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小檗具有良好的保肝作用，其活性成分可通过抑制炎症反应、调节肝脏组织氧化应激水平、调节细胞凋亡和自噬等发挥保肝作用，对酒精性肝损伤、化学试剂致肝损伤、缺血再灌注诱导肝损伤、非酒精性脂肪性肝病、自身免疫性肝炎、肝硬化、肝癌等疾病有一定的治疗潜力。本文通过介绍小檗及其活性单体对各类型肝病的保护及机制的研究进展，旨在为肝脏疾病药物开发提供参考。
小檗（Berberis）是我国的传统中药，《中国药典》[1]规定小檗属植物假豪猪刺（Berberis soulieana Schneid）、小黄连刺（Berberis wilsonae Hems.l）、细叶小檗（Berberis poiretii Schneid）和匙叶小檗（Berberis vernae Schneid）等同属数种植物的干燥根，为中药小檗。《本草拾遗》[2]记载小檗如石榴，皮黄；子赤如枸杞子，两头尖。小檗在世界范围内也有广泛的研究，如俄罗斯[3]、伊朗[4]、印度[5]等国家认为其是一种药食同源的植物，其果实可作为能量补剂，而欧洲国家如波兰和德国[6-7]，以及美国等[8]均对小檗开展研究，发现其具有多种药理活性，包括神经保护[9]、降血糖[10]、皮肤保护[11]、视网膜保护[11]、降血脂[12]、抗炎、抗氧化[13-14]、抗肿瘤[15]等。
在我国小檗俗称三颗针、山石榴、刺黄柏、子檗等，其广泛分布于我国甘肃、湖北、四川和云南[16-17]等地。使用小檗治疗肝脏疾病的历史悠久，《中华本草》[18]记载小檗味苦、性寒，归肺、肝、脾经。中医认为，小檗属于清热燥湿药，可以清肝明目治疗湿热黄疸，肝硬化腹水[19]，《陕西中草药》[20]中提及小檗清肝热，主治肝炎。同时在藏药中，用于治疗胆囊炎、初期黄疸型肝炎的传统方剂五味獐牙菜散、八味獐牙菜散、九味獐牙菜丸和十三味榜嘎均含有小檗的成分[21]。而由小檗皮等药材组成的中成药十味蒂达胶囊具有疏肝理气，利胆溶石疗效，临床用于肝胆湿热所致胁痛、口苦、恶心、嗳气、泛酸、腹胀。在国外，小檗被用作肝脏保护类药物亦有记载，伊斯兰传统医学书籍中记录了小檗属植物的保肝和抗炎活性，其果实的水提物也被视作一种肝脏补品[22]；在伊朗，小檗被用作治疗肝脏肿大，脾脏肿大、黄疸等疾病[23]；在印度草药典籍中，人们使用小檗促进葡萄糖代谢，使脂质代谢正常，并恢复正常的肝功能[24]。由此可见，小檗治疗肝脏疾病的价值十分突出。
如今，肝损伤性疾病发病率在全球呈上升趋势，包括病毒感染、药物性肝损伤、脂肪肝、酒精性肝病、肝硬化和肝癌等，造成疾病的原因有药物、饮食、环境等诸多因素[25]。目前关于中药小檗及其活性成分在肝脏相关疾病中的保护作用及作用机制已有较多报道，中药小檗中的多种有效成分，均有较好的药理活性，具有一定的研究意义。本文通过介绍小檗及其活性单体对各类型肝病的保护及机制的研究进展，旨在为肝脏疾病药物开发提供参考。
1 小檗属植物的化学成分
我国小檗属植物包括甘肃小檗（Berberis kansuensis C.K. Schneid.）、黄芦木（Berberis amurensis Rupr.）、大叶小檗（Berberis ferdinandi-coburgii C.K. Schneid.）、威宁小檗（Berberis weiningensis Ying）、豪猪刺（Berberis julianae C.K. Schneid）等约200多种[26]。