CC  >> Vol. 2 No. 4 (December 2018)

    小檗碱药理作用研究进展
    Progress in Pharmacological Effects of Berberine

  • 全文下载: PDF(611KB) HTML   XML   PP.125-133   DOI: 10.12677/CC.2018.24015  
  • 下载量: 357  浏览量: 1,127  

作者:  

付梦蕾,曲有乐:浙江海洋大学食品与医药学院,浙江 舟山;
胡文祥

关键词:
小檗碱药理作用研究进展Berberine Pharmacological Effects Research Progress

摘要:

小檗碱(berberine, Ber),是从毛莨科黄连属植物黄连的根和皮中提取的异喹啉类生物碱,有较强的清热解毒作用。近年来研究表明,小檗碱不仅在抗菌、抗炎等方面有显著疗效,对肿瘤、糖尿病、心血管方面的疾病也有很高的临床应用价值,本文主要对小檗碱的药理作用综述如下。

Berberine (Ber), also known as berberine, is oquinoline alkaloid extracted from the roots and skin of Coptis chinensis, which has a strong heat-clearing and detoxifying effect. In recent years, studies have shown that berberine has not only remarkable effects in antibacterial and anti-inflammatory aspects, but also has high clinical application value for diseases such as cancer, diabetes and cardiovascular diseases. This article reviews the pharmacological studies of berberine.

1. 引言

小檗碱俗称黄连素,是从传统中药黄连中得到的一种生物碱,除了在治疗急性肠胃炎方面有非常显著的疗效,还有许多其它药理作用。胡文祥教授研究小组发现小檗碱能减轻胰岛素抵抗作用,预示其在治疗糖尿病方面具有潜在的应用价值 [1] ,许多学者对其进行了广泛的研究 [2] [3] [4]。本文综述了其在心血管、抗肿瘤、治疗糖尿病、抗炎、抗氧化等诸多方面的药理作用。

2. 心血管效应

2.1. 抗心律失常

小檗碱通过降低室性早搏的发生率和抑制室性心动过速的发生,在大鼠心肌梗死后的拉伸诱发的心律失常中显示出抗心律失常作用 [5]。在糖尿病大鼠中,小檗碱也产生抗心律失常作用,小檗碱对IK1/Kir2.1的作用可能是这种抗心律失常作用的重要机制 [6] [7]。链脲佐菌素诱导的糖尿病大鼠的全细胞膜片钳通过左冠状动脉前降支闭塞进行心脏缺血,表明口服小檗碱(100 mg/kg)可以恢复抑制的I(to)和I(Ca)电流并显著缩短延长的QTc间期。此外,小檗碱还抑制超极化激活的环核苷酸化四通道的电流,这可能有助于起搏器电流(Ifs)及其抗心律失常作用 [8]。

2.2. 对心肌缺血的保护

研究表明,小檗碱显著降低AMPK蛋白浓度、缺血区心肌中二磷酸腺苷/三磷酸腺苷(ATP)和AMP/ATP的比例,以及非缺血区域中AMP/ATP和ADP/ATP的比例 [9]。在培养的新生大鼠心肌细胞中,小檗碱通过激活AMPK和PI3K-AkteNOS信号传导显示出抗细胞凋亡作用并改善心肌I/R后的心功能恢复 [10] [11]。

通过抑制p38丝裂原活化蛋白激酶(MAPK)和磷酸化Akt信号通路的激活 [12] 和上调Notch1/Hes1-PTEN/Akt信号传导来促进自噬 [13] 是另一种减轻心肌梗死后左心室重塑和心功能不全的机制。

2.3. 抗高血压

Ber静脉注射0.1~20 mg/kg能使麻醉犬、猫、兔、大鼠、蛙及清醒大鼠产生明显的降压作用,随剂量的增加,降压幅度和时间也增加,反复给药无快速耐受性,舒张压的降低程度较收缩压大 [14]。在低剂量时,Ber可阻断血管内皮上的a1受体,抑制胆碱酯酶的活性,提高突触间隙内的乙酰胆碱浓度,促进血管内皮合成和释放NO,产生内皮依赖性血管扩张而降压 [15] [16] [17]。在高剂量时,活化某些K+通道,使血管平滑肌细胞膜电位超极化,产生不依赖内皮的血管扩张而起到降压作用 [17]。

2.4. 降血脂

血脂异常是心血管疾病的主要危险因素,其特征是总胆固醇、甘油三酯和低密度脂蛋白胆固醇(LDL)水平升高,以及高密度脂蛋白(HDL)水平下降 [18]。AMPK被认为是一种控制细胞内脂质和葡萄糖代谢的关键因素 [19] ,一旦激活,AMPK就会关闭合成代谢途径,如胆固醇,脂肪酸和甘油三酯的生物合成,以及开启产生三磷酸腺苷(ATP)的分解代谢途径,如脂肪酸氧化。

