中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
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WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
HERALD OF MEDICINE, 2018, 37(5): 586-592
doi: 10.3870/j.issn.1004-0781.2018.05.018
雷公藤的药理作用研究进展
胡德俊1, 彭泽燕2, 何东初2,

摘要:

雷公藤是一种化学成分复杂的中草药,随着基础和临床研究的深入,其药理作用的研究内容也日益丰富。雷公藤具有抗炎、调节免疫、镇痛、抗动脉粥样硬化、抗排异、抗肿瘤、抗生育、抗支原体、抗艾滋病毒、保护神经、保护肾脏、保护关节软骨等多种药理作用。该文综述了雷公藤的药理作用研究进展,为雷公藤的进一步研究提供理论基础,为雷公藤的临床合理应用提供参考。

关键词: 雷公藤 ; 药理作用 ; 合理用药

Abstract:

雷公藤(Tripterygium Wilfordii)的药用部位为卫矛科植物雷公藤的根,其别名众多,常用的有断肠草、钩吻。其性寒,味苦,有大毒,归属心、肝、胃、肾四经。雷公藤具有清热解毒、祛风除湿、舒筋活血通络、消肿止痛、杀虫止痒的功效。临床常用于治疗类风湿关节炎、急慢性肾小球肾炎等自身免疫性疾病,以及牛皮癣、湿疹等皮肤病,近年来也用于肿瘤的治疗。现代药理学研究表明:雷公藤治疗上述疾病的机制是通过调节免疫、抗炎等作用实现的。但其具体作用靶点不明确,仍需进一步探究,笔者综述了雷公藤药理作用的研究进展。

1 化学成分

雷公藤的化学成分十分复杂,目前已从雷公藤属植物中分离出380余种成分,就雷公藤一味中药分离出来的化学单体就高达70多种,包含生物碱类,萜类(二萜类、三萜类、倍半萜)以及糖类,其活性成分大部分为萜类物质和生物碱类[1]。近年来新兴的网络药理学也被用于雷公藤药理的研究,利用计算机模拟直观展示了雷公藤治疗类风湿关节炎的多成分、多靶点、多途径作用。严培晶等[2]基于分子对接的网络药理学计算机模拟方法,构建了雷公藤的化合物-靶点作用网络,发现其药效物质基础含有苯乙烯南蛇碱、表没食子儿茶精、雷公藤新碱和雷公藤甲素等46种化合物,可作用于肿瘤坏死因子α(TNF-α)、非受体酪氨酸激酶-1(janus kinase,JAK-1)、基质金属蛋白酶1(matrix metalloprotein-1,MMP-1)、MMP-3和MMP-9等10个靶点,以此发挥抗炎、调节免疫应答、抑制软骨和骨的破坏、改善类风湿关节炎血淤证等作用。雷公藤的化学成分很多,一系列低毒性成分逐渐被发现。TANG等[3]发现新型雷公藤内酯类似物(5R)-5-羟基雷公藤内酯,它的作用机制涉及多种免疫细胞和分子,包括限制性T细胞功能和增殖抑制巨噬细胞活化,诱导调控T细胞的扩增,干扰相关信号转导,不影响自然杀伤细胞的细胞毒活性,探索一系列新颖的、毒性低的雷公藤内酯类似物仍需深入研究。

2 药理作用
2.1 抗炎作用

雷公藤在炎症过程的早期及炎症递质的产生和释放过程中发挥着重要的抗炎作用。抗炎机制是通过抑制炎症递质、炎症细胞因子及炎症趋化因子的产生而实现的,例如抑制炎症因子TNF-α,白细胞介素-6(IL- 6),IL-8和黏附分子如血管细胞黏附分子(vascular cell adhesion molecule,VCAM),细胞间黏附分子(intercellular adhesion molecule,ICAM)等的表达[4],降低环氧化酶2(cyclooxygenase,COX-2)表达,提高血清超氧化物歧化酶水平和总抗氧化能力从而抑制炎症反应[5]。樊丹平等[6]用雷公藤甲素(triptolide,TP)干扰胶原诱导关节炎大鼠的研究中发现TP能抑制炎症趋化因子巨噬细胞炎症蛋白(MIP-1α)、嗜酸粒细胞趋化因子(eotaxin)和单核细胞趋化蛋白(MCP-1)的表达从而发挥抗炎作用。近年来研究发现雷公藤多苷(TWP)抑制炎症因子的机制可能与相关的信号通路有关。钦丹萍等[7]用雷公藤多苷干预用三硝基苯磺酸(TNBS)/乙醇灌胃建立的溃疡性结肠炎(ulcerative colitis,UC)大鼠模型,采用实时-聚合酶联免疫反应(RT-PCR)法和Western blotting法检测UC模型大鼠结肠组织中TLR4/MyD88非依赖信号通路上游因子[toll样受体4(TLR4)、核因子-κB(nuclear factor κB, NF-κB)]和末端炎症因子γ干扰素(interferon-γ,IFN-γ)在mRNA及蛋白水平的表达情况,结果提示雷公藤多苷能够改善UC大鼠的临床症状,促使黏膜愈合,抑制细胞因子TLR4,NF-κB,IFN-γ的产生。提示雷公藤多苷可以通过抑制TLR4/MyD88非依赖信号通路发挥抗炎作用。进一步研究发现雷公藤多苷片通过抑制miR-146a和miR-146b的表达,并能抑制TLR4/MyD88依赖信号通路及炎症因子IL-1β及TNF-α释放从而发挥抗炎作用[8]。郑健豪等[9]在研究雷公藤多苷对UC小鼠的作用机制中提出雷公藤多苷降低IL-1α、TNF-α等促炎因子的表达可能是通过抑制烟酰胺腺嘌呤二核苷酸磷酸氧化酶-活性氧簇- 氧化氮二氧合酶样受体蛋白3(nicotinamide adenine dinucleotide phosphate oxidase-reactive oxygen species- nitric oxide dioxygenase like receptor protein 3,NOXs-ROS-NLRP3)炎症小体信号通路而实现的。目前在探讨雷公藤抑制炎症因子的具体机制方面,一部分研究者认为与相关信号通路有关,但对具体炎症通路的认识不一致,这有待进一步研究佐证。

胡伟锋等[10]通过动物实验研究发现雷公藤内酯醇可降低类风湿关节炎模型大鼠血清中炎症细胞因子TNF-α、 IL-4 、IL-6的表达水平;进一步从网络药理学方面阐明雷公藤内酯醇的抗炎机制为通过调节丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导通路来抑制炎症细胞因子的产生和调节血管内皮生长因子(vascular endothelial growth factor,VEGF)信号转导通路在病变关节中抑制细胞因子的表达,来减少胶原蛋白的产生、抑制滑膜细胞增殖、减弱侵袭能力等。二者相互配合,从两个方面起到抗炎治疗作用。除了抑制炎症细胞因子的产生外,雷公藤多苷还通过抑制与炎症相关的细胞发挥抗炎作用。ZHAO等[11]研究表明雷公藤多苷可改善咪喹莫特诱导的皮肤损伤,机制是通过抑制信号传导及转录激活因子(signal transducers and activators of transcription,STAT3)的磷酸化抑制Th17细胞的作用。

雷公藤多苷抑制炎症反应的作用机制是抑制炎症递质、炎症细胞因子及炎症趋化因子的产生以及抑制Th17细胞作用而实现的。最新研究发现雷公藤多苷抑制炎症因子的机制可能与TLR4/MyD88非依赖信号通路、TLR4/MyD88依赖信号通路、NOXs-ROS-NLRP3炎症小体信号通路、MAPK信号转导通路以及VEGF信号转导通路有关;但仍未明确雷公藤在发挥抗炎作用的过程中各通路的关系及具体的分子靶点。这有待进一步探讨。