部分其他科植物如毛茛科（Coptis、Hydrastis和Xanthorhiza）、芸香科（Evodia、Phellodendron 和Zanthoxyllum）和番荔枝科（Annickia、Coelocline、Rollinia和Xylopia）均含有小檗科（Berberis、Caulophyllum、Jeffersonia、Mahonia、Nandina和Sinopodophyllum）代表性化合物小檗碱和其他生物碱，但小檗属植物是分布最广泛和主要的小檗碱天然来源，小檗的树皮含有超过8%的生物碱，其中小檗碱是主要的生物碱约占5%[27]。通过总结近年来对小檗属植物化合物成分报道，为中药小檗成分分析提供指导依据。
小檗属植物中含有多种活性成分，其中包括多种类型化合物，如生物碱类[28-29]、黄酮类 [30]、甾体类[31]、三萜类[32]和酚类[33]等（表1）。生物碱类化合物包括[34-47]小檗碱、四氢小檗碱、氯化小檗红碱、二氢小檗碱、唐松草定、氧化小檗碱、N-methylcanadine、巴马汀、非洲防己碱、四氢棕榈碱、药根碱、去亚甲基小檗碱、jatrorubine、(+)-白屈菜碱、智利宁、脱氢油尿碱、杏黄罂粟碱、(S)-reticuline、reticuline、berbidine、obaberine、obamegine、小檗胺、异汉防己甲素、bersavine、muraricine、aromoline、刺檗碱、异波尔定碱、木兰花碱、海罂粟碱、isocorydine、talikmidine、thalicmidine、乙酰基黄酮胺、吲哚白氨酸、英替布利明、Thaligrisine、沙利福林、6,7-二甲氧基-1,2,3,4-四氢异喹啉、格拉齐文、pronuciferine N-oxide、pronuciferine、假原生素（图1）。
小檗中所含的酚酸类化合物[48~50]主要包括绿原酸、没食子酸、咖啡酸、丁香酸、肉桂酸、阿魏酸、邻香豆酸、原儿茶酸、香草酸、苹果酸、柠檬酸、酒石酸、丁二酸、扁桃酸、芥子酸。脂肪酸类化合物包括[50]肉豆蔻酸、软脂酸、正壬酸、十五烷酸（图2）。
小檗中含有的黄酮类化合物[48, 52-54]包括芹菜素、槲皮素、儿茶酚、木犀草素、异鼠李素、山奈酚、芦丁、菊花素、金丝桃苷、天竺葵。小檗中类黄酮如花青素类化合物[48]：失车菊素-3,5-O-双葡萄糖苷、飞燕草素-3,5-O-二葡萄糖苷、飞燕草素-3-O-葡萄糖苷、矮牵牛素-3,5-葡萄糖苷、失车菊素-3-O-葡萄糖苷、天竺葵素-3-O-葡萄糖苷（图3）。
小檗中含有的甾体类化合物[51-52, 56]包括β-谷甾醇、豆甾醇、豆甾-4-烯-3-酮、羽扇豆醇、齐墩果酸、类固醇甾醇、豆甾醇葡萄糖甙，小檗中含有的三萜类化合物[43-57]：熊果酸、2α,3α,19α-trihydroxy-urs-12-en-24-formyl-28-oic acid、2α,3β,21α-trihydroxy-urs-12-en-28-oic acid、3β-acetyloxy-1-oxo-olean-12-en-28-oic acid（图4）。
小檗中的其他类型化合物，如联苯类[57]berbekorin A、2′-hydroxy-3,4,5-trimethoxybiphenyl、4,5-dihydroxy-3-methoxybiphenyl（图5）。
2 小檗及活性成分对肝脏损伤的保护与作用机制
2.1 酒精性肝损伤