2.5. 抗动脉粥样硬化

长期高血脂是导致动脉粥样硬化斑块形成的一个重要原因。据报道,小檗碱会影响肝细胞中的LDL受体以降低肝细胞人体血清胆固醇水平 [20] [21] [22]。在载脂蛋白E基因缺陷(apoE)小鼠中,小檗碱诱导清道夫受体A(SR-A)表达以增加修饰的LDL (DiO-Ac-LDL)的摄取。其次被认为,是由于小檗碱提高了超氧化物岐化酶(SOD)活性,抑制诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)活力,阻止NO的过量合成,避免NO与超氧阴离子反应,防止了具有细胞毒性的过氧化亚硝基阴离子生成,减少脂质过氧化物产生,从而预防动脉粥样硬化的发生。

2.6. 强心作用

小檗碱具有正性肌力作用,已被用于治疗充血性心力衰竭 [23]。高剂量小檗碱(63 mg/kg)可降低左心室舒张末期压力,改善[-dp/dt(max)],延长左心室舒张时间常数,降低舒张期心力衰竭大鼠模型中Ca2+水平 [24]。小檗碱还可降低慢性充血性心力衰竭大鼠的血浆脑利钠肽水平 [25]。通过减轻心脏脂质积累并促进葡萄糖转运,小檗碱的强心功效也在由高血糖/高胆固醇血症诱导的心脏功能障碍中发挥作用 [26]。

3. 免疫与抗炎作用

炎症是许多疾病的常见机制。在炎症病灶处,中性粒细胞可以产生ROS,例如超氧阴离子和一氧化氮(NO),其诱导组织损伤。脂多糖(LPS)诱导的炎症伴随着IL-6、NO、前列腺素E2(PGE2)的产生,环氧合酶-2(COX-2)和iNOS mRNA的表达,以及小鼠巨噬细胞RAW 264.7细胞中NF-κB的激活 [27]。

药根碱是小檗碱的主要代谢产物,被证实是一种抗炎化合物。在LPS刺激的RAW 264.7细胞模型中,药根碱(100 μg/mL)表现出抗炎作用,其对iNOS和COX-2表达的抑制活性分别为45%和29% [28]。在LPS诱导的体外山羊子宫内膜上皮细胞(gEECs)炎症模型中,巴马汀治疗(80 μg/mL)显著降低促炎因子的产生,如TNF-α、IL-1β、IL-6、NO,与对照组相比,增加抗炎因子IL-10和促分辨介质的产生,用酶联免疫吸附试验(ELISA),定量RT-PCR和蛋白质印迹法测定 [29]。

NF-κB在先天免疫和炎症的调节中具有确定的作用 [30]。在炎症期间,趋化因子是小蛋白质的超家族,例如白细胞介素-8和单核细胞趋化蛋白-1(MCP-1),在募集和激活白细胞中起重要作用 [31]。小檗碱(1~25 μM)剂量依赖性地抑制IL-1β或TNF-α刺激的人视网膜色素上皮细胞(ARPE-19)中白细胞介素-8和MCP-1表达,蛋白质分泌和NF-κB易位的增加 [32]。这些发现表明小檗碱的抗炎作用可能受益于其抑制白细胞介素-8的产生 [33]。

4. 内分泌效应

4.1. 糖尿病

糖尿病(DM)是一种代谢紊乱,其特征在于胰腺B细胞不能产生足够的胰岛素而导致的血糖水平升高(高血糖),或者丧失对胰岛素的有效靶组织反应 [34]。在1型或胰岛素依赖型糖尿病中,胰腺不能分泌胰岛素。2型糖尿病(T2DM)是以胰岛素抵抗为主的糖代谢紊乱综合征,占糖尿病患者的90%~95%,T2DM在以前称为非胰岛素依赖性糖尿病 [35]。

小檗碱的降糖作用是在20世纪80年代治疗具有糖尿病的腹泻患者偶然发现的。大量实验研究表明小檗碱能提高胰岛素受体的表达、促进糖酵解、增强胰岛素敏感性、促进胰岛素的释放与分泌、增加肝细胞对葡萄糖的消耗等,因其对T2DM的治疗效果显著,毒副作用小而备受关注。T2DM的发病机制较为复杂,其中主要表现为胰岛素抵抗,胰岛素抵抗是肝脏、肌肉和脂肪组织等周围靶组织细胞对胰岛素等敏感性降低而产生的一系列临床表现,也是目前糖尿病治疗面临的难题。

