷Rb139 HFD小鼠 10 mg/kg PPAR-γ↑
    人参皂苷Re40 HFD小鼠 20/40 mg/kg

    PI3K/AKT↓

    TLR4/NF-κB↓

    人参皂苷RO41 HFD小鼠 45/90 mg/kg

    GLP-1↑

    TGR5↑

    黄芪皂苷Ⅳ42 HFD大鼠 20/40/80 mg/kg TLR4↓、MyD88 ↓、NF-κB↓
    绞股蓝皂苷LXXV43

    MCD小鼠;

    PA诱导HepG2细胞;

    TGF-β诱导LX2细胞;

    LPS+ATP诱导THP-1细胞

    体内:15/30 mg/kg;

    体外:0.001~10 μg/mL

    α-SMA、TGF-β1、TNF-α、MCP-1、IL-1β、NF-κB、GRP78↓
    下载: 导出CSV

    表  2  治疗NAFLD的中药有效成分复方

    Table  2.   Effective component compound of traditional Chinese medicine for the treatment of NAFLD

    中药有效成分复方 比例及剂量 作用机制
    栀子苷+绿原酸46-48

    67.16∶1;

    90 mg/kg+1.34 mg/kg

    SCD-1↓ LPS/TLR-4、TNF-α、

    IL-1β↓ MAPK↓

    花生皮提取物+栀子苷+异槲皮素49

    16∶10∶1;

    80 mg/kg+50 mg/kg+5 mg/kg

    TLR4/NF-κB↓ AMPK/ACC/CPT1↑

    AMPK/UKL-1/LC3B↑

    葛根素+小檗碱51 10∶1~40∶1 PPARγ
    葛根素+小檗碱+黄芩苷52 10∶1∶1~10∶1∶2 PPARγ
    小檗碱+姜黄素53-54 50 mg/kg+50 mg/kg

    PPARγ↑ caveolin-1↑

    SREBP-1c↓ SCD-1↓

    NF-κB↓TNF-α↓

    小檗碱+生育三烯酚+绿原酸56

    小鼠:87.84 mg/kg+5.27 mg/kg+5.28 mg/kg;

    人:500 mg+30 mg+30 mg

    miR-122↑ miR-34a↓
    丹酚酸B+苦杏仁苷+五味子酯甲1057 16 mg/kg+0.5 mg/kg+2 mg/kg

    CK7、CK19、EpCAM、OV6↓

    Notch↓

    水飞蓟宾+丹酚酸B+葛根素58 总质量100.3 g,干预饲料含:0.101 g+0.046 g+0.042 g

    益生菌↑:Akkermansia、Blautia

    次生胆汁酸合成相关的属↓:Clostridium、Bacteroides

    原人参二醇+丹参酮ⅡA+大黄素60 10∶10∶1 血清ALT、TC、HDL-c、LDL-c ↓
    阿魏酸+香豆酸61 1∶1.3

    HDAC1↓

    PPARγ/FABP/CD36↓

    木犀草素+番茄红素62

    体内:20 mg/kg+20 mg/kg;

    体外:20 μmol/L+10 μmol/L

    Sirt1/AMPK/β氧化↑

    NF-κB/IL-6、IL-1β、TNF-α↓

    毛冬青皂苷A1+海南冬青苷D63 41.6∶54.4,60/120/240 mg/kg ZO-1、Occludin↑ Akkermansia↑ Desulfovibrio↓
    EGCG+咖啡因64 40 mg/kg+20 mg/kg TNF-α、IL-6、MCP-1↓
    姜黄素+白藜芦醇65 8∶2,150 mg/kg