酒精性肝损伤（alcoholic liver disease，ALD）的主要致病因素是长期大量饮酒，但发病机制复杂，涉及多个演变环节，是氧应激损伤、免疫损伤与程序性细胞死亡等多方面因素共同作用的结果[58]，因此小檗中减轻炎症反应，调节脂代谢和细胞自噬的物质是发挥作用的主要活性成分。
小檗的天然活性成分小檗胺通过抑制核因子κB/信号转导因子和转录激活因子3（nuclear factor-κB/signal transducer and activator of transcription 3，NF-κB/STAT3）通路来降低炎症因子的产生，使脂多糖诱导的白细胞介素（interleukin，IL）-1β、IL-6等炎症因子的mRNA表达降低，减轻肝脏炎症等ALD诱导因素，在乙醇诱导肝损伤小鼠模型中，小檗胺治疗后炎症细胞的浸润和脂质积累现象减少，并且血清和肝脏中甘油三酯（triglyceride，TG）和总胆固醇（total cholesterol，TC）含量降低，起到改善ALD的作用[59]。Zeng等[60]研究表明，小檗中的槲皮素通过降低脂周素2（perilipin 2，PLIN 2）水平、激活单磷酸腺苷活化蛋白激酶（AMP-activated protein kinase，AMPK）活性以及增加肝脏微管相关蛋白1轻链3-II（Microtubule-associated protein 1 light chain 3，LC3-II）和PLIN 2蛋白的共定位，起到促进脂质消耗，减轻肝损伤，下调血清丙氨酸氨基转移酶（alanine aminotransferase，ALT）和天门冬氨酸氨基转移酶（aspartate aminotransferase，AST）水平，可作为ALD早期干预的潜在候选药物。此外，小檗中的儿茶素还会降低小鼠血清中TC含量，增加超氧化物歧化酶（superoxide dismutase，SOD）活性改善氧化应激，调节酒精诱导的肝脏脂代谢，起到治疗 ALD的作用[61]。
细胞自噬是真核细胞降解体内有害物质的主要途径[62]，自噬也可以介导受损细胞器的回收，维持细胞内细胞器的稳态[63]，因此促进细胞自噬在乙醇诱导的ALD中存在关键的作用[64]。Lin等[65]研究表明小檗的活性单体巴马汀可通过激活AMPK/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路调控细胞自噬途径改善ALD，巴马汀促进细胞自噬物LC3-Ⅱ的转化和暂时增强蛋白p62的降解，促凋亡蛋白B淋巴细胞瘤-2基因（B-cell lymphoma-2，Bcl-2）相关X蛋白（Bax）、天冬氨酸特异性的半胱氨酸蛋白水解酶（cysteinyl aspartate specific proteinase，Caspase）-3和Caspase-9的表达水平明显降低，抗凋亡蛋白Bcl-2的表达水平增加，抑制细胞凋亡促进自噬以减轻乙醇诱导的肝细胞损伤。
2.2 小檗对化学类试剂致肝损伤的保护与作用机制
2.2.1 四氯化碳诱导的肝损伤
四氯化碳（CCl4）是研究化学物质对肝脏毒害影响的常用试剂，肝脏中细胞色素P450可代谢CCl4生成三氯甲基自由基（CCl3+）,可诱导脂质过氧化、炎症反应、影响核酸合成与分裂，导致肝损伤[66]。