研究表明,BBR能改善胰岛素抵抗,增强胰岛素敏感性。其表现出与二甲双胍作用无明显差异,均属于胰岛素增敏剂范畴。欧阳礼枝等 [36] 研究小檗碱对胰岛素抵抗大鼠糖脂代谢相关指标的影响,以小檗碱干预胰岛素抵抗大鼠4周,结果小檗碱组餐后60 min血糖水平下降[分别为(7.2 ± 1.4) mmol/L,(8.0 ± 1.2) mmol/L, P < 0.05],FFA水平下降[分别为(258 ± 29) mmol/L,(479 ± 34) mmol/L,P < 0.05],IsI增强[分别为(−4.9 ± 0.3),(−5.4 ± 0.4),P < 0.05],GK活性增强[分别为(13.6 ± 1.7),(5.6 ± 0.8),P < 0.05];二甲双胍阳性对照组取得类似结果。研究表明,小檗碱能调节胰岛素抵抗大鼠的糖脂代谢水平,增强胰岛素敏感性,可作为抗糖尿病药物。

4.2. 肥胖

抗肥胖作用归因于抗脂肪形成活性,它还抑制CCAAT/增强子结合蛋白(C/EBP)α,过氧化物酶体增殖物激活受体γ2(PPARγ2)和其他脂肪形成基因的表达。在3T3-L1前脂肪细胞分化的早期阶段,它降低由3-异丁基-1-甲基黄嘌呤和毛喉素诱导的cAMP反应元件结合蛋白磷酸化和C/EBPβ的表达 [37]。小檗碱增强小鼠肝脏CD36表达并提高甘油三酯水平 [38]。它以SIRT1依赖性方式促进小鼠的肝基因表达和FGF21的循环水平,以增强高脂肪,高蔗糖饮食喂养的肥胖小鼠肝脏中的自噬。它在肝脏中起调节脂质并维持全身能量代谢的作用,且发现小鼠的肝脏脂质代谢和能量消耗受小檗碱诱导自噬的调节,因为在HFHS饮食喂养的肥胖小鼠和小鼠原代肝细胞的肝脏中存在营养传感器SIRT1的缺乏症 [39]。

5. 抗肿瘤

关于小檗碱的抗癌作用已有大量报道。研究表明,小檗碱可通过与各种靶标和机制的相互作用来抑制肿瘤细胞的增殖。小檗碱可以改变癌基因和癌发生相关基因的表达,通过上调腺苷一磷酸激活蛋白激酶(AMPK)的活性,小檗碱激活血管平滑肌细胞中肿瘤抑制基因p53的磷酸化 [40] ,还抑制致癌相关酶 [41]。据报道,小檗碱剂量依赖性地抑制几种肿瘤细胞中的N-乙酰转移酶活性,包括人膀胱肿瘤(癌)细胞(T24) [42] ,人结肠肿瘤(腺癌)细胞 [43] 和脑胶质母细胞瘤多形式(GBM 8401)细胞 [44]。此外,小檗碱抑制N-乙酰转移酶的基因和蛋白质表达在体外以剂量和时间依赖的方式 [45]。小檗碱通过与抗癌剂喜树碱相似的机制靶向拓扑异构酶I并抑制断裂的DNA链的再连接,其被归类为拓扑异构酶I毒物 [46]。此外,小檗碱与DNA和RNA相互作用。事实上,在早期研究中,小檗碱被用于染色DNA和RNA。因此,小檗碱-DNA或小檗碱-RNA复合物的形成被认为是其抗癌作用的一般机制之一。

盐酸小檗碱可减少子宫(HeLa S3),肺(H69),胃(KATO III),结肠(COLO 205),前列腺(DU145)和神经(SK-N-MC)中热休克蛋白27(HSP27)的产生)癌细胞。HSP27的表达似乎是胃癌的预后因素,与淋巴结转移相关。因此,盐酸小檗碱有利于预防癌症的恶性进展。事实上,黄连提取物主要含有小檗碱,可降低调节因子和标志物的表达,如CDK4,CDK6,细胞周期蛋白D3(G1/S调节因子),细胞周期蛋白B1(G2/M调节因子),波形蛋白(间充质标记物),癌症干细胞中的ALDH1A1,β-catenin和ABCG2(癌症干细胞标记物),这表明它可以减少它们的生长和转移 [47]。小檗碱对人肺癌细胞具有选择性细胞毒性(Lu 1, IC50: 11.9 μM) [48] 但对其他癌细胞无效:人结肠癌(Col2),鼻咽部表皮样癌(KB),长春碱抗性KB(KB-V),和激素依赖性人前列腺癌(LNCaP)细胞(IC50: >59.5 μM)。含有小檗碱的黄连提取物对A549细胞具有细胞毒性(腺癌人肺泡基底上皮细胞,IC50:7 μM)并分别在24和48小时后阻滞细胞周期G1和G2期。

6. 抗氧化

氧化应激是一种有害过程,可能是细胞结构受损的重要介质,从而诱发各种疾病状态,如心血管疾病,癌症,神经系统疾病和糖尿病。活性氧(ROS)的过量产生,最常见的是通过细胞因子过度刺激NADPH或通过线粒体电子传递链和黄嘌呤氧化酶,可导致氧化应激 [49]。羟基(-OH)是ROS的最具反应性的产物。采用电子自旋共振光谱法研究了小檗碱的主要代谢产物的清除活性。在浓度为1 mM时,小檗碱的代谢产物和小檗碱显示出优异的-OH清除活性,分别为85%和23% [50]。进一步的结果表明,小檗碱的清除活性与其亚铁离子螯合活性密切相关,而小檗碱的C-9羟基是必需的部分。