2.2 免疫调节作用

2.2.1 对细胞免疫的调节 雷公藤甲素呈剂量相关性抑制T细胞的增殖、诱导T细胞的凋亡、恢复Th1/Th2细胞平衡,调节细胞免疫。牛瑞芳等[12]在研究雷公藤多苷短期治疗对桥本病甲状腺组织中T细胞亚群等免疫学指标的影响中发现:雷公藤多苷通过下调总T淋巴细胞,减轻淋巴细胞浸润程度;能够下调C D 3 + C D 4 + 辅助性T细胞,降低T细胞亚群中辅助性T细胞百分比,纠正Th1/Th2失衡状态,减少自身抗体产生;提高C D 4 + C D 25 + 调节性T细胞百分比,提示雷公藤多苷可提高Treg细胞的数量,上调Treg细胞的百分比,进而抑制自身反应性T细胞的活化、增殖,维持机体免疫耐受;上调C D 3 + C D 8 + 细胞毒T细胞,抑制免疫亢进,改善免疫紊乱。自身免疫性疾病多因免疫功能紊乱而发生,雷公藤可恢复T淋巴细胞的比例,调节免疫功能,可能是它治疗免疫性疾病的机制之一。进一步研究[13]发现雷公藤调节细胞免疫的机制是不同程度地抑制T细胞中因刺激产生的NF-κB激酶抑制因子α(inhibitor α of nuclear factor kappa-B kinase,IKKα)和IKKβ。由此可知雷公藤调节细胞免疫的机制是通过抑制IKKα和IKKβ实现的。

2.2.2 对体液免疫的调节作用 雷公藤可以抑制B细胞增殖及免疫球蛋白的产生,调节体液免疫。刘敏等[14]研究发现雷公藤多苷治疗类风湿关节炎具有调节患者免疫功能的作用。雷公藤多苷能减少免疫球蛋白(IgG和IgM)、类风湿因子和免疫复合物的产生和形成,降低细胞活性物质在滑膜的沉积,降低类风湿关节炎患者的血清VEGF、VEGFR2表达水平,调节体液免疫。由此可知,雷公藤多苷在治疗自身免疫性疾病的机制是通过减少免疫球蛋白的产生进而调节体液免疫。近年来研究者发现其调节免疫功能可能与信号通路有关。张敏等[15]用雷公藤多苷干预变应性鼻炎模型大鼠,免疫组化法检测TNF-α、IL-5及免疫球蛋白(IgE)的量,RT-PCR及Western blotting检测TLR4和NF-κB的表达情况。研究发现雷公藤多苷通过影响TLR-NF-κB信号传导通路,降低IL-5、IgE、 TLR4和NF-κB的表达,发挥免疫调节作用。

2.3 镇痛作用

研究发现雷公藤内酯醇具有镇痛作用,能明显降低大鼠的的机械痛阈。对其镇痛机制的进一步研究发现,雷公藤内酯醇可能通过影响p38MAPK信号通路中相关蛋白的表达发挥镇痛作用。研究者通过检测p38MAPK信号通路中的相关指标发现其下调脊髓背角的磷酸化水平,从而降低星形胶质细胞和小胶质细胞的活性[16]。证实其镇痛作用与抑制信号通路髓背角的磷酸化有密切的关系。张旭东等[17]研究发现雷公藤内酯醇对佐剂性关节炎具有良好镇痛作用,其机制可能是抑制佐剂性关节炎大鼠脊髓背根神经节中单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)及趋化因子受体-2(chemokine receptor 2,CCR2)的表达。TANG等[18]研究发现雷公藤内酯呈剂量依赖性地发挥镇痛效果,机制可能是下调TNF-α、IL-1β和IL-6的水平,随后通过抑制JAK-STAT3信号通路的传导,从而阻止星形胶质细胞的激活。雷公藤内酯醇镇痛作用的具体机制可能与信号通路及炎症因子有关,目前国内外尚无定论,有待进一步研究。

2.4 抗动脉粥样硬化

动脉粥样硬化是一种炎症性疾病,雷公藤通过抑制炎症因子的表达具有抗动脉粥样硬化的作用。程治平等[19]用不同浓度雷公藤内酯醇腹腔注射处理动脉粥样硬化ApoE-/-小鼠。研究发现,经过3周雷公藤内酯醇腹腔注射治疗后,ApoE-/-小鼠主动脉的动脉粥样硬化病变程度均有不同程度缓解;与此同时也能使血清中抗炎因子IL-10的表达水平上调、促炎因子IL-12表达下调;其中,在75 μg·kg-1·d-1给药处理下效果最佳。GU等[20]研究发现雷公藤红素减少了NF-κB的抑制蛋白(inhibitor of NF-κB,IκB)的磷酸化和降解,降低诱导型一氧化氮合酶(inducible nitric oxide synthase,INOS),一氧化氮(NO)和促炎性细胞因子如TNF-α和IL-6的产生。研究结果提示,雷公藤红素可抑制ApoE(-/-)小鼠中动脉粥样硬化斑块形成,其机制是通过抑制脂蛋白受体-1的功能和减少氧化应激反应。抑制炎症反应可能为雷公藤内酯醇治疗动脉粥样硬化的机制之一。

2.5 抗排异作用

研究发现雷公藤在器官移植的抗排异反应中,具有疗效好、不良反应少、适用范围广等特点,其机制是抑制细胞和体液免疫。王远涛等[21]研究发现肾移植手术后应用雷公藤内酯醇可以明显降低肾移植手术后早期急性排斥发生率,加快患者肌酐恢复至正常的速度,同时降低手术后6个月急性排斥反应发生率,提示雷公藤有抗排异作用。正常健康个体具有免疫力,能保护机体免受外来生物的侵害,但是对于器官移植患者,只有减少其排异反应,才能增加移植成功的机率,其排异作用可能与抑制机体免疫功能有关。蔡龙俊等[22]研究发现雷公藤甲素剂量依赖性地抑制C D 4 + T淋巴细胞的增殖和促进活化的细胞凋亡;雷公藤甲素对转化生长因子β1(transforming growth factor beta 1,TGF-β1)诱导的Foxp3+Treg细胞有增强作用;在撤除抗C D 3 + 单抗刺激的条件下,雷公藤甲素进一步诱导C D 4 + T淋巴细胞表达Foxp3; 雷公藤甲素减少移植肾组织C D 3 + 、C D 4 + 、C D 25 + T淋巴细胞的浸润程度,增加脾脏Foxp3+ T淋巴细胞的比例,并延长同种大鼠移植肾的存活时间。该研究证实雷公藤通过抑制移植肾组织中淋巴细胞的浸润而发挥其抗排异作用。但其具体的分子机制仍处于研究阶段。

2.6 神经保护作用

实验表明,雷公藤内酯醇类(雷公藤内酯醇、雷公藤氯内酯醇和5-羟雷公藤内酯醇)可能通过抑制小胶质细胞活化和炎症反应因子的释放、抑制MAPKs和NF-κB信号通路、抗氧化活性、促进神经营养因子释放、拮抗兴奋性神经毒性和Ca2+超载,发挥神经保护作用。LI等[23]研究发现雷公藤内酯呈剂量依赖性地减少小胶质细胞的总数,并将小胶质细胞转化为静息状态,减少与小胶质细胞活化相关的促炎细胞因子的生成,对阿尔茨海默病发挥其保护作用。周子懿等[24]报道,雷公藤内酯有确切的小胶质细胞抑制作用,可减轻多巴胺能神经元的损伤。同时观察到雷公藤内酯可抑制CX3C趋化因子受体1(CX3C chemokine receptor 1,CX3CR1)的表达,提示CX3CR1可能是其抑制小胶质细胞的途径之一。王会玲等[25]报道,雷公藤内酯醇可抑制阿尔茨海默病细胞模型中小胶质细胞NF-κB的活化,该抑制作用可能参与了雷公藤内酯醇在阿尔茨海默病治疗中的神经保护机制。BAI等[26]研究发现雷公藤内酯醇发挥神经保护的机制是通过抑制NF-κB信号通路。LI等[27]研究发现雷公藤内酯醇在大脑中动脉闭塞大鼠模型中的神经保护作用的机制是使胞内磷脂酰肌醇激酶(intracellular phosphatidylinositol kinase,PI3K )/蛋白激酶B (protein kinase B,Akt) /哺乳类雷帕霉素靶蛋白( mammalian target of rapamycin,mTOR)通路激活和使ERK1/2通路的失活。