买买提·司马义等[67]使用红果小檗的成熟果实乙醇提取物治疗CCl4肝损伤模型小鼠，结果显示小鼠血清中ALT、AST及丙二醛（malondialdehyde，MDA）含量降低，血清ALT、AST水平升高程度下调，证明肝脏损伤程度被减轻[68]，同时小鼠肝组织中谷胱甘肽过氧化物酶（glutathione peroxidase，GSH-Px）含量和SOD的含量升高，小鼠的肝小叶结构、肝细胞形态恢复正常，炎性细胞浸润减少。小檗碱下调载脂蛋白E（apolipoproteinE，ApoE）的表达水平，降低肝细胞脂质沉积，通过转化生长因子β1（transforming growth factor β1，TGF-β1）途径抑制肝星状细胞活化，清除氮自由基以及过氧化物，并通过调节脂质过氧化治疗CCl4诱导的肝纤维化[69]。万星等[70]研究表明，小檗中成分儿茶素可通过抑制硬脂酰辅酶A去饱和酶-1（stearoyl-coenzyme a desaturase 1，SCD-1）的表达，减少脂质合成，调控α-平滑肌肌动蛋白（α smooth muscle actin，α-SMA）和调节肝星状细胞I型胶原蛋白、降低TG的含量，抑制CCl4引起的肝纤维化[71]。
2.2.2 D-(+)-氨基半乳糖胺诱导的肝损伤
D-(+)-氨基半乳糖胺（D-galactosa-mine，D-Gal N）是肝细胞磷酸尿嘧啶核苷干扰剂，可引起核苷酸单磷酸尿苷和三磷酸尿苷缺乏，导致肝细胞膜损伤，Ca+内流增加，引起代谢紊乱 [72]，当D-Gal N进入机体后与二磷酸尿苷结合形成二磷酸尿苷-半乳糖胺，诱导细胞膜脂质过氧化反应，引起急性肝损伤[73]。买买提·司马义等[74]研究表明，红果小檗乙醇提取物可能通过升高SOD和GSH-Px的含量，降低MDA含量提高机体抗氧化和清除机体氧化自由基能力，减轻肝细胞膜氧化程度，进而保护D-Gal N诱导的肝损伤小鼠的作用。这可能与小檗中的活性成分巴马汀可降低肿瘤坏死因子α（tumour necrosis factor-α，TNF-α）mRNA表达，增加IL-10 mRNA表达降低肝细胞凋亡，缓解D-Gal N诱导的肝损伤有关[75]。
2.2.3 异烟肼诱导的肝损伤
异烟肼是抗结核病药物，主要代谢部位为肝脏，其代谢为乙酰异烟肼在细胞色素酶作用下生成乙酰自由基、乙酰溴离子、乙酰二氮烯、乙酰氯离子、酮烯等毒性中间代谢产物，引起氧化应激，炎症反应，线粒体功能障碍，产生肝毒性[76]。
唐玲等[77]研究表明小檗碱可以显著抑制炎症介质IL-6的表达，上调抗炎介质IL-10的表达。IL-6是主要的促炎症因子，但IL-10由免疫细胞产生有抗炎作用，可抑制炎症介质IL-6和TNF-α的作用，上调可溶性TNF受体等抗炎介质，促进体内炎症介质/抗炎介质趋于平衡，减轻异烟肼性肝损伤[78-79]。Zhang等[80]研究表明，小檗中槲皮素提高了细胞活力，增强了SOD和GSH的水平，缓解氧化应激促进毒性物质代谢，同时降低了AST和ALT的水平证明其对炎症起到改善作用。此外，槲皮素通过上调细胞凋亡的相关蛋白Bcl-2的表达水平、降低Bax、Caspase-3和Caspase-9的水平来消除异烟肼诱导的线粒体功能障碍和细胞凋亡。
2.3 小檗对缺血再灌注诱导肝损伤中的作用与机制
肝缺血再灌注损伤（hepatic ischemia-reperfusion injury，HIRI）是在肝脏移植、肝部分切除和严重肝脏创伤性手术中面临的重要问题。研究显示肝缺血再灌注引起大量炎症释放导致炎症反应，产生炎症因子，导致细胞凋亡[81]，同时缺血和再灌注过程也会导致线粒体功能的恶化，能量代谢的改变会导致肝脏损伤[82]。