7. 抗微生物

7.1. 抗菌

小檗碱被广泛用作传统医学中的抗感染药物 [51]。小檗碱已显示出对多种细菌具有抗菌活性,包括无乳链球菌(MIC = 78 mug/mL) [52] ,胸膜肺炎放线杆菌(MIC = 0.3125 mg/mL) [53] ,不同的葡萄球菌菌株(MIC = 16至512微克/毫升) [54] 和痢疾志贺氏菌 [55]。小檗碱还有效地防止在钛盘表面上形成表皮葡萄球菌生物膜,并且是治疗假体周围感染的潜在药剂 [56] [57]。

关于可能的抗菌作用的小檗碱机制有几项研究。有研究表明,小檗碱是一种DNA配体,能够在体外结合单链和双链DNA [58]。因此,小檗碱与细菌中DNA的结合可导致DNA损伤。最近的一项研究表明,小檗碱的抗菌作用的主要机制是由于细胞分裂蛋白FtsZ的抑制。小檗碱与一些常见抗生素具有协同作用,尤其是利奈唑胺,头孢西丁和红霉素 [54]。这表明小檗碱与其他抗生素联合使用可能作为抗生素耐药性细菌感染的有效治疗工具。

7.2. 抗病毒

小檗碱在Vero细胞中显示出针对1型和2型单纯疱疹病毒(HSV-1,2)的抗病毒特性 [59] [60]。小檗碱在150 μg/mL时对HSV-1斑块的抑制率为76.5%,对HSV-2的抑制率为80% [61] ,并且强烈抑制甲型流感病毒的两种H1N1毒株(PR/8/34或WS/33)的生长。小檗碱不会阻止关键病毒蛋白的表达,但可以通过诱导宿主细胞细胞质内病毒蛋白聚集体的形成来减少病毒的生长。小鼠体内流感病毒模型也显示小檗碱在感染后第2天将小鼠死亡率从90%降低至55%并降低肺中的病毒滴度 [62]。小檗碱还抑制呼吸道合胞病毒在上皮细胞中的复制,可能是通过抑制RSV介导的早期p38 MAPK活化 [63]。

8. 与其他药物的相互作用

二甲双胍,在大鼠单次静脉内共同给予10 mg/kg小檗碱和2 mg/kg二甲双胍,增加了二甲双胍的初始血浆浓度和AUC,并降低了大鼠二甲双胍的分布容积和全身清除率,表明小檗碱通过OCT1和OCT2抑制二甲双胍的处置。小檗碱抑制OCT1和OCT2的转运活性,并且具有与二甲双胍药物相互作用的显著潜力 [64]。关于小檗碱在糖尿病患者中的常见使用,这种药物-药物相互作用非常重要。

酮康唑,与在雄性大鼠中单独施用酮康唑的那些相比,口服共同施用60 mg/kg小檗碱与10 mg/kg酮康唑使酮康唑的AUC增加至215%。与单用小檗碱相比,小檗碱的AUC增加至173%。这些药代动力学相互作用可能在小檗碱和酮康唑的协同作用中起一定作用 [65]。

9. 其他作用

9.1. 在农业方面的应用

1982年Eberhar等用黄连素防治马铃薯疫病获得专利,佟树敏等 [66] 用小檗碱与0.6%苦参碱复合配方的杀菌剂防治苹果腐烂病、轮纹病及黄瓜霜霉病,均取得较好的治疗效果。有实验表明,小檗碱水剂防治南瓜白粉病效果显著,且安全性较高。更有昆虫毒理学研究表明,小檗碱内部亚甲二氧基苯环结构能作为一种增效基团对毒杀昆虫起增效作用。

9.2. 对牙周病的治疗

余占海等 [67] 采用细胞培养技术,MTT比色法、考马斯亮蓝法、酶动力学法等研究小檗碱对人牙周膜细胞(PDLC)增殖活性、蛋白合成以及碱性磷酸酶活性的影响。研究表明小檗碱在0.01~0.02 g/L浓度范围内能促进PDLC的增殖及生物合成,使人牙周膜细胞能有效的在根面附着、增殖和分化,从而增强牙周组织的再生。

10. 小结

如今小檗碱已可以人工合成,成本比较低,且随着医学研究的发展和化学研究的深入,小檗碱显示出越来越多的药用效果,小檗碱不仅在传统的药理研究中的抗菌、抗炎、抗病毒的作用不可取代,而且在抗肿瘤、抗糖尿病、治疗心脑血管疾病方面也取得显著成果,受到广泛关注。小檗碱因其效果显著且毒副作用小在临床应用方面得以推广,前景广阔。随着细胞生物学的发展,小檗碱的药理作用机制将从细胞水平乃至分子、靶点水平得以阐明,为其临床应用提供更多的理论依据。