    PI3K/AKT/mTOR/STAT3/

    HIF-1α/VEGF↓

    下载: 导出CSV
  • [1] BRUNT EM, WONG VWS, NOBILI V, et al. Nonalcoholic fatty liver disease[J]. Nat Rev Dis Primers, 2015, 1: 15080. DOI: 10.1038/nrdp.2015.80.
    [2] POWELL EE, WONG VWS, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397( 10290): 2212- 2224. DOI: 10.1016/S0140-6736(20)32511-3.
    [3] LE MH, YEO YH, ZOU BY, et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical Bayesian approach[J]. Clin Mol Hepatol, 2022, 28( 4): 841- 850. DOI: 10.3350/cmh.2022.0239.
    [4] SABET A. A phase 3 trial of resmetirom in NASH with liver fibrosis[J]. N Engl J Med, 2024, 390( 17): 1632. DOI: 10.1056/NEJMc2402905.
    [5] DAY CP, JAMES OFW. Steatohepatitis: A tale of two“hits”?[J]. Gastroenterology, 1998, 114( 4): 842- 845. DOI: 10.1016/S0016-5085(98)70599-2.
    [6] TILG H, ADOLPH TE, MOSCHEN AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade[J]. Hepatology, 2021, 73( 2): 833- 842. DOI: 10.1002/hep.31518.
    [7] LIU QH, LI XJ, PAN YQ, et al. Efficacy and safety of Qushi Huayu, a traditional Chinese medicine, in patients with nonalcoholic fatty liver disease in a randomized controlled trial[J]. Phytomedicine, 2024, 130: 155398. DOI: 10.1016/j.phymed.2024.155398.
    [8] ZOU JJ, XIANG Q, TAN DN, et al. Zuogui-Jiangtang-Qinggan-Fang alleviates high-fat diet-induced type 2 diabetes mellitus with non-alcoholic fatty liver disease by modulating gut microbiome-metabolites-short chain fatty acid composition[J]. Biomedecine Pharmacother, 2023, 157: 114002. DOI: 10.1016/j.biopha.2022.114002.
    [9] KHEONG C WAH, MUSTAPHA NR NIK, MAHADEVA S. A randomized trial of silymarin for the treatment ofNonalcoholic steatohepatitis[J]. Clin Gastroenterol Hepatol, 2017, 15( 12): 1940- 1949. e 8. DOI: 10.1016/j.cgh.2017.04.016.
    [10] FU YD, HU YH, XIAO Z, et al. Study of the Chinese herbal compound JY5 against biliary hepatic fibrosis through inhibition of ductular reaction[J]. Tradit Chin Drug Res Clin Pharmacol, 2022, 33( 10): 1298- 1306. DOI: 10.19378/j.issn.1003-9783.2022.10.002.