细胞中AMPK通路，会在机体缺血能量匮乏，ATP耗竭AMP增加时，抑制ATP消耗促进ATP合成，同时起到激活细胞自噬维持稳态作用[83-84]。从炎症因子的产生和激活细胞自噬维持稳态两方面来看，张馨月[85]研究表明小檗碱可能通过激活AMPK抑制内质网应激（endoplasmic reticulum stress，ERS）对HIRI发挥保护，ERS 能够激活其下游硫氧还蛋白结合蛋白-核苷酸结合寡聚化结构域样受体3通路（thioredoxin-interacting protein-NLR family pyrin domain containing 3，TXNIP-NLRP3）炎性小体信号通路这会促进炎症因子的产生，减轻ERS也能调节内质网自噬，可以缓解大鼠脂肪HIRI，从而发挥保护作用[86]，在大鼠肝缺血再灌注模型中使用小檗碱二甲基亚砜溶液进行治疗，显著降低炎症小体相关蛋白TXNIP的表达，并观察到血清中炎症因子IL-1β、IL-18水平下降，同时免疫组化显示NLRP3蛋白含量明显降低[87]。
Kahraman等[88]研究发现小檗中的槲皮素上调AMPK磷酸化，抑制了mTOR磷酸化，调节自噬信号通路，激活受损细胞自噬，研究发现在HIR进程中发现中性粒细胞衍生的活性氧（reactive oxygen species，ROS）扩散到肝细胞会攻击线粒体，线粒体功能障碍发生，致肝细胞走向坏死[89]。此外槲皮素可以清除OH自由基、超氧阴离子自由基（O2-）产生Fenton反应减少ROS造成的线粒体损伤，并且槲皮素能螯合Fe和Cu来终止脂质过氧化链反应调节氧化应激，Uylaş等[90]的研究表明50 mg/kg槲皮素对大鼠HIRI有明显的保护作用。
3 小檗及活性成分对非酒精性脂肪性肝病的保肝作用
非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）是指除酒精和其他明确肝损伤因素外所致的，以肝细胞内脂肪过度沉积为主要特征的临床病理综合征，不仅发生于肥胖人群中，还与糖尿病、高血压病和血脂异常等代谢功能障碍的疾病有关[91-92]。部分临床实验表明对于有肝脏脂质堆积和肝脏相关酶升高的患者，小檗种的提取物可降低血清ALT、AST、体重、TG和TC含量[93]。小檗醇提取物治疗后，患者的体重指数、TC、TG、低密度脂蛋白胆固醇、空胶血糖、AST、ALT和碱性磷酸酶显著降低，高密度脂蛋白胆固醇、GSH-Px和总抗氧化能力显著升高，这表明小檗提取物对NAFLD可能具有治疗作用[94]，同时患者血糖、胰岛素水平显著降低，提取物使胰岛素受体表达明显增加，改善NAFLD的血糖谱和肝脏脂肪变性[95]。
Sun等[96]发现小檗碱能诱导肝细胞脂代谢调节剂成纤维细胞生长因子21（fibroblast growth factor，FGF 21）对脱乙酰酶sirtuin 1（sirtuin 1，SIRT1）的需要和以SIRT1依赖的方式诱导自噬以改善肝脏脂肪变性。研究发现小檗碱能增加FGF21信号传递、改善全身能量消耗和白色脂肪组织的褐变，介导热量摄入肝脏脂质代谢，维持肝脏脂质稳态有关[97-98]。此外，小檗碱能降低TG在诱导游离脂肪酸中的积聚治疗肝脂肪变性[99]，通过调控肝组织AMPK/SIRT1/解偶联蛋白（uncoupling protein 2，UCP2）信号通路相关基因及蛋白的表达，改善肝脏细胞内环境的能量代谢，调节脂质代谢紊乱，抑制肝脏脂肪变性，抑制脂质沉积，调整氧化与抗氧化失衡来治疗NAFLD[100]。