文章引用:
付梦蕾, 曲有乐, 胡文祥. 小檗碱药理作用研究进展[J]. 比较化学, 2018, 2(4): 125-133. https://doi.org/10.12677/CC.2018.24015

参考文献

[1] 胡文祥, 等. 一种降糖及降脂药物组合物及其制备方法[P]. 中国发明专利, ZL200710179390.3.
[2] 韩谢, 邵开元, 胡文祥. 小檗碱结构修饰的研究进展[J]. 武汉工程大学学报, 2018, 40(1): 1-7.
[3] 韩谢, 邵开元, 胡文祥. 微波辐射合成9-氧-2-溴乙基小檗碱工艺研究[J]. 微波化学, 2017, 1(1): 8-14.
[4] Xie, H., Shao, K.Y. and Hu, W.X. (2018) Synthesis of 9-Substituted Berberine Derivatives with Microwave Irradiation. Chemical Research in Chinese Universities, 1, 1-7.
[5] Cao, J.X., Fu, L. and Sun, D.N. (2012) The Effect of Berberine on Arrhythmia Caused by Stretch of Myocardium, in Vitro, of Rats after Myocardial Ischemia. Chinese Journal of Emergency Medicine, 21, 683-686.
[6] Yu, F., Lin, M.S. and Zhang, W.D. (2009) Inhibition of Berberine on IKr, IKs and IK1 in Thyroxine Induced Cardiomyopathic Guinea Pig Ventricular Myocytes. Journal of China Pharmaceutical University, 40, 244-249.
[7] Fu, Y. (2011) Berberine Elicits Anti-Arrhythmic Effects via IK1/Kir2.1 in the Rat Type 2 Diabetic Myocardial Infarction Model. Phytotherapy Research, 25, 33-37.
https://doi.org/10.1002/ptr.3097
[8] Chen, H., Chen, Y., Tang, Y., et al. (2014) Berberine Attenuates Spontaneous Action Potentials in Sinoatrial Node Cells and the Currents of Human HCN4 Channels Expressed in Xenopus Laevis Oocytes. Molecular Medicine Reports, 10, 1576.
https://doi.org/10.3892/mmr.2014.2377
[9] Chang, W., Zhang, M., Li, J., et al. (2012) Berberine Attenuates Is-chemia-Reperfusion Injury via Regulation of Adenosine-5’-Monophosphate Kinase Activity in Both Non-Ischemic and Ischemic Areas of the Rat Heart. Cardiovascular Drugs & Therapy, 26, 467-478.
https://doi.org/10.1007/s10557-012-6422-0
[10] Zhang, T., Yang, S. and Du, J. (2014) Protective Effects of Ber-berine on Isoproterenol-Induced Acute Myocardial Ischemia in Rats through Regulating HMGB1-TLR4 Axis. Evi-dence-Based Complementray and Alternative Medicine, 11, 849783.
[11] Yu, L., Li, F., Zhao, G., et al. (2015) Protec-tive Effect of Berberine against Myocardial Ischemia Reperfusion Injury: Role of Notch1/Hes1-PTEN/Akt Signaling. Apoptosis, 20, 796.
https://doi.org/10.1007/s10495-015-1122-4
[12] Zhang, Y.J., Yang, S.H., Li, M.H., et al. (2014) Berberine Attenuates Adverse Left Ventricular Remodeling and Cardiac Dysfunction after Acute Myocardial Infarction in Rats: Role of Autophagy. Clinical & Experimental Pharmacology & Physiology, 41, 995.
https://doi.org/10.1111/1440-1681.12309
[13] Li, M.H., Zhang, Y.J., Yu, Y.H., et al. (2014) Berberine Improves Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction through Enhanced Autophagy. European Journal of Pharmacology, 728, 67-76.
https://doi.org/10.1016/j.ejphar.2014.01.061
[14] Wang, J.L. and Fang, D.C. (1995) Influence of Berberine on Rat Cardiac Output and on the Effect of Ouabain in Guinea Pig Left Etria. Chinese Journal of Pharmacology and Toxicology, 5, 1
[15] 黄伟民, 严桦, 于以庆, 等. 黄连素对冠状动脉的作用及机理[J]. 中华心血管病杂志, 1990, 18(4): 231.
[16] Shin, D.H., Yu, H. and Hsu, W.H. (1993) A Paradoxical Stimulatory Effect of Berberine on Guinea-Pig Ileum Contractility: Possible Involvement of Acetylcholine Release from the Postganglionic Parasympathetic Nerve and Cholinesterase Inhibition. Life Sciences, 53, 1495-1500.
https://doi.org/10.1016/0024-3205(93)90623-B
[17] Wong, K.K. (1998) Mechanism of the Aortic Relaxation Induced by Low Concentrations of Berberine. Planta Medica, 64, 756-757.
https://doi.org/10.1055/s-2006-957575
[18] He, K., Kou, S., Zou, Z., et al. (2016) Hypolipidemic Effects of Alkaloids from Rhizoma Coptidis in Diet-Induced Hyperlipidemic Hamsters. Planta Medica, 82, 690-697.