    付亚东, 胡永红, 肖准, 等. 中药成分复方JY5通过抑制胆管反应抗胆汁性肝纤维化的研究[J]. 中药新药与临床药理, 2022, 33( 10): 1298- 1306. DOI: 10.19378/j.issn.1003-9783.2022.10.002.
    [11] XIN X, JIN Y, WANG X, et al. A combination of geniposide and chlorogenic acid combination ameliorates nonalcoholic steatohepatitis in mice by inhibiting kupffer cell activation[J]. Biomed Res Int, 2021, 2021: 6615881. DOI: 10.1155/2021/6615881.
    [12] YANG TT, WANG YY, CAO XY, et al. Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation[J]. Phytomedicine, 2023, 113: 154703. DOI: 10.1016/j.phymed.2023.154703.
    [13] LI XX, WANG YP, XING YL, et al. Changes of gut microbiota during silybin-mediated treatment of high-fat diet-induced non-alcoholic fatty liver disease in mice[J]. Hepatol Res, 2020, 50( 1): 5- 14. DOI: 10.1111/hepr.13444.
    [14] SUN WL, YANG JW, DOU HY, et al. Anti-inflammatory effect of luteolin is related to the changes in the gut microbiota and contributes to preventing the progression from simple steatosis to nonalcoholic steatohepatitis[J]. Bioorg Chem, 2021, 112: 104966. DOI: 10.1016/j.bioorg.2021.104966.
    [15] ZHOU HL, MA C, WANG C, et al. Research progress in use of traditional Chinese medicine monomer for treatment of non-alcoholic fatty liver disease[J]. Eur J Pharmacol, 2021, 898: 173976. DOI: 10.1016/j.ejphar.2021.173976.
    [16] FANG XX, LAN XT, ZHU M, et al. Puerarin induces macrophage M2 polarization to exert antinonalcoholic steatohepatitis pharmacological activity via the activation of autophagy[J]. J Agric Food Chem, 2024, 72( 13): 7187- 7202. DOI: 10.1021/acs.jafc.3c09601.
    [17] CHEN SH, ZHAO XL, WAN J, et al. Dihydromyricetin improves glucose and lipid metabolism and exerts anti-inflammatory effects in nonalcoholic fatty liver disease: A randomized controlled trial[J]. Pharmacol Res, 2015, 99: 74- 81. DOI: 10.1016/j.phrs.2015.05.009.
    [18] YANG Y, QIU W, XIAO JY, et al. Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα- mediated autophagy pathway[J]. J Transl Med, 2024, 22( 1): 309. DOI: 10.1186/s12967-024-05060-7.
    [19] YAO YX, YU YJ, DAI S, et al. Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis[J]. Biomedecine Pharmacother, 2024, 175: 116694. DOI: 10.1016/j.biopha.2024.116694.
    [20] LI N, YIN L, SHANG JM, et al. Kaempferol attenuates nonalcoholic fatty liver disease in type 2 diabetic mice via the Sirt1/AMPK signaling pathway[J]. Biomedecine Pharmacother, 2023, 165: 115113. DOI: 10.1016/j.biopha.2023.115113.
    [21] CHEN MT, HOU PF, ZHOU M, et al. Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system[J]. Clin Nutr, 2020, 39( 4): 1264- 1275. DOI: 10.1016/j.clnu.2019.05.020.
    [22] WU JZ, LI MY, HUANG N, et al. Curcumin alleviates high-fat diet-induced nonalcoholic steatohepatitis via improving hepatic endothelial function with microbial biotransformation in rats[J]. J Agric Food Chem, 2023, 71( 27): 10338- 10348. DOI: 10.1021/acs.jafc.3c01067.
    [23] MENG FT, SONG CC, LIU J, et al. Chlorogenic acid modulates autophagy by inhibiting the activity of ALKBH5 demethylase, thereby ameliorating hepatic steatosis[J]. J Agric Food Chem, 2023, 71( 41): 15073- 15086. DOI: 10.1021/acs.jafc.3c03710.
    [24] ZUO GL, CHEN MY, ZUO YP, et al. Tea polyphenol epigallocatechin gallate protects against nonalcoholic fatty liver disease and associated endotoxemia in rats via modulating gut microbiota dysbiosis and alleviating intestinal barrier dysfunction and related inflammation[J]. J Agric Food Chem, 2024. DOI: 10.1021/acs.jafc.3c04832.[ Online ahead of print]
    [25] LIU JX, ZHANG T, ZHU JZ, et al. Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy[J]. Chin Med, 2021, 16( 1): 115. DOI: 10.1186/s13020-021-00528-w.
    [26] SHEN BY, FENG HH, CHENG JQ, et al. Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways[J]. J Cell Mol Med, 2020, 24( 9): 5097- 5108. DOI: 10.1111/jcmm.15139.
    [27] LI Q, TAN JX, HE Y, et al. Atractylenolide iii ameliorates non-alcoholic fatty liver disease by activating hepatic adiponectin receptor 1-Mediated ampk pathway[J]. Int J Biol Sci, 2022, 18( 4): 1594- 1611. DOI: 10.7150/ijbs.68873.
    [28] MU Q, WANG H, TONG L, et al. Betulinic acid improves nonalcoholic fatty liver disease through YY1/FAS signaling pathway[J]. FASEB J, 2020, 34( 9): 13033- 13048. DOI: 10.1096/fj.202000546R.
    [29] GAO WY, CHEN PY, HSU HJ, et al. Tanshinone IIA downregulates lipogenic gene expression and attenuates lipid accumulation through the modulation of LXRα/SREBP1 pathway in HepG2 cells[J]. Biomedicines, 2021, 9( 3): 326. DOI: 10.3390/biomedicines9030326.
    [30] LENG YR, ZHANG MH, LUO JG, et al. Pathogenesis of NASH and promising natural products[J]. Chin J Nat Med, 2021, 19( 1): 12- 27. DOI: 10.1016/S1875-5364(21)60002-X.
    [31] LI CL, ZHOU WJ, JI G, et al. Natural products that target macrophages in treating non-alcoholic steatohepatitis[J]. World J Gastroenterol, 2020, 26( 18): 2155- 2165. DOI: 10.3748/wjg.v26.i18.2155.
    [32] WANG L, YAN YH, WU LF, et al. Natural products in non-alcoholic fatty liver disease(NAFLD): Novel lead discovery for drug development[J]. Pharmacol Res, 2023, 196: 106925. DOI: 10.1016/j.phrs.2023.106925.
    [33] ZHANG Y, CHEN Q, FU X, et al. Current advances in the regulatory effects of bioactive compounds from dietary resources on nonalcoholic fatty liver disease: Role of autophagy[J]. J Agric Food Chem, 2023, 71( 46): 17554- 17569. DOI: 10.1021/acs.jafc.3c04692.
    [34] YU MY, ALIMUJIANG M, HU LL, et al. Berberine alleviates lipid metabolism disorders via inhibition of mitochondrial complex I in gut and liver[J]. Int J Biol Sci, 2021, 17( 7): 1693- 1707. DOI: 10.7150/ijbs.54604.
    [35] LI QP, DOU YX, HUANG ZW, et al. Therapeutic effect of oxyberberine on obese non-alcoholic fatty liver disease rats[J]. Phytomedicine, 2021, 85: 153550. DOI: 10.1016/j.phymed.2021.153550.
    [36] SEO J, KWON D, KIM SH, et al. Role of autophagy in betaine-promoted hepatoprotection against non-alcoholic fatty liver disease in mice[J]. Curr Res Food Sci, 2024, 8: 100663. DOI: 10.1016/j.crfs.2023.100663.
    [37] LOU D, FANG Q, HE YH, et al. Oxymatrine alleviates high-fat diet/streptozotocin-induced non-alcoholic fatty liver disease in C57BL/6 J mice by modulating oxidative stress, inflammation and fibrosis[J]. Biomedecine Pharmacother, 2024, 174: 116491. DOI: 10.1016/j.biopha.2024.116491.
    [38] ZHONG GC, LIAO ZH, CHEN Y, et al. Research progress on pharmacological effects of ginsenoside Rb1 in treatment of non-alcoholic fatty liver disease[J]. Chin Arch Tradit Chin Med, 2023, 41( 4): 162- 168. DOI: 10.13193/j.issn.1673-7717.2023.04.032.