2.7 保护肾脏固有细胞功能

雷公藤甲素具有保护肾脏固有细胞的功能。该功能的发挥除了与免疫抑制、抗炎有关外,近年来研究发现还与雷公藤甲素可稳定足细胞骨架结构、抑制足突融合,可上调/增强Nephrin和Podocin、抑制细胞凋亡、调节足细胞Smad3,Smad7异常表达、遏制ROS的产生及P-38 MAPK信号通路的活化有关[28]。张勇军等[29]通过观察雷公藤多苷对糖尿病大鼠尿蛋白、肾小球硬化及足细胞的影响,发现雷公藤多苷具有减少糖尿病大鼠尿蛋白和肾组织中IV型胶原表达的作用,能增加肾组织中Nephrin、Podocin蛋白的表达,其作用效果与厄贝沙坦相似。雷公藤多苷有可能通过保护及修复糖尿病大鼠的足细胞功能,减轻肾小球硬化,改善肾功能,减少尿蛋白,发挥保护肾脏固有细胞的功能。王晓彤等[30]研究发现雷公藤甲素能够促使snail表达下调和Nephrin表达上调。其中Nephrin是构成足细胞裂孔隔膜的关键分子,在维持肾小球滤过屏障完整性及维护足细胞正常功能中发挥重要作用;snail可以抑制Nephrin的表达。由此可知雷公藤甲素保护肾脏的作用与调节足细胞相关蛋白的表达有关。MA等[31]研究发现雷公藤联合厄贝沙坦可以降低2型糖尿病肾病患者尿蛋白和足细胞的排泄,其机制可能是通过降低结缔组织生长因子(connective tissue growth factor,CTGF)和TGF-β1的水平。雷公藤通过调节足细胞相关蛋白的表达,维持足细胞的结构的稳定从而保护肾脏。但其具体的分子机制仍有待证实,目前认为可能与P-38 MAPK信号通路的活化有关。

2.8 骨保护作用

雷公藤多苷对关节炎软骨具有保护作用。其骨保护作用与免疫抑制和抗炎作用有密切关系;此外其骨保护作用还与抑制滑膜细胞增生和软骨组织表达NF-κB受体活化因子(receptor activator for nuclear factor-κB,RANK)和NF-κB受体活化因子配体(receptor activator for nuclear factor-κB ligand,RANKL)有关,其机制为通过调节MAPK信号转导通路来抑制炎症细胞因子的产生和调节VEGF信号转导通路在关节抑制细胞因子的表达,减少胶原蛋白的产生、抑制滑膜细胞增殖、减弱侵袭能力等[32]。陈晓昱[33]研究发现雷公藤甲素可抑制模型大鼠膝骨关节炎滑膜中c-Jun及MMP-9表达,降低外周血前列腺素E2及IL-8水平,抑制炎症反应,对骨关节炎有治疗作用。提示雷公藤多苷治疗膝骨关节炎的机制是通过抑制炎症因子的产生,从而保护关节。

2.9 抗肿瘤作用

雷公藤抗肿瘤作用逐渐成为研究的热点,研究表明雷公藤甲素可抑制多种恶性肿瘤的侵袭和转移作用,如鼻咽癌、食管癌、胃癌、肝癌、乳腺癌以及胰腺癌等[34]。迄今,研究发现其抗肿瘤作用的机制是抑制肿瘤细胞生长、阻滞细胞周期和诱导凋亡,可能与抑制癌细胞蛋白酶(Caspase蛋白酶)、信号通路(ERK信号通路和MAPK信号通路)、调控基因Bax(促凋亡基因)、Bcl-2(抑凋亡基因)、p53、Bcl-xL及XIAP的表达[35,36]有关。焦晓琳等[37]在研究雷公藤甲素诱导耐伊马替尼的白血病K562/G01细胞的凋亡中发现其机制可能是通过抑制p53基因的表达而发挥作用。王伟等[38]研究雷公藤在肺癌中的作用机制发现:雷公藤甲素能够抑制肺癌A549的细胞活力,并且诱导其发生自噬,同时还能够增加p-ERK的蛋白水平。ERK是一类丝/苏氨酸蛋白激酶,属于MAPK家族的一员,从而推测MAPK信号通路可能参与雷公藤甲素诱导的自噬。ZHAO等[39]研究发现,雷公藤内酯可诱导人前列腺癌细胞的保护性自噬,其机制可能是雷公藤内酯诱导内质网应激,导致内质网释放钙。 高细胞钙水平激活CaMKKβ-AMPK信号通路,其随后在人前列腺癌细胞中诱导细胞保护性自噬。同时,抑制自噬增强了雷公藤内酯的抗人前列腺癌细胞效应。该研究提示雷公藤内酯和药物自噬抑制药的联合治疗将是前列腺癌的有效治疗方法。XIE等[40]实验结果表明,雷公藤甲素呈剂量依赖性地抑制人肺癌耐药细胞A549/Taxol细胞的增殖,其机制可能是通过调节JNK和ERK信号通路来发挥其抑制作用。雷公藤内酯已被证明能促凋亡蛋白活化诱导细胞凋亡,抑制NF-κB和c-KIT的通路,抑制JAK2基因转录,激活MAPK8 / JNK信号通路和调节热休克反应。CHAUHAN等[41]进一步观察到雷公藤内酯的生物活性与2号染色体上调节凋亡途径的基因显著相关,例如CFLAR,PPIL3,Caspase 8 / 10,NF-κB和STAT6;并验证了调节凋亡途径的上游调节因子CFLAR在胰腺癌细胞系中对雷公藤内酯诱导的细胞毒性具有重要的作用。LI等[42]研究发现雷公藤内酯醇对雌激素受体阳性的人乳腺癌细胞的抑制作用可能是通过雌激素受体-α介导的信号通路的传导。目前认为其抗肿瘤作用与信号通路密切相关,但尚无定论,具体的生物靶点有待进一步研究。

2.10 抗生育作用

雷公藤甲素有显著的抗生育作用,在雄性生殖系统中影响生精过程和精子成熟,导致精子质量和活力下降;在雌性生殖系统中抑制卵巢功能,使卵母细胞受精率下降。雷公藤的抗生育作用可能与其能够抑制T型Ca2+通道有关[43]。目前研究发现其抗生育能力的具体机制可能与激活相关信号通路,诱导相关凋亡蛋白的表达有关。LIU等[44]研究发现雷公藤引起卵巢组织损伤、肉芽肿细胞肿胀坏死,炎症细胞浸润、出血的发生,卵巢肉芽肿细胞的凋亡尤为明显。研究表明其机制是雷公藤激活了大鼠卵巢组织中stkll-p53-p21信号转导通路,诱导p53蛋白的转录,激活的p53蛋白结合p21基因启动子,导致卵巢肉芽肿细胞的凋亡。雷公藤抗生育作用具有可逆性,明确其药理作用可为其在避孕方面的应用提供理论依据。

2.11 抗血管生成作用

雷公藤具有治疗类风湿关节炎的作用。类风湿关节炎以长期的慢性炎症及血管翳的生成为特点。由于血管翳的生成被认为是长期存在的炎症和免疫反应导致的结果,所以阻止类风湿关节炎的血管翳生长、血管生成的抑制作用已被提出作为类风湿性关节炎治疗的新策略。KONG等[45]研究发现雷公藤甲素能明显降低在发炎的关节滑膜组织中的血管翳生成。此外,雷公藤甲素显著降低血管因子包括TNF-α、IL-17、VEGF、VEGFR、Ang-1、Ang-2和Tie2,以及抑制IL-1β诱导的磷酸化ERK、p38和JNK蛋白水平。推测雷公藤甲素可能具有抗血管生成作用,其机制可能是通过下调血管生成因子和抑制丝裂原活化蛋白激酶的下游信号通路的传导。但这有待进一步研究证实。

2.12 其他作用(抗解脲支原体、艾滋病毒等)

雷公藤甲素和雷公藤红素具有抗艾滋病毒作用,其机制可能与影响相关基因的表达有关。研究表明其可以影响脂多糖(LPS)刺激后抗反转录病毒治疗的HIV-1患者外周血单个核细胞中干扰素刺激基因15 (ISG15)、MxA和MxB基因的表达[46,47]。此外,雷公藤多苷可用于治疗解脲支原体感染的前列腺炎。研究证实[48]其机制是下调解脲支原体诱导的非细菌性前列腺炎大鼠模型中的TNF-α、ICAM-1和NF-κB表达。

3 结束语

综上所述,雷公藤有抗炎、调节免疫、镇痛、抗动脉粥样硬化、抗排异、抗肿瘤、抗生育、抗血管生成、抗解脲支原体、抗艾滋病毒、保护神经、保护肾脏、保护关节软骨等多种药理作用。目前抗肿瘤作用的研究逐渐成为热点,但均处于细胞实验研究阶段,今后可从动物模型及相关信号通路方面进一步研究。目前,雷公藤药理作用的研究深度从细胞生物学水平深达基因学水平,从动物实验、细胞学实验发展到计算机网络药理学。多系统、多层次的研究更加全面地阐述了雷公藤的药理作用。但其具体作用靶点仍不十分明确,信号通路研究成为当今探讨其机制的热点,是今后研究雷公藤药理作用及其机制的方向。

The authors have declared that no competing interests exist.