https://doi.org/10.1055/s-0035-1568261
[19] Thomson, D.M. and Winder, W.W. (2009) AMP-Activated Protein Kinase Control of Fat Metabolism in Skeletal Muscle. Acta Physiologica, 196, 147-154.
https://doi.org/10.1111/j.1748-1716.2009.01973.x
[20] Jiang, J.D., Kong, W.J., Zhao, L.X., et al. (2007) Methods and Compositions for the Treatment of Hyperlipidemia. US EP 1796666 A1.
[21] Wang, C., Huang, Z., Wang, L., et al. (2014) Application of Berberine Derivative in Preparation of Drug for Treating Atherosclerosis. CN 103804374 A.
[22] Liu, H., Li, G., Wang, J., et al. (2011) Berberine Derivatives Useful for Modulating Lipid Levels and Their Methods of Synthesis: WO, WO/2011/006000.
[23] Salehi, S. (2009) Effects of Medicinal Herbs on Contraction Rate of Cultured Cardiomyocyte. Possible Mechanisms Involved in the Chronotropic Effects of Hawthorn and Berberine in Neonatal Murine Cardiomyocyte. Dissertations & Theses Gradworks.
[24] Zhang, X.D., Ren, H.M. and Liu, L. (2008) Effects of Different Dose Berberine on Hemodynamic Parameters and [Ca2+]i of Cardiac Myocytes of Diastolic Heart Failure Rat Model. China Journal of Chinese Materia Medica, 33, 818.
[25] Li, Y.M., Chen, X.C., Liu, H., et al. (2009) Effects of Ginseng Total Saponins with Berberine on Plasma Brain Natriuretic Pep Tide and Ca2+ Concentration in Experimental Rats with Chronic Congestive Heart Failure. China Journal of Chinese Materia Medica, 34, 324-327.
[26] Dong, S.F., Hong, Y., Liu, M., et al. (2011) Berberine Attenuates Cardiac Dysfunction in Hyperglycemic and Hypercholesterolemic Rats. European Journal of Pharmacology, 660, 368-374.
https://doi.org/10.1016/j.ejphar.2011.03.024
[27] Mizokami, S.S., Hohmann, M.S.N., Staurengoferrari, L., et al. (2016) Pimaradienoic Acid Inhibits Carrageenan-Induced Inflammatory Leukocyte Recruitment and Eedema in Mice: Inhibition of Oxidative Stress, Nitric Oxide and Cytokine Production. PLoS ONE, 11, e0149656.
https://doi.org/10.1371/journal.pone.0149656
[28] Cho, Y.J. (2011) Anti-Inflammatory Effect of Jatrorhizine form Phellodendron amurense in Lipopolysaccharide-Stimulated Raw 264.7 Cells. Journal of Applied Biological Chemistry, 54, 114-119.
https://doi.org/10.3839/jabc.2011.020
[29] Yan, B., Wang, D., Dong, S., et al. (2017) Palmatine Inhibits TRIF-Dependent NF-κB Pathway against Inflammation Induced by LPS in Goat Endometrial Epithelial Cells. Interna-tional Immunopharmacology, 45, 194-200.
https://doi.org/10.1016/j.intimp.2017.02.004
[30] Gambhir, S., Vyas, D., Hollis, M., et al. (2015) Nuclear Factor Kappa B Role in Inflammation Associated Gastrointestinal Malignancies. World Journal of Gastroenterology, 21, 3174.
https://doi.org/10.3748/wjg.v21.i11.3174
[31] Mishra, K.P., Sharma, N., Soree, P., et al. (2016) Hypoxia-Induced Inflammatory Chemokines in Subjects with a History of High-Altitude Pulmonary Edema. Indian Journal of Clinical Biochemistry, 31, 81-86.
https://doi.org/10.1007/s12291-015-0491-3
[32] Cui, H.S., Hayasaka, S., Zhang, X.Y., et al. (2006) Effect of Berberrubine on Interleukin-8 and Monocyte Chemotactic Protein-1 Expression in Human Retinal Pigment Epithelial Cell Line. Life Sciences, 79, 949-956.
https://doi.org/10.1016/j.lfs.2006.05.004
[33] Zhou, H. and Mineshita, S. (2000) The Effect of Berberine Chloride on Experimental Colitis in Rats in Vivo and in Vitro. Journal of Pharmacology & Experimental Therapeutics, 294, 822-829.
[34] Yang, T.C., Chao, H.F., Shi, L.S., et al. (2014) Alkaloids from Coptis Chinensis Root Promote Glucose Uptake in C2C12 Myotubes. Fitoterapia, 93, 239-244.
https://doi.org/10.1016/j.fitote.2014.01.008