    钟光成, 廖志涵, 陈依, 等. 人参皂苷Rb1治疗非酒精性脂肪性肝病药理作用的研究进展[J]. 中华中医药学刊, 2023, 41( 4): 162- 168. DOI: 10.13193/j.issn.1673-7717.2023.04.032.
    [39] SONG B, SUN Y, CHU YF, et al. Ginsenoside Rb1 alleviated high-fat-diet-induced hepatocytic apoptosis via peroxisome proliferator-activated receptor γ[J]. Biomed Res Int, 2020, 2020: 2315230. DOI: 10.1155/2020/2315230.
    [40] ZHANG JS, DUAN MF, WU SH, et al. Comprehensive pharmacological and experimental study of Ginsenoside Re as a potential therapeutic agent for non-alcoholic fatty liver disease[J]. Biomedecine Pharmacother, 2024, 177: 116955. DOI: 10.1016/j.biopha.2024.116955.
    [41] JIANG LS, LI W, ZHUANG TX, et al. Ginsenoside ro ameliorates high-fat diet-induced obesity and insulin resistance in mice via activation of the G protein-coupled bile acid receptor 5 pathway[J]. J Pharmacol Exp Ther, 2021, 377( 3): 441- 451. DOI: 10.1124/jpet.120.000435.
    [42] LIU YL, ZHANG QZ, WANG YR, et al. Astragaloside IV improves high-fat diet-induced hepatic steatosis in nonalcoholic fatty liver disease rats by regulating inflammatory factors level via TLR4/NF-κB signaling pathway[J]. Front Pharmacol, 2020, 11: 605064. DOI: 10.3389/fphar.2020.605064.
    [43] LEE JH, OH JY, KIM SH, et al. Pharmaceutical efficacy of gypenoside LXXV on non-alcoholic steatohepatitis(NASH)[J]. Biomolecules, 2020, 10( 10): 1426. DOI: 10.3390/biom10101426.
    [44] LENG J, HUANG F, HAI YM, et al. Amelioration of non-alcoholic steatohepatitis by Qushi Huayu decoction is associated with inhibition of the intestinal mitogen-activated protein kinase pathway[J]. Phytomedicine, 2020, 66: 153135. DOI: 10.1016/j.phymed.2019.153135.
    [45] TIAN HJ, FANG Y, LIU W, et al. Inhibition on XBP1s-driven lipogenesis by Qushi Huayu Decoction contributes to amelioration of hepatic steatosis induced by fructose[J]. J Ethnopharmacol, 2023, 301: 115806. DOI: 10.1016/j.jep.2022.115806.
    [46] TANG YJ, MENG SX, FENG Q, et al. Screen and verification of Chinese medicine by uniform design for the prevention and treatment of fatty liver[J]. Acta Univ Tradit Med Sin Pharmacol Shanghai, 2013, 27( 4): 53- 57. DOI: 10.16306/j.1008-861x.2013.04.022.