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[7] 钦丹萍,周毅骏,孙佩娜,.雷公藤多苷对溃疡性结肠炎大鼠TLR4 / MyD88 非依赖信号通路的作用研究[J].中国中药杂志,2016,41(6):1093-1099.
为了研究雷公藤多苷(TWP)对三硝基苯磺酸(TNBS)/乙醇溃疡性结肠炎(UC)大鼠TLR4/My D88非依赖信号通路的调控作用,采用了TNBS/乙醇联合灌肠的方法建立TNBS/乙醇UC大鼠模型。模型建立成功后,将90只雄性Wistar大鼠随机分为正常对照组,模型对照组,TWP低、中、高剂量组(3,6,12 mg·kg~(-1)),硫唑嘌呤(AZA)组(6 g·kg~(-1)),每组15只。各组分别给予相应药物连续灌胃14 d。每隔3 d评估UC大鼠疾病活动指数(DAI)。14 d后解剖所有大鼠,留取相应结肠组织观察各组大鼠结肠组织大体及镜下病理表现,并对其进行评分。采用Western blot法和RT-PCR法检测UC大鼠结肠组织中TLR4/My D88非依赖信号通路相关分子(TLR4,TRAM,TRIF,NF-κB,IFN-γ)在mRNA及蛋白水平的表达情况。结果提示,DAI评分、大体及镜下表现和评分均提示TNBS/乙醇UC大鼠模型造模成功,TWP对UC大鼠临床症状的改善及黏膜愈合具有一定作用,该作用与AZA相比相当或强于AZA。RT-PCR及Western blot实验均提示,与正常对照组相比,模型对照组中TLR4/My D88非依赖信号通路相关的分子无论在mRNA还是蛋白水平表达均显著升高(P0.01)。与模型对照组相比,TWP呈剂量依赖性地抑制该信号通路上各节点分子mRNA及蛋白水平的表达,其中TWP高剂量组中各节点分子mRNA及蛋白表达水平显著低于模型对照组(P0.05)。与AZA组相比,TWP高剂量组对该信号通路上游因子(TLR4,TRAM,TRIF,NF-κB)mRNA及蛋白表达水平的抑制作用略好于AZA组,而对该信号通路的末端炎症因子IFN-γmRNA及蛋白水平的抑制作用却略逊于AZA组,但上述2种差异均无统计学意义。因此,在TNBS/乙醇UC大鼠模型中,My D88非依赖信号通路参与了炎症活动的调控,TWP可以通过抑制TLR4/My D88非依赖信号通路抑制IFN-γ的释放,发挥抗炎作用,其作用强度与剂量呈正相关。
DOI:10.4268/cjcmm20160620      URL    
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[8] 周毅骏,钦丹萍,杨新艳,.雷公藤多昔片对溃疡性结肠炎大鼠miR-146a,miR-146b及TLR4/MyD88依赖信号通路的调控作用研究[J].中草药,2016,47(10):1723-1730.
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[9] 郑健豪,钟继红,曹海军,.雷公藤多苷通过NOXs-ROS-NLRP3炎症小体信号通路抑制结肠炎症[J].中国病理生理杂志,2016,32(9):1653-1659.
<p><strong>目的:</strong>观察雷公藤多苷对右旋葡聚糖硫酸钠(dextran sulphate sodium,DSS)诱导的小鼠溃疡性结肠炎(ulcerative colitis,UC)的防治作用及对黏膜组织NADPH氧化酶(NADPH oxidases,NOXs)-活性氧簇(reactive oxygen species,ROS)-NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)炎症小体信号通路表达的影响,探讨其治疗溃疡性结肠炎的作用及机制。<strong>方法:</strong>BALB/c小鼠随机分为5组:模型组;低、中及高剂量雷公藤多苷灌胃组;正常组。采用DSS诱发UC动物模型,雷公藤多苷灌胃21 d后,取结肠组织,运用实时荧光定量PCR法检测结肠黏膜组织NLRP3、ASC及caspase-1的mRNA表达,免疫组化法检测结肠黏膜组织caspase-1的表达,ELISA法检测结肠组织匀浆上清IL-1&alpha;、TNF-&alpha;及IL-13的含量,鲁米诺化学发光法检测结肠黏膜组织ROS的生成和经DPI(NOXs抑制剂)抑制后的NADPH消耗率来分析NOXs活性;体外分离结肠组织中性粒细胞,检测分离的中性粒细胞中ROS的生成、NOXs活性以及NLRP3、ASC、caspase-1的mRNA表达。<strong>结果:</strong>雷公藤多苷灌胃各组小鼠结肠黏膜组织病理均存在不同程度异常,但组织病理学评分均低于模型组;雷公藤多苷灌胃各组结肠黏膜组织和分离的中性粒细胞中,除高剂量组结肠黏膜组织caspase-1的mRNA表达与正常组相比差异无统计学显著性外,其余各组ROS生成、NOXs活性及NLRP3、ASC、caspase-1的mRNA表达水平低于模型组(<em>P</em>&lt;0.05),高于正常组(<em>P</em>&lt;0.05);雷公藤多苷灌胃各组间两两比较发现,除中、高剂量组结肠黏膜组织及分离的中性粒细胞caspase-1的mRNA表达差异无统计学显著性外,其它指标相比均有统计学显著性(<em>P</em>&lt;0.05);雷公藤多苷灌胃各组小鼠结肠组织匀浆上清中促炎因子(IL1&alpha;和TNF-&alpha;)含量低于模型组(<em>P</em>&lt;0.05),高于正常组(<em>P</em>&lt;0.05),抑炎因子(IL-13)含量各组间比较差异无统计学显著性。<strong>结论:</strong>雷公藤多苷可能通过抑制NOXs-ROS-NLRP3炎症小体信号通路来降低IL-1&alpha;、TNF-&alpha;等促炎因子的表达从而对DSS诱导的UC小鼠起保护作用,中性粒细胞可能是参与其保护作用的主要炎性细胞。</p>
DOI:10.3969/j.issn.1000-4718.2016.09.020      Magsci     URL    
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[10] 胡伟锋,王昌兴.雷公藤内醋醇对类风湿关节炎大鼠的治疗作用及其网络药理学研究[J].中国全科医学,2016,19(12):1408-1413.
目的:评价雷公藤内酯醇对类风湿关节炎大鼠的治疗作用,并研究其作用机制的网络药理学。方法2014年12月—2015年7月选取 SPF 级健康 Wistar 大鼠40只,采用随机数字表法分为4组,分别为对照组、模型组、双氯芬酸组、雷公藤内酯醇组,每组10只。采用热杀死结核分枝杆菌诱导大鼠构建类风湿关节炎模型,造模成功后,双氯芬酸组大鼠给予10 mg/ kg 双氯芬酸灌胃,雷公藤内酯醇组大鼠给予6 mg/ kg 雷公藤内酯醇灌胃,对照组和模型组大鼠给予等量0.9%氯化钠溶液灌胃。采用酶联免疫吸附法测定大鼠血清中炎性细胞因子〔肿瘤坏死因子α(TNF-α)、白介素(IL)-4、IL-6〕表达水平;评价关节炎指数及足体积;利用 Chemidraw 2010软件将雷公藤内酯醇转换成3D形式,预测其可能的作用靶点;利用 Cytoscape 软件通过 BLAST 数据库和美国国家生物技术信息中心(NCBI)数据库进行蛋白质的功能注释和分类,得到雷公藤内酯醇的网络药理图。结果模型组、双氯芬酸组、雷公藤内酯醇组大鼠血清中TNF-α、IL-4、IL-6表达水平较对照组升高(P 0.05)。第4、8、12、16、20天双氯芬酸组、雷公藤内酯醇组大鼠关节炎指数较模型组降低(P 0.05)。第2、4、6、8、10、12、14、16、18、20天模型组、双氯芬酸组、雷公藤内酯醇组大鼠足体积较对照组增大(P 0.05);第18天双氯芬酸组大鼠足体积较雷公藤内酯醇组减小( P <0.05)。网络药理学研究示,6个靶点(MP2K1、ADH5、BACE1、ADK、GLO1、AKR1B1)存在基因-靶点-信号转导通路网络,9条信号转导通路与免疫和炎症相关,包括 focal adhesion、丝裂原活化蛋白激酶( MAPK)、血管内皮生长因子( VEGF)、toll - like receptor、ErbB、促性腺激素释放激素(GnRH)、NK cell - mediated cytotoxicity、Fc epsilon RI 和 B cell receptor 信号转导通路。结论雷公藤内酯醇治疗类风湿关节炎大鼠可降低TNF-α、IL-4、IL-6表达水平、关节炎指数、足体积,其治疗作用主要是通过调节 MAPK 和 VEGF 等信号转导通路实现。
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[11] ZHAO J Z,DI T T,WANG Y,et al.Multi-glycoside of Tripterygium wilfordii Hook F ameliorates imiquimod-induced skin lesions through a STAT3-dependent mechanism involving the inhibition of Th17-mediated inflammatory responses[J].Int J Mole Med,2016,38(3):747-757.