[35] Hamid, A., Yusoff, M.M., Liu, M., et al. (2015) α-Glucosidase and α-Amylase Inhibitory Constituents of Tinospora Crispa: Isolation and Chemical Profile Confirmation by Ultra-High Performance Liquid Chromatography-Quadrupole Time-of-Flight/Mass Spectrometry. Journal of Functional Foods, 16, 74-80.
https://doi.org/10.1016/j.jff.2015.04.011
[36] 欧阳礼枝, 陆付耳. 小檗碱对胰岛素抵抗大鼠糖脂代谢影响的研究[J]. 中国药物与临床, 2010, 10(10): 1089-1091.
[37] Zhang, J., Tang, H., Deng, R., et al. (2015) Berberine Sup-presses Adipocyte Differentiation via Decreasing CREB Transcriptional Activity. PLoS ONE, 10, e0125667.
https://doi.org/10.1371/journal.pone.0125667
[38] Choi, Y.J., Lee, K.Y., Jung, S.H., et al. (2017) Activation of AMPK by Berberine Induces Hepatic Lipid Accumulation by Upregulation of Fatty Acid Translocase CD36 in Mice. Toxicology & Applied Pharmacology, 316, 74-82.
https://doi.org/10.1016/j.taap.2016.12.019
[39] Sun, Y., Xia, M., Yan, H., et al. (2018) Berberine Attenuates He-patic Steatosis and Enhances Energy Expenditure in Mice by Inducing Autophagy and Fibroblast Growth Factor 21. British Journal of Pharmacology, 175, 374-387.
https://doi.org/10.1111/bph.14079
[40] Liang, K.W., Yin, S.C., Ting, C.T., et al. (2008) Berberine Inhibits Plate-let-Derived Growth Factor-Induced Growth and Migration Partly through an AMPK-Dependent Pathway in Vascular Smooth Muscle Cells. European Journal of Pharmacology, 590, 343-354.
https://doi.org/10.1016/j.ejphar.2008.06.034
[41] Hartmut, L., Mcmurray, H.R. and Sampson, E.R. (2009) Methods and Compositions Related to Synergistic Responses to Oncogenic Mutations. US, WO/2009/045443.
[42] Chung, J.G., Wu, L.T., Chu, C.B., et al. (1999) Effects of Berberine on Arylamine N-Acetyltransferase Activity in Human Bladder Tumour Cells. Food & Chemical Toxicology, 37, 319-326.
https://doi.org/10.1016/S0278-6915(99)00016-2
[43] Lin, J.G., Chung, J.G., Wu, L.T., et al. (1999) Effects of Berberine on Arylamine N-Acetyltransferase Activity in Human Colon Tumor Cells. The American Journal of Chinese Medicine, 27, 265-275.
https://doi.org/10.1142/S0192415X99000306
[44] Wang, D.Y., Yeh, C.C., Lee, J.H., et al. (2002) Berberine In-hibited Arylamine N-Acetyltransferase Activity and Gene Expression and DNA Adduct Formation in Human Malignant Astrocytoma (G9T/VGH) and Brain Glioblastoma Multiforms (GBM 8401) Cells. Neurochemical Research, 27, 883-889.
https://doi.org/10.1023/A:1020335430016
[45] Lin, S.S., Chung, J.G., Lin, J.P., et al. (2005) Berberine Inhibits Arylamine N-Acetyltransferase Activity and Gene Expression in Mouse Leukemia L1210 Cells. Phytomedicine, 12, 351.
https://doi.org/10.1016/j.phymed.2003.11.008
[46] Qin, Y., Pang, J.Y., Chen, W.H., et al. (2010) Inhibition of DNA Topoisomerase I by Natural and Synthetic Mono- and Dimeric Protoberberine Alkaloids. Chemistry & Biodiversity, 4, 481-487.
https://doi.org/10.1002/cbdv.200790040
[47] Hsieh, H.M., Lee, C.Y., Shen, C.C., et al. (2015) Berberine-Containing Pharmaceutical Composition for Inhibiting Cancer Stem Cell Growth or Carcinoma Metastasis and Application Thereof. US, US20150320738.
[48] Tin-Wa, M. (2007) Berberine as a Selective Lung Cancer Agent. US, US 20070298132 A1.
[49] Valko, M., Leibfritz, D., Moncol, J., et al. (2007) Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease. International Journal of Biochemistry & Cell Biology, 39, 44-84.
https://doi.org/10.1016/j.biocel.2006.07.001
[50] Jang, M.H., Kim, H.Y., Kang, K.S., et al. (2009) Hydroxyl Radical Scavenging Activities of Isoquinoline Alkaloids Isolated from Coptis chinensis. Archives of Pharmacal Research, 32, 341-345.