Sharma等[101]研究表明小檗中小檗胺通过肝激酶B1（liver kinase b1，LKB1）和活化AMPK增强SIRT1脱乙酰化酶活性，激活SIRT1/LKB1/AMPK信号通路，诱导其超微结构变化，阻止下游靶乙酰辅酶A羧化酶（acetyl-coa carboxylase，ACC）、脂肪酸合成酶（fatty acid synthase, FAS）以及甾醇辅酶A去饱和酶（stearoyl-coa desaturase 1，SCD1）表达的升高从而调节脂质代谢，并且小檗胺可调节维持脂肪酸稳态的脂质代谢关键转录因子（peroxisome proliferator-activated receptors，PPARs）的表达。此外，小檗胺显着减轻氧化损伤，抑制TG和胆固醇的合成，对自噬标志物LC3 A/B、Beclin 1和p62的表达进行评估，确定小檗胺可以改善NAFLD肝脏脂质代谢紊乱，从而改善了细胞内环境，减少了肝细胞自噬发生。
在2型糖尿病（type 2 diabetes mellitus，T2DM）诱导小鼠的NAFLD研究中，Yang等 [102]研究表明小檗活性单体槲皮素显著减弱了T2DM诱导的IL-1β、IL-6和TNF-α的产生抑制了炎症反应。此外，槲皮素恢复了肝脏中的的SOD、过氧化氨酶和GSH的含量减轻了肝细胞的氧化应激，同时，槲皮素通过激活法尼醇X受体1（farnesoid x receptor 1，FXR 1）和胆汁酸G蛋白偶联受体5（takeda G protein-coupled receptor 5，TGR 5）信号通路，减少小鼠肝脏的脂质堆积，间接抑制了肝脏细胞的氧化应激和炎症反应，达到治疗T2DM导致NAFLD的作用。
Miao等[103]研究表明小檗活性成分绿原酸通过破坏TGF-β/Smad2/3信号通路和减少血清高迁移率族蛋白B1（high mobility group box 1，HMGB1）诱导的肝血管内皮细胞肝脏细胞外基质（extracellular matrix，ECM）生成，抑制肝星状细胞（hepatic stellate cells，HSCs）活化，并且促进线粒体生物发生，改善非酒精性脂肪性肝炎（non-alcoholic steatohepatitis，NASH）发育过程中的肝纤维化。同时Shi等[104]研究表明绿原酸能够调节肠道菌群改善由细菌内毒素引起的肝脏疾病，并且绿原酸能增加胰高糖素样肽-1（glucagon-like peptide-1，GLP-1）分泌调节葡萄糖代谢，调节脂质代谢，促使GLP激活AMPK间接的调节能量代谢，同时GLP-1还通过中枢GLP-1R起到降低进食量的作用，来影响高脂饮食诱导的肝脏脂肪变性和炎症，可以预防和治疗NAFLD。具体见图6。
4 小檗对自身免疫性肝炎的保肝作用
自身免疫性肝炎（autoimmune hepatitis，AIH）是一种被触发因素（例如病毒、环境、化学物质）诱导的，由T细胞针对肝脏细胞的自身免疫反应，AIH的诊断依据为血清转氨酶和免疫球蛋白G水平上升，自身抗体异常增加，肝脏组织学上的界面性肝炎[105]。AIH发病机制复杂，但免疫抑制在AIH中发挥至关重要的作用，以高γ球蛋白血症、血清自身抗体阳性为特点，主要表现为细胞因子的表达异常和失调、T淋巴细胞的浸润等[106-107]。使用刀豆蛋白A诱导的AIH小鼠模型中，小檗中活性单体小檗胺能降低TNF-α和干扰素-P（interferon-P，IFN-P）的表达阻断NF-κB信号，来减轻刀豆蛋白A诱导的肝损伤，具有治疗AIH的药效学潜力[108-109]。Wang等[110]研究发现小檗碱可以激活AMPK，导致NF-κB和c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）途径受到抑制，介导炎症刺激，减少细胞因子的表达和释放，同时能抑制T细胞介导的免疫反应 [111-112]。另一种活性单体槲皮素可以抑制TNF-α mRNA在肝内的表达，也能抑制NF-κB的激活通路，调控肝细胞凋亡，治疗AIH[113]。提示小檗胺、小檗碱和槲皮素在AIH疾病治疗中的潜在作用。