Multi-glycoside ofTripterygium wilfordiiHook. f. (GTW) possesses anti-inflammatory and immunosuppressive properties, and has been used as a traditional treatment for psoriasis for many years, although the underlying immunological mechanisms remain poorly understood. The T helper (Th)17 cell response is considered to play a major role in the pathogenesis of psoriasis. Th17 cells are implicated in the mechanism of pathogenesis of imiquimod (IMQ)-induced skin inflammation. Using a mouse model, we demonstrated that GTW protected mice from developing psoriasis-like lesions induced by topical IMQ administration. This protection was associated with significantly decreased mRNA levels of Th17 cytokines such as interleukin (IL)-17A, IL-17F and IL-22 in mouse skin samples as well as fewer IL-17-secreting splenic CD4+lymphocytes in IMQ-exposed mice. There were no significant effects on the proportion of CD4+interferon (IFN)-+T cells, CD4+IL-4+T cells and CD4+CD25+Foxp3+Treg cells in the spleen cells. Taken together with the unchanged mRNA levels of Th1 cytokine IFN-, Th2 cytokine IL-4 and Treg cytokine IL-10 in IMQ-exposed mouse skin following GTW administration, our findings suggest that the immunosuppressive effect of GTW in psoriasis is exerted mainly on Th17 cells, rather than on Th1, Th2 or Treg cells. Furthermore, we showed that GTW suppressed Th17 function through the inhibition of STAT3 phosphorylation. These results have the potential to pave the way for the use of GTW as an agent for the treatment of psoriasis.
DOI:10.3892/ijmm.2016.2670      PMID:27431437      URL    
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[12] 牛瑞芳,张春玲,翟亚萍,.雷公藤多苷短程治疗对桥本病甲状腺组织T细胞亚群的影响[J].山东大学学报(医学版),2014,25(3):86-91.
目的观察雷公藤多苷(TwP)短期治疗对桥本病甲状腺组织中T细胞亚群等免疫学指标的影响。方法60例桥本病患者随机平均分为2组,对照组根据甲状腺功能选用左旋甲状腺素钠或赛治治疗;雷公藤多苷组在对照组的基础上加服TWP。观察随访3个月,比较两组甲状腺组织中T细胞亚群:总T淋巴细胞(CD3^+)、调节性T细胞(Treg细胞)(CD4^+CD25^+)、辅助性T细胞(Tll细胞)(CD3^+CD4^+)、总B淋巴细胞(CD3-CDl9^+)、细胞毒T淋巴细胞(CD3^+CD8^+)百分比变化,淋巴细胞的浸润程度及外周血甲状腺球蛋白抗体(TG—Ab)、甲状腺过氧化物酶抗体(TPO—Ab)、促甲状腺激素受体抗体(TRAb)水平的差异。结果雷公藤多苷组:①甲状腺组织中CD3^+总T淋巴细胞、CD3^+CD4^+辅助性T细胞较治疗前下降(P均〈0.05),低于对照组(P均〈0.05);CD3^+CD8^+细胞毒T淋巴细胞、CD4^+CD25^+调节性T细胞较治疗前升高(P均〈0.05),高于对照组(P均〈0.05)。②甲状腺组织内重度淋巴细胞浸润例数较治疗前明显下降(P〈0.05),低于对照组(P〈0.05);⑧外周血TRAb转阴患者数较治疗前显著增高(P〈0.05),高于对照组(P〈0.05);TG—Ab及TPO—Ab的水平较治疗前明显下降(P〈0.05),低于对照组(P均〈0.05)。结论TWP短期治疗对桥本病甲状腺组织中T细胞亚群的分布有显著的调节作用,同时能降低甲状腺组织中淋巴细胞的浸润及自身免疫性抗体的水平。
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[13] HO L J,CHANG W L,CHEN A,et al.Differential immu-nomodulatory effects by Tripterygium wilfordii Hook F derived refined extract PG27 and its purified component PG490 (triptolide) in human peripheral blood T cells:potential therapeutics for arthritis and possible mechanisms explaining in part Chinese herbal theory “Junn-Chenn-Zuou-SS”[J].J Tran Med,2013,11(1):294.
DOI:10.1186/1479-5876-11-294      URL    
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[14] 刘敏,王培蓉,马方伟,.雷公藤多苷治疗类风湿性关节炎的临床观察及对血清VEGF、VEGFR2表达水平的影响研究[J].陕西中医,2016,37(1):72-74.
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[15] 张敏,王守安,刘黎星.雷公藤多苷干预TLR-NF-κB通路发挥免疫抑制作用[J].中草药,2014,45(9):1288-1292.
目的探讨雷公藤多苷在变应性鼻炎(allergic rhinitis,AR)发病中干预TLR-NF-κB通路的机制。方法100只大鼠随机分成4组:对照组、模型组、雷公藤多苷组、倍氯米松组,每组25只。应用卵清白蛋白制备AR模型,施加雷公藤多苷干预。HE染色观察鼻黏膜形态改变并计数炎性细胞浸润数,免疫组化法检测肿瘤坏死因子-α(TNF-α)、白细胞介素-5(IL-5)及免疫球蛋白(IgE)的量,实时定量PCR及Westernblotting检测Toll样受体(TLR4)和核因子-kB(NF-kB)的表达情况。结果模型组变应性损伤明显,鼻黏膜以嗜酸性粒细胞浸润为主,TNF-α、IL-5及IgE的表达较对照组明显增高,TLR4和NF-kB的表达较对照组也明显增高(P〈0.05);雷公藤多苷及倍氯米松组鼻黏膜以少量中性粒细胞浸润为主,IL-5、IgE、TLR4和NF-kB的表达较模型组明显降低(P〈0.05)。结论雷公藤多苷可通过影响TLR-NF-kB信号传导通路,降低TLR4及NF-kB的表达发挥免疫调节作用。
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[16] 王健,张春奎,张青,.雷公藤内酯醇(T10)通过抑制脊髓背角内p38-MAPK的磷酸化发挥镇痛作用的机制研究[J].神经解剖学杂志,2016,32(1):18-24.
目的:观察鞘内给予雷公藤内酯(triptolide,T10)对于慢性炎性痛和神经病理性痛模型大鼠脊髓背角小胶质细胞内p38丝裂原激活的蛋白激酶(p38 mitogen-activated protein kinase,MAPK)的磷酸化水平的影响。方法:采用大鼠足底注射完全弗式佐剂(complete Freund’s adjuvant,CFA)构建慢性炎性痛模型,L5脊神经结扎(spinal nerve ligation,SNL)和坐骨神经分支选择性结扎(spared nerve injury,SNI)的方法制作慢性神经病理性痛模型。利用von Frey丝刺激法连续观察造模后大鼠的痛行为变化;应用免疫荧光染色方法观察大鼠腰膨大节段胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)和电离钙绑定衔接分子1(ionized calcium binding adaptor molecule-1,Iba-1)的表达水平;应用Western Blot方法观察大鼠腰膨大节段p38 MAPK的磷酸化水平。结果:(1)行为学结果显示:CFA、SNL、SNI模型大鼠机械性痛阈均明显降低,且术后一周内与正常对照组相比均保持在较低水平(P0.01)。从术后第1 d起鞘内连续给予T10至第7 d,分别观察到T10能够明显提高上述模型大鼠手术侧后足的机械性痛阈(P0.05);但T10在SNL模型和SNI模型大鼠中的效果要弱于CFA引起的慢性炎性痛(P0.05)。(2)免疫荧光染色结果显示:CFA、SNL和SNI模型大鼠腰膨大脊髓背角内GFAP、Iba-1的表达明显高于正常对照组,而p-p38 MAPK阳性产物主要表达于小胶质细胞内。(3)Western Blot结果显示:造模后7 d脊髓背角内p-p38 MAPK的表达明显上调,鞘内给予T10后可以显著下调脊髓背角内p38的磷酸化水平(P0.05)。结论:鞘内给予T10有效缓解由于CFA、SNL和SNI诱导的慢性痛模型大鼠的机械性痛阈的机制可能是通过下调脊髓背角内p38 MAPK信号通路的磷酸化水平,进而达到抑制小胶质细胞和星形胶质细胞的活化。其次,T10对不同类型的疼痛模型的作用效果存在差异,对由CFA引起的慢性炎性痛的作用效果要强于由SNL和SNI诱导的慢性神经病理性痛。
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[17] 张旭东,杨若松,陈伟,.雷公藤内酯醇对佐剂性关节炎大鼠脊髓背根神经节中MCP-1及CCR2表达的影响[J].中成药,2016,38(6):1390-1393.
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[18] TANG J,LI Z H,GE S N,et al.The inhibition of spinal astrocytic JAK2-STAT3 pathway activation correlates with the analgesic effects of triptolide in the rat neuropathic pain model[M].//The Orient on the Victorian Stage :Cambridge University Press,2012:277-293.