https://doi.org/10.1007/s12272-009-1305-z
[51] Boberek, J.M., Stach, J. and Good, L. (2010) Genetic Evidence for Inhibition of Bacterial Division Protein FtsZ by Berberine. PLoS ONE, 5, e13745.
https://doi.org/10.1371/journal.pone.0013745
[52] Peng, L., Shuai, K., Yin, Z., et al. (2015) Antibacterial Activity and Mechanism of Berberine against Streptococcus agalactiae. International Journal of Clinical and Experimental Pathology, 8, 5217-5223.
[53] Kang, S., Li, Z., Yin, Z., et al. (2015) The Antibacterial Mechanism of Berberine against Actinobacillus pleuropneumoniae. Natural Product Research, 29, 2203-2206.
https://doi.org/10.1080/14786419.2014.1001388
[54] Wojtyczka, R.D., Dziedzic, A., Kępa, M., et al. (2014) Berberine Enhances the Antibacterial Activity of Selected Antibiotics against Coagulase-Negative Staphylococcus Strains in Vitro. Molecules, 19, 6583-6596.
https://doi.org/10.3390/molecules19056583
[55] Kong, W., Li, Z., Xiao, X., et al. (2010) Activity of Berberine on Shigella Dysenteriae, Investigated by Microcalorimetry and Multivariate Analysis. Journal of Thermal Analysis & Calorimetry, 102, 331-336.
https://doi.org/10.1007/s10973-010-0778-9
[56] Wang, X., Qiu, S., Yao, X., et al. (2009) Berberine Inhibits Staphylococcus Epidermidis Adhesion and Biofilm Formation on the Surface of Titanium Alloy. Journal of Orthopaedic Research, 27, 1487.
https://doi.org/10.1002/jor.20917
[57] Wang, X., Yao, X., Zhu, Z., et al. (2009) Effect of Berberine on Staphylococcus Epidermidis Biofilm Formation. International Journal of Antimicrobial Agents, 34, 60-66.
https://doi.org/10.1016/j.ijantimicag.2008.10.033
[58] Bae, J., Lee, D., Yun, K.K., et al. (2013) Berberine Protects 6-Hydroxydopamine-Induced Human Dopaminergic Neuronal Cell Death through the Induction of Heme Oxygenase-1. Molecules & Cells, 35, 151-157.
https://doi.org/10.1007/s10059-013-2298-5
[59] Chin, L.S.W., Cheng, Y.W., Lin, S.S., et al. (2010) Anti-Herpes Simplex Virus Effects of Berberine from Coptidis Rhizoma, a Major Component of a Chinese Herbal Medicine, Ching-Wei-San. Archives of Virology, 155, 1933-1941.
https://doi.org/10.1007/s00705-010-0779-9
[60] Dkhil, M.A. and Al-Quraishy, S. (2014) Evaluation of Antiviral Activity of Berberine against Herpes Simplex Viruses. Journal of Pure & Applied Microbiology, 8, 155-159.
[61] Dkhil, M.A. (2014) Role of Berberine in Ameliorating Schistosoma Mansoni-Induced Hepatic Injury in Mice. Biological Research, 47, 1-7.
[62] Wu, Y., Li, J.Q., Kim, Y.J., et al. (2011) In Vivo and in Vitro Antiviral Effects of Berberine on Influenza Virus. Chinese Journal of Integrative Medicine, 17,444-452.
https://doi.org/10.1007/s11655-011-0640-3
[63] Shin, H.B., Choi, M.S., Yi, C.M., et al. (2015) Inhibition of Respiratory Syncytial Virus Replication and Virus-Induced p38 Kinase Activity by Berberine. International Im-munopharmacology, 27, 65-68.
https://doi.org/10.1016/j.intimp.2015.04.045
[64] Kwon, M., Choi, Y.A., Choi, M.K., et al. (2015) Organic Cation Transporter-Mediated Drug-Drug Interaction Potential between Berberine and Metformin. Archives of Pharmacal Research, 38, 849-856.
https://doi.org/10.1007/s12272-014-0510-6
[65] Zhou, Y., He, P., Liu, A., et al. (2012) Drug-Drug Interactions between Ketoconazole and Berberine in Rats: Pharmacokinetic Effects Benefit Pharmacodynamic Synergism. Phyto-therapy Research, 26,772-777.
https://doi.org/10.1002/ptr.3621
[66] 佟树敏, 李学静, 杨先芹. 0.6%苦•小檗碱杀菌水剂研制及在苹果树上的应用[J]. 农业环境科学学报, 2002, 21(1): 67-69.
[67] 余占海, 张国英, 张小恒, 等. 盐酸小檗碱对体外培养人牙周膜细胞生物活性的影响[J]. 实用口腔医学杂志, 2007, 23(5): 637-640.