5 小檗对肝硬化的治疗作用
肝硬化由各种慢性肝脏类疾病引起，例如非酒精性脂肪肝、大量饮酒、乙型或丙型肝炎感染、自身免疫性疾病等导致健康的肝实质被纤维化组织和再生结节取代，主要表现为肝脏合成功能障碍及门静脉高压症[114-115]。窦芊等[116]研究发现，在CCl4加乙醇复合法诱导肝硬化大鼠模型中，小檗碱能通过抑制TGF-β1/Smads信号通路，阻碍致肝纤维化细胞因子（TGF-β）激活，来减轻大鼠的肝脏炎症反应，促进肝脏胶原降解，降低肝脏纤维化程度，从而保护肝功能，治疗肝硬化。生物体内IFN-γ是Th1细胞的特征细胞因子，起到调节免疫应答作用，能激活巨噬细胞杀伤潜在癌细胞抑制血吸虫肝纤维化的细胞恶性癌变 [117- 118]。骆中华等[119]研究发现小檗碱可以与吡喹酮合用，对血吸虫病导致的大鼠晚期肝硬化疾病起协同、增效作用，小檗碱能促进IFN-γ表达和降低端粒酶活性抑制血吸虫肝纤维化。
肝脏纤维化是肝硬化发展的中间环节，患病肝脏中肝纤维化和肝组织再生之间具有平衡关系，不良外因导致肝脏微环境紊乱会促进肝纤维化加速肝硬化的进程[120-121]，而肝纤维化的基本原因是肝星状细胞的（hepatic stellate cell，HSC）的激活[122]。研究发现小檗碱能调节HSC的激活 [123]，在G1期诱导HSC周期停滞[124]，诱导亚铁离子氧化还原反应，以激活ROS介导的肝星状细胞铁凋亡[125]，治疗肝纤维化。此外，小檗碱被证明激活AMPK通路并抑制巨噬细胞极化和TGF-β1/Smad3信号传导，对抗肝纤维化降低肝硬化的风险[126]。
6 小檗及活性成分对肝癌的治疗作用
肝癌是世界上常见的恶性肿瘤，早期肝癌症状无特异性，肿瘤微环境是导致肝脏细胞发生恶性转变的重要原因之一[127]。研究[128]表明小檗根皮的甲醇粗提物再以正己烷、氯仿进行萃取得到的提取物对人肝癌细胞系HepG2具有细胞毒性，Ilyas等[129]证实了异环磷酰胺与小檗根提取物联合治疗肿瘤可以增强异环磷酰胺的抗癌作用并明显改善其副作用。小檗乙醇提取物可以诱导人肝癌细胞系HepG2细胞死亡，并恢复其抗氧化活性 [130]。抗癌药物顺铂会引起肝损伤，伴随着肝脏生化指标和形态学的改变[131]，Gholampour等[132]研究表明小檗提取物可诱导氧化相关的酶的活性，可通过调控Toll 样受体4相关基因表达，改善肝脏细胞脂质过氧化进程，具有对抗顺铂诱导的氧化应激并且减弱组织炎症的作用。
Lin等[133]研究表明非洲防己碱通过抑制磷脂酰肌醇3激酶/蛋白激酶（phosphatidylinositide 3-kinases/protein kinase，BBPI3K/AKT）、p38和细胞外调节蛋白激酶1/2/丝裂原活化蛋白激酶（extracellular regulated protein kinases1/2/mitogen-activated protein kinase，ERK1/2 MAPKs）信号通路，使E-钙粘蛋白的表达升高，N-钙粘蛋白、基质金属蛋白酶2和基质金属蛋白酶9的表达降低，促使Caspase-3与PAPR蛋白加成物的裂解，Bcl-2关联死亡启动子的上调和Bcl-2的下调，降低肝癌细胞迁移及侵袭的能力，通过限制增殖细胞核抗原表达降低细胞的增殖和集落，产生对肝癌SMMC-7721细胞的抑制的作用。