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[19] 程治平,余斌,熊军,.雷公藤内醋醇对ApoE-/-小鼠动脉粥样硬化的作用研究[J].海南医学,2014,25(12):1725-1729.
目的:研究不同剂量雷公藤内酯醇对ApoE-/-小鼠动脉粥样硬化(Atherosclerosis,AS)的治疗效果。方法将4只10周龄雄性ApoE-/-小鼠作为模型组,4只10周龄雄性C57BL/6J小鼠作为对照组,适应性喂养1周后处死,取主动脉标本做HE染色。另将10周龄雄性ApoE-/-小鼠32只作为实验组,按每天每千克体重给药量随机分为4组:50μg/(kg·d)、75μg/(kg·d)组、100μg/(kg·d)、空白对照组,每组8只。10周龄雄性C57BL/6J小鼠8只作为阴性对照组。给药3周后处死小鼠,取主动脉标本做HE染色;收集血清,测定IL-10、IL-12含量。结果(1)在11周龄时两组主动脉HE染色Roberts&amp;Thompson方法评分分别为:模型组[(5.250±0.500)分]>对照组[(0.500±0.577)分],差异有统计学意义。(2)经不同浓度雷公藤内酯醇处理3周后,各组主动脉HE染色Roberts&amp;Thompson方法评分分别为:空白对照组[(6.500±0.189)分]>100μg/(kg·d)组[(4.625±0.183)分]>50μg/(kg·d)组[(3.375±0.183)分]>75μg/(kg·d)组[(1.375±0.183)分]>阴性对照组[(0.000±0.000)分],差异有统计学意义。(3)75μg/(kg·d)组血清中IL-10浓度升高最明显,与各组比较差异均有统计学意义(P<0.001);各组血清中IL-12浓度均较空白对照组降低,其中75μg/(kg·d)组降低最明显,两者之间的差异有统计学意义( P<0.01)。结论(1)在11周龄时,ApoE-/-小鼠能形成AS模型。(2)不同浓度雷公藤内酯醇处理3周后,ApoE-/-小鼠AS病变有不同程度缓解,其中75μg/(kg·d)浓度下效果最佳。(3)雷公藤内酯醇能够上调IL-10、下调IL-12的表达水平,抑制炎症反应,减轻粥样斑块的形成,此可能为免疫抑制剂抗动脉粥样硬化的机制之一。
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[20] GU L,BAI W,LI S,et al.Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress.[J].PLoS One,2013,8(6):e65477.
Celastrol is a triterpenoid compound extracted from the Chinese herb Tripterygium wilfordii Hook F. Previous research has revealed its anti-oxidant, anti-inflammatory, anti-cancer and immunosuppressive properties. Here, we investigated whether celastrol inhibits oxidized low-density lipoprotein (oxLDL) induced oxidative stress in RAW 264.7 cells. In addition, the effect of celastrol on atherosclerosis in vivo was assessed in apolipoprotein E knockout (apoE(-/-)) mouse fed a high-fat/high-cholesterol diet (HFC). We found that celastrol significantly attenuated oxLDL-induced excessive expression of lectin-like oxidized low density lipoprotein receptor-1(LOX-1) and generation of reactive oxygen species (ROS) in cultured RAW264.7 macrophages. Celastrol also decreased IB phosphorylation and degradation and reduced production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)- and IL-6. Celastrol reduced atherosclerotic plaque size in apoE(-/-) mice. The expression of LOX-1 within the atherosclerotic lesions and generation of superoxide in mouse aorta were also significantly reduced by celastrol while the lipid profile was not improved. In conclusion, our results show that celastrol inhibits atherosclerotic plaque developing in apoE(-/-) mice via inhibiting LOX-1 and oxidative stress.
DOI:10.1371/journal.pone.0065477      PMID:23799016      URL    
[本文引用:1]
[21] 王远涛,高宝山,姚立宇,.雷公藤多苷片在肾移植术后早期抗排斥中的作用[J].中国老年学杂志,2015,35(21):6190-6191.
目的探讨肾移植术后围术期及术后6个月应用雷公藤(TW)多苷的临床效果。方法对80例同期肾移植受者进行对照性临床研究,随机分为TW组和未应用TW环孢素(Cs A)组各40例。患者术后给予Cs A、吗替麦考酚酯及激素三联免疫抑制疗法。观察患者围术期及术后6个月排斥反应发生情况。结果肾移植术后应用TW可以明显降低肾移植术后早期急性排斥发生率,加快患者肌酐恢复至正常的速度,同时降低术后6个月急性排斥反应发生率。结论 TW多苷片可降肾移植早期急性排斥反应发生率,加快患者恢复速度。
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[22] 蔡龙俊,张古田,吴鸿雁,.雷公藤甲素抑制大鼠移植肾排斥反应的免疫调节作用及其机制[J].中华器官移植杂志,2014,35(3):170-174.
目的 评价雷公藤甲素(TPT)对诱导调节性T淋巴细胞(Treg细胞)的影响和抑制同种大鼠移植肾急性排斥反应的作用及其可能机制.方法 利用磁珠分选纯化大鼠CD4+T淋巴细胞,观察TPT抑制CD4+T淋巴细胞增殖和促进其凋亡的效应;经抗CD3单抗和抗CD28单抗共刺激与转化生长因 子β1 (TGF-β1)的联合作用诱导Foxp3+ Treg细胞的分化,在分别加入不同剂量的TPT、环孢素A或撤除抗CD3单抗刺激因素的条件下,检测Foxp3表达水平的变化.建立同种大鼠肾移植急性 排斥反应模型,受者腹腔注射TPT,观察移植肾组织淋巴细胞浸润和脾脏淋巴细胞亚群的变化及移植肾存活时间.结果 TPT剂量依赖性的抑制CD4+T淋巴细胞的增殖和促进活化的细胞凋亡;与环孢素A相比,TPT对TGF-β1诱导的Foxp3+ Treg细胞有增强作用;在撤除抗CD3单抗刺激刺激的条件下,TPT进一步诱导CD4+T淋巴细胞表达Foxp3; TPT减少移植肾组织CD3+、CD4+、CD25+T淋巴细胞的浸润程度,增加脾脏Foxp3+T淋巴细胞的比例,并延长同种大鼠移植肾的存活时间 (P<0.05).结论 TPT可促进CD4+T淋巴细胞分化为Foxp3+ Treg细胞,可能是TPT发挥免疫抑制作用的机制之一.
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[23] LI J M,ZHAANG Y,TANG L,et al.Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer’s disease[J].Neu Rege Res,2016,11(9):1492-1498.
The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.
DOI:10.4103/1673-5374.191224      PMID:5090855      URL    
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[24] 周子懿,高俊鹏,向军,.CX3CR1参与雷公藤内酯对MPP+帕金森病大鼠多巴胺能神经元的保护作用[J].中国病理生理杂志,2015,31(4):659-663.
<p>目的: 探讨雷公藤内酯对1-甲基-4-苯基吡啶(MPP<sup>+</sup>)帕金森病模型大鼠的保护作用及其可能机制。方法: 采用MPP<sup>+</sup>黑质内注射建立帕金森病大鼠模型。实验分为假手术组、模型组、雷公藤内酯组及其溶剂对照组,利用酪氨酸羟化酶(TH)免疫荧光强度测定多巴胺神经元存活率、小胶质细胞标记物OX-42免疫荧光强度测定小胶质细胞激活程度、Western blotting测定趋化因子受体CX3CR1表达量。结果: 免疫组化结果表明,MPP<sup>+</sup>黑质内注射可使模型组OX-42免疫荧光强度增高,DA神经元进行性变性死亡。雷公藤内酯组OX-42免疫荧光强度较模型组低(<em>P</em>&lt;0.01),TH阳性神经元数量较模型组多(<em>P</em>&lt;0.01)。Western blotting结果提示雷公藤内酯组CX3CR1表达量较模型组低(<em>P</em>&lt;0.05)。结论: 雷公藤内酯对MPP<sup>+</sup>帕金森病大鼠模型具有神经保护作用,其机制可能与抑制小胶质细胞激活有关,抑制CX3CR1可能是其抑制小胶质细胞的途径之一。</p>