    唐亚军, 孟胜喜, 冯琴, 等. 基于均匀设计的防治脂肪肝中药有效组分复方筛选与验证[J]. 上海中医药大学学报, 2013, 27( 4): 53- 57. DOI: 10.16306/j.1008-861x.2013.04.022.
    [47] CHEN C, XIN X, LIU Q, et al. Geniposide and chlorogenic acid combination improves non-alcoholic fatty liver disease involving the potent suppression of elevated hepatic SCD-1[J]. Front Pharmacol, 2021, 12: 653641. DOI: 10.3389/fphar.2021.653641.
    [48] PENG JH, LENG J, TIAN HJ, et al. Geniposide and chlorogenic acid combination ameliorates non-alcoholic steatohepatitis involving the protection on the gut barrier function in mouse induced by high-fat diet[J]. Front Pharmacol, 2018, 9: 1399. DOI: 10.3389/fphar.2018.01399.
    [49] YI MJ, FASINA OB, LI YJ, et al. Mixture of peanut skin extract, geniposide, and isoquercitrin improves the hepatic lipid accumulation of mice via modification of gut microbiota homeostasis and the TLR4 and AMPK signaling pathways[J]. Int J Mol Sci, 2023, 24( 23): 16684. DOI: 10.3390/ijms242316684.
    [50] ZHANG CY, FEI N, HE PF, et al. The mechanism of Gegen Qinlian Decoction regulating PI3K/AKT/FOXO1 signaling pathway on anti-inflammatory and anti-oxidative stress in rats with non-alcoholic steatohepatitis[J/OL]. Chin J Immunol, 1- 11[ 2024-08-23]. http://kns.cnki.net/kcms/detail/22.1126.r.20230517.1515.006.html. http://kns.cnki.net/kcms/detail/22.1126.r.20230517.1515.006.html

    张超云, 费娜, 郝鹏飞, 等. 葛根芩连汤调控PI3K/AKT/FOXO1信号通路对非酒精性脂肪肝炎大鼠抗炎和抗氧化应激的作用机制[J/OL]. 中国免疫学杂志, 1- 11[ 2024-08-23]. http://kns.cnki.net/kcms/detail/22.1126.r.20230517.1515.006.html. http://kns.cnki.net/kcms/detail/22.1126.r.20230517.1515.006.html
    [51] WANG YL, YE Y, CHENG JW, et al. Experimental studies of the combination effects of berberine and puerarin on NASH invitro[J]. Chin J Integr Tradit West Med Dig, 2015, 23( 5): 321- 326. DOI: 10.3969/j.issn.1671-038X.2015.05.05.

    王允亮, 叶杨, 程佳伟, 等. 葛根素和小檗碱联合用药干预NASH细胞模型的实验研究[J]. 中国中西医结合消化杂志, 2015, 23( 5): 321- 326. DOI: 10.3969/j.issn.1671-038X.2015.05.05.
    [52] WANG YL. Study on the mechanism of Gegen Qinlian decoction and its effective components in intervening PPARγ in nonalcoholic steatohepatitis[D]. Beijing: Beijing University of Chinese Medicine, 2014.

    王允亮. 葛根芩连汤及其有效组分干预非酒精性脂肪性肝炎PPARγ的作用机制研究[D]. 北京: 北京中医药大学, 2014.
    [53] KUANG SY. Study on the activity of three traditional Chinese medicines and their effective components based on the treatment of NAFLD[D]. Changsha: Hunan University of Chinese Medicine, 2014.

    匡双玉. 基于治疗NAFLD的三味中药及有效成分的活性研究[D]. 长沙: 湖南中医药大学, 2014.
    [54] FENG WW, KUANG SY, TU C, et al. Natural products berberine and curcumin exhibited better ameliorative effects on rats with non-alcohol fatty liver disease than lovastatin[J]. Biomedecine Pharmacother, 2018, 99: 325- 333. DOI: 10.1016/j.biopha.2018.01.071.
    [55] COSSIGA V, LEMBO V, GUARINO M, et al. Berberis aristata, Elaeis guineensis and Coffea canephora extracts modulate the insulin receptor expression and improve hepatic steatosis in nafld patients: A pilot clinical trial[J]. Nutrients, 2019, 11( 12): 3070. DOI: 10.3390/nu11123070.
    [56] COSSIGA V, LEMBO V, NIGRO C, et al. The combination of berberine, tocotrienols and coffee extracts improves metabolic profile and liver steatosis by the modulation of gut microbiota and hepatic miR-122 and miR-34a expression in mice[J]. Nutrients, 2021, 13( 4): 1281. DOI: 10.3390/nu13041281.
    [57] XIAO Z, FU YD, HU YH, et al. Study on the compatibility of the main components of fuzheng Huayu formula against hepatic fibrosis[J]. Mod Tradit Chin Med Mater Med World Sci Technol, 2021, 23( 5): 1567- 1578. DOI: 10.11842/wst.20201102002.