Yu等[134]研究表明从小檗中提取到的小檗胺可增强Cx32蛋白的表达，抑制PI3K/AKT信号通路抑制SMMC-7721细胞的迁移和侵袭，此外小檗胺进一步上调p53表达、下调凋亡抑制基因Survivin的表达，促进Caspase-3、Caspase-9诱导SMMC-7721细胞凋亡[135-136]。在小鼠肝癌模型中，Meng等[137]研究表明小檗中的小檗胺可靶向Ca2+/钙调素依赖性蛋白激酶II（calcium/calmodulin-dependent protein kinase II，CAMKII）有效抑制肝癌细胞增殖并诱导癌细胞死亡，可抑制非肥胖型糖尿病/重症联合免疫小鼠肝癌细胞的体内致瘤性。近年来对于小檗胺的联合用药有着新的报道，Yang等 [138]发现小檗胺作为Na+/K+-ATP酶配体与抗癌药索拉非尼联用诱导Src-表皮生长因子受体（epithelial growth factor receptor，EGFR）-ERK信号通路有着靶向抗肝癌潜力。此外，小檗胺能抑制CIP2A的表达，促使CREB/激活转录因子1磷酸化下调，其联合阿司匹林在体内外均能显著抑制肝癌[139]。此外，Carrasco-Torres等[140]研究表明槲皮素通过下调了EGFR的表达，以及增高Src、STAT5和Sp1的磷酸化状态，调控胰岛素样生长因子1可以逆转肝癌前的细胞病变。小檗的主要活性成分、作用机制和适应疾病相关总结见表2。
7 结语
小檗碱、小檗胺、槲皮素、儿茶素、巴马汀等化合物均有研究证明其护肝作用，有潜在成药价值。开发小檗提取物或者小檗中单体化合物作为保肝护肝药物的难点在于，对小檗的研究还处在药理活性阶段，临床研究较少，而且缺乏同甘草酸制剂，水飞蓟宾和姜黄素等护肝化合物的比较性研究；单体化合物如小檗碱的口服利用度低，更需结构修饰[141]。随着对小檗中小檗碱等化合物进行结构修饰的研究在不断深入，以及医药领域中药物递送系统也不断优化，延长小檗碱在体内代谢的时间和靶向肝脏的作用有重要价值。通过制备纳米乳、聚合物胶束和pH响应型复合水凝胶微球等搭载小檗碱提高其溶解度；使用肽基促进剂、表面活性剂和聚合物提高肠吸收通透性；用聚氧乙烯蓖麻油、泊洛萨姆、环糊精和聚乙二醇等抑制剂来减弱P糖蛋白蛋白外排；以及结构改造并修饰化合物等手段提高小檗碱等活性单体生物利用度和靶向能力[142]。
此外，天然植物及其提取物作为保肝剂具有的低毒性和绿色健康等特点，受到社会青睐。水飞蓟[Silybum marianum (L.) Gaertn.]、甘草（Glycyrrhiza uralensis Fisch.）、决明子（Cassia fistula L）和银杏叶（Ginkgo biloba L.）等植物粗提取物或活性单体加以辅料制成胶囊、片剂或口服液的形式发挥保肝护肝作用的研究日益成熟 [143]，临床上也多采用联合保肝方案，如多烯磷脂酰胆碱-甘草酸制剂、多烯磷脂酰胆碱-双环醇类制剂和甘草酸制剂-熊去氧胆酸等[144]。目前已有盐酸小檗碱联合复方甘草酸苷治疗NAFLD的临床案例[145]，可利用小檗药食同源的特性，开发以小檗皮或果实提取物以及活性单体制成的药物，通过联合给药等方案，减轻机体炎症和氧化应激，调节机体糖代谢和脂质代谢，改善慢性肝脏疾病。本文阐述的小檗及其活性单体对各类型肝病的保护及机制的研究，希望为肝脏疾病药物开发提供参考。
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