DOI:10.3969/j.issn.1000-4718.2015.04.015      Magsci     URL    
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[25] 王会玲,周晓春,龚理,.雷公藤内醋醇对AD细胞模型核因子κB表达及炎症因子释放的影响[J].时珍国医国药,2013,24(5):1100-1102.
目的观察雷公藤内酯醇(triptolide,T10)对β-淀粉样蛋白(β- amyloid,Aβ)1-42激活的小胶质细胞核因子κB(nuclear factor,NF-κB)表达及炎性因子释放的影响。方法用10μmol/L Aβ1-42作用12 h建立小胶质细胞活化-AD炎症细胞模型。用不同浓度的T10(10-11,10-10,10-9,10-8mol/L)预孵育小胶质细胞12 h,然后加入10μmol/L Aβ1-42共孵育12 h,ELISA法检测上清肿瘤坏死因子(tumor necrosis factor,TNF-α)、白介素(interleukin,IL-1β)的含量,West-ern blot检测NF-κB的表达。结果与Aβ组相比T10可减少Aβ1-42诱导的小胶质细胞TNF-α、IL-1β的释放和NF-κB的表达,差别具有显 著性。结论雷公藤内酯醇可抑制AD细胞模型中小胶质细胞NF-κB的活化,该抑制作用可能参与了T10在AD治疗中的神经保护机制。
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[26] BAI S,HU Z,YANG Y,et al.Anti-inflammatory and neuro-protective effects of triptolide via the NF-κB signaling pathway in a rat MCAO model[J].Anatomical Record,2016,299(2):256-266.
Stroke is the leading cause of neurological disability in humans. Middle cerebral artery occlusion (MCAO) followed by reperfusion is widely accepted to mimic stroke in basic medical research. Triptolide is one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, and has been reported to have potent anti-inflammatory and immunosuppressive properties. Since its preclinical effects on stroke were still unclear, we decided to study the effects of Triptolide on focal cerebral ischemia/reperfusion injury in this study. The results showed that Triptolide treatment significantly attenuates brain infarction volume, water content, neurological deficits, and neuronal cell death rate, which were increased in the MCAO model rats. Immunohistochemistry was used to analyze the expression of glial fibrillary acidic protein (GFAP), Cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), and NF-κB in the ischemic brains. The administration of Triptolide showed down-regulation of the iNOS, COX-2, GFAP, and NF-κB expression in MCAO rats. It also increased the expression of bcl-2, and suppressed levels of bax and caspase-3 compared with the MCAO group. Our findings revealed that Triptolide exerts its neuroprotective effects against inflammation with the involvement of inhibition of NF-κB activation. Anat Rec, 299:256–266, 2016. 08 2015 Wiley Periodicals, Inc.
DOI:10.1002/ar.23293      PMID:26575184      URL    
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[27] LI W Y,YANG Y,HU Z,et al.Neuroprotective effects of DAHP and triptolide in focal cerebral ischemia via apoptosis inhibition and PI3K/Akt/mTOR pathway activation[J].Fron Neu,2015,9(48):48-60.
Triptolide (TP), one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, and 2, 4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of tetrahydrobiopterin (BH4) synthesis, have been reported to have potent anti-inflammatory and immunosuppressive properties. However, the protective effects of TP and DAHP on cerebral ischemia have not been reported yet. In this study, we investigated the neuroprotective effects of TP and DAHP in a middle cerebral artery occlusion (MCAO) rat model. Furthermore, we examined whether the neuroprotective effects of TP and DAHP were associated with the inhibition of apoptosis through suppressing BH4 and inducible NOS (iNOS) synthesis or the activation of the phosphoinositide-3-kinase/serine-threonine kinase Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Our results showed that pretreatments with TP (0.2 mg/kg) and DAHP (0.5 g/kg) significantly reduced ischemic lesion volume, water content, and neuronal cell death compared with the vehicle MCAO rats. In addition, compared with the MCAO group, TP, and DAHP pretreatment groups significantly reduced astrocyte numbers, caspase-3, cleaved caspase-3, and NF-B up-regulation, while increased Bcl-2 expression. Moreover, protein expressions of PI3K, Akt, and mTOR increased, while extracellular signal-regulated protein kinases 1 and 2 (ERK1 and ERK2) phosphorylation decreased in both the TP-treated rats and DAHP-treated rats. These results demonstrate that TP and DAHP can decrease cell apoptosis in focal cerebral ischemia rat brains and that the mechanism may be related to the activation of the PI3K/Akt/mTOR pathway and inactivation of the ERK1/2 pathway. Thus our hypothesis was reached PI3K/Akt/mTOR and ERK1/2 pathways may provide distinct cellular targets for a new generation of therapeutic agents for the treatment of stroke, and TP and DAHP may be potential neuroprotective agents for cerebral ischemia/reperfusion injury.