    肖准, 付亚东, 胡永红, 等. 扶正化瘀方抗肝纤维化主要成分的配伍研究[J]. 世界科学技术-中医药现代化, 2021, 23( 5): 1567- 1578. DOI: 10.11842/wst.20201102002.
    [58] WANG X, JIN YF, DI C, et al. Supplementation of silymarin alone or in combination with salvianolic acids B and puerarin regulates gut microbiota and its metabolism to improve high-fat diet-induced NAFLD in mice[J]. Nutrients, 2024, 16( 8): 1169. DOI: 10.3390/nu16081169.
    [59] SHU XB, ZHAO YT, YANG ZX. Clinical observation of Jiangzhi Granule combined with lifestyle intervention in treating NAFLD patients with damp-heat accumulation syndrome[J]. Shanghai J Tradit Chin Med, 2023, 57( 2): 35- 40. DOI: 10.16305/j.1007-1334.2023.2208086.

    舒祥兵, 赵燕婷, 杨志新. 降脂颗粒联合生活方式干预治疗湿热蕴结型非酒精性脂肪性肝病的临床观察[J]. 上海中医药杂志, 2023, 57( 2): 35- 40. DOI: 10.16305/j.1007-1334.2023.2208086.
    [60] LIU Y, XU JY, YANG LL, et al. Optimization of active components compatibility of Jiangzhi Granule to improve NAFLD based on weighed modification method[J]. Shanghai J Tradit Chin Med, 2021, 55( 3): 65- 73. DOI: 10.16305/j.1007-1334.2021.2011005.

    刘洋, 徐娇雅, 杨丽丽, 等. 基于权重配方法的降脂颗粒改善非酒精性脂肪性肝病的有效成分配伍优化研究[J]. 上海中医药杂志, 2021, 55( 3): 65- 73. DOI: 10.16305/j.1007-1334.2021.2011005.
    [61] CUI KL, ZHANG LC, LA XQ, et al. Ferulic acid and P-coumaric acid synergistically attenuate non-alcoholic fatty liver disease through HDAC1/PPARG-mediated free fatty acid uptake[J]. Int J Mol Sci, 2022, 23( 23): 15297. DOI: 10.3390/ijms232315297.
    [62] ZHU YX, LIU RJ, SHEN ZL, et al. Combination of luteolin and lycopene effectively protect against the“two-hit” in NAFLD through Sirt1/AMPK signal pathway[J]. Life Sci, 2020, 256: 117990. DOI: 10.1016/j.lfs.2020.117990.
    [63] ZHAO WW, XIAO M, YANG J, et al. The combination of Ilexhainanoside D and ilexsaponin A1 reduces liver inflammation and improves intestinal barrier function in mice with high-fat diet-induced non-alcoholic fatty liver disease[J]. Phytomedicine, 2019, 63: 153039. DOI: 10.1016/j.phymed.2019.153039.
    [64] YANG Z, ZHU MZ, ZHANG YB, et al. Coadministration of epigallocatechin-3-gallate(EGCG) and caffeine in low dose ameliorates obesity and nonalcoholic fatty liver disease in obese rats[J]. Phytother Res, 2019, 33( 4): 1019- 1026. DOI: 10.1002/ptr.6295.
    [65] HE YH, WANG H, LIN SL, et al. Advanced effect of curcumin and resveratrol on mitigating hepatic steatosis in metabolic associated fatty liver disease via the PI3K/AKT/mTOR and HIF-1/VEGF cascade[J]. Biomedecine Pharmacother, 2023, 165: 115279. DOI: 10.1016/j.biopha.2023.115279.
  • 期刊类型引用(2)

    1. 孙屿昕,童光东. 复方中药干预代谢相关脂肪性肝病的研究进展. 西南医科大学学报. 2025(01): 11-16 . 百度学术
    2. 宋伟,严倩茹,邬伟魁. 民族药滇黄芩研究现状与思考. 中国药事. 2024(12): 1438-1446 . 百度学术

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