DOI:10.3389/fnana.2015.00048      PMID:25954164      URL    
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[28] 李响,程晓霞.雷公藤甲素对足细胞保护机制的研究进展[J].江西中医药大学学报,2016,28(1):118-121.
雷公藤甲素(Triptolide,T10),又名雷公藤内酯醇,是雷公藤多种有效提取成分中免疫抑制及抗炎作用最强的单体。近年研究发现,T10不仅能通过诱导淋巴细胞凋亡、抑制淋巴细胞增殖来减少蛋白尿、治疗肾脏疾病,还能通过多种机制对肾小球滤过屏障的重要成分足细胞起到保护作用。本文从足细胞损伤机制出发,将T10对足细胞保护机制的研究进展进行综述。
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[29] 张勇军,刘冬,孙永苹,.雷公藤多苷对糖尿病大鼠尿蛋白、肾小球硬化及足细胞的影响[J].新医学,2013,44(7):504-507.
目的 观察雷公藤多甙(TWP)对糖尿病大鼠尿蛋白、肾小球硬化及足细胞的影响,探讨TWP对糖尿病大鼠肾脏保护作用的效果及可能的机制.方法 运用链脲佐菌素(STZ)建立糖尿病大鼠模型,设立TWP组(给予TWP治疗8周)、厄贝沙坦组(给予厄贝沙坦治疗8周)、模型对照组及正常对照组各8 只,检测各组的24h尿蛋白定量、Ⅳ型胶原表达水平以及肾组织中Nephrin蛋白与Podocin蛋白表达水平,并进行比较.结果 8周后各药物干预组24 h尿蛋白定量和肾组织中的Ⅳ型胶原表达水平均低于模型组(P均<0.05),其中TWP组和厄贝沙坦组间的24 h尿蛋白定量比较差异无统计学意义,但TWP组的Ⅳ型胶原表达水平低于厄贝沙坦组(P <0.05);TWP组和厄贝沙坦组Nephrin和Podocin蛋白表达均强于模型对照组,但TWP组和厄贝沙坦组间比较差异无统计学意义.结论 TWP可能通过减少糖尿病大鼠的尿蛋白及减轻其肾小球硬化达到保护肾脏的作用,其机制可能与TWP具有保护肾脏足细胞的功能有关.
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[30] 王晓彤,崔国峰.雷公藤甲素干预足细胞snaill 、nephrin表达的研究[J].中国中西医结合肾病杂志,2014,15(10):903-905.
目的:通过观察高糖刺激对小鼠足细胞 snail1、nephrin 表达的影响及雷公藤甲素(triptolide,TP)的干预作用,探讨 TP 保护足细胞的分子机制。方法:以体外培养的小鼠永生化足细胞为研究对象,将其分为正常糖组、高糖组、甘露醇组、TP 干预组,培养时间为48 h。采用荧光定量 PCR 法和 western blot 分别检测各组足细胞 snail1、nephrin mRNA 和蛋白的表达量。结果:与正常糖组相比,高糖刺激可以上调足细胞 snail1表达、下调 nephrin 表达;与高糖组相比,TP 干预组 snail1表达减少,而 nephrin 表达增加。结论:TP 可以减轻高糖引起的 snail 表达上调和 nephrin 表达下调,这可能是雷公藤甲素发挥足细胞保护作用的重要分子机制。
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[31] MA R X,XU Y,JIANG W,et al.Combination of Tripterv-gium wilfordii Hook F and angiotensin receptor blocker synergistically reduces excretion of urinary podocytes in patients with type 2 diabetic kidney disease[J].Biotech Biotechnol Equip,2015,29,(1):139-146.
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[32] 胡伟锋,王昌兴.雷公藤内酯醇对类风湿关节炎大鼠的治疗作用及其网络药理学研究[J].中国全科医学,2016,19(12):1408-1413.
目的:评价雷公藤内酯醇对类风湿关节炎大鼠的治疗作用,并研究其作用机制的网络药理学。方法2014年12月—2015年7月选取 SPF 级健康 Wistar 大鼠40只,采用随机数字表法分为4组,分别为对照组、模型组、双氯芬酸组、雷公藤内酯醇组,每组10只。采用热杀死结核分枝杆菌诱导大鼠构建类风湿关节炎模型,造模成功后,双氯芬酸组大鼠给予10 mg/ kg 双氯芬酸灌胃,雷公藤内酯醇组大鼠给予6 mg/ kg 雷公藤内酯醇灌胃,对照组和模型组大鼠给予等量0.9%氯化钠溶液灌胃。采用酶联免疫吸附法测定大鼠血清中炎性细胞因子〔肿瘤坏死因子α(TNF-α)、白介素(IL)-4、IL-6〕表达水平;评价关节炎指数及足体积;利用 Chemidraw 2010软件将雷公藤内酯醇转换成3D形式,预测其可能的作用靶点;利用 Cytoscape 软件通过 BLAST 数据库和美国国家生物技术信息中心(NCBI)数据库进行蛋白质的功能注释和分类,得到雷公藤内酯醇的网络药理图。结果模型组、双氯芬酸组、雷公藤内酯醇组大鼠血清中TNF-α、IL-4、IL-6表达水平较对照组升高(P 0.05)。第4、8、12、16、20天双氯芬酸组、雷公藤内酯醇组大鼠关节炎指数较模型组降低(P 0.05)。第2、4、6、8、10、12、14、16、18、20天模型组、双氯芬酸组、雷公藤内酯醇组大鼠足体积较对照组增大(P 0.05);第18天双氯芬酸组大鼠足体积较雷公藤内酯醇组减小( P <0.05)。网络药理学研究示,6个靶点(MP2K1、ADH5、BACE1、ADK、GLO1、AKR1B1)存在基因-靶点-信号转导通路网络,9条信号转导通路与免疫和炎症相关,包括 focal adhesion、丝裂原活化蛋白激酶( MAPK)、血管内皮生长因子( VEGF)、toll - like receptor、ErbB、促性腺激素释放激素(GnRH)、NK cell - mediated cytotoxicity、Fc epsilon RI 和 B cell receptor 信号转导通路。结论雷公藤内酯醇治疗类风湿关节炎大鼠可降低TNF-α、IL-4、IL-6表达水平、关节炎指数、足体积,其治疗作用主要是通过调节 MAPK 和 VEGF 等信号转导通路实现。
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[33] 陈晓昱. 雷公藤甲素对MIA模型大鼠膝骨关节炎c-Jun,MMP-9表达及血清炎性标志物的影响[J].实用药物与临床,2015,18(11):1293-1296.
目的观察雷公藤甲素对膝部骨关节炎滑膜c-Jun、MMP-9及血清PGE2、IL-8水平的影响,探讨其在膝部骨关节炎中的药理学价值。方法 45只SD大鼠随机分为正常对照组、模型对照组及雷公藤甲素组,建立碘乙酸钠(Monosodium iodoacetate,MIA)膝关节炎模型,并给予雷公藤甲素干预,以Western blot及(qRT)-PCR法检测c-Jun及M M P-9在膝关节滑膜中蛋白及mRNA水平表达,以酶联免疫法检测外周血中PGE2及IL-8水平。结果 Western blot及(qRT)-PCR显示,c-Jun及MMP-9在膝关节滑膜组织中蛋白及mRNA水平上均有表达,雷公藤甲素组及正常对照组明显低于模型对照组(P〈0.01),雷公藤甲素组与正常对照组比较差异无统计学意义(P〉0.05);在血清PGE2及IL-8表达上,雷公藤甲素组及正常对照组明显低于模型对照组(P〈0.05)。结论雷公藤甲素可抑制骨关节炎滑膜中c-Jun及MMP-9表达,降低外周血PGE2及IL-8水平,抑制炎症反应,对骨关节炎有治疗作用。
DOI:10.14053/j.cnki.ppcr.201511006      URL    
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[34] 张静. 雷公藤甲素在调控人鼻咽癌转移相关基因中的作用及机制[J].医药导报,2013,32(12):1560-1562.
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[35] 袁菱,董德银.雷公藤红素及其制剂的抗肿瘤研究进展[J].中国医院药学杂志,2016,36(14):1224-1229.
在2006年Huanjie Yang等发现雷公藤红素可以诱导前列腺癌细胞凋亡及肿瘤坏死,是一种有效的天然蛋白酶抑制剂,自此引发了雷公藤红素抗癌作用及其机制的研究热潮。雷公藤红素可以通过多方面发挥其抗癌作用,包括抑制肿瘤细胞生长、阻滞细胞周期和诱导凋亡,抑制癌细胞蛋白酶,抑制信号通路,影响肿瘤相关蛋白、肿瘤坏死因子等,是一种潜在的天然抗肿瘤药物,对前列腺癌、肺癌、肝癌、白血病、胶质瘤、黑色素瘤、结肠癌、卵巢癌、乳腺癌等肿瘤细胞具有一定的抗肿瘤作用。然而由于其性质较为不稳定,而且存在毒性,为了拓宽雷公藤红素的临床应用,充分发挥其药理药效作用,采用药物制剂新技术降低雷公藤红素毒性,提高其溶解度是目前重要的研究方向之一。本文对2006年以来雷公藤红素及其制剂的抗肿瘤作用相关文献资料进行分析和综述,为今后雷公藤红素抗肿瘤新型制剂的研究提供参考。
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[36] 许永亮. 雷公藤甲素抗生育作用研究进展[J].海峡药学,2015,27(11):11-13.
雷公藤甲素为雷公藤多苷片主要有效成分之一,具有显著的抗癌、抗炎、免疫抑制等药理活性,被临床广泛用于治疗类风湿性关节炎、系统性红斑狼疮等自身免疫疾病,同时雷公藤甲素有显著的抗生育作用,影响雄性生殖系统的生精过程和精子成熟,导致精子质量和活力下降;影响雌性生殖系统卵巢功能,使卵母细胞受精率下降。本文将近年来有关雷公藤甲素抗生育作用的研究进行综述,分析总结了雷公藤甲素对雄性生殖系统和雌性生殖系统的损害机制和毒性作用,并提出雷公藤甲素新的研究方向,为其在临床安全合理地应用提供依据。
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[37] 焦晓琳,马梁明,鹿育晋.雷公藤甲素通过MDM2-p53通路诱导白血病K562/G01细胞凋亡的研究[J].白血病·淋巴瘤,2016,25(6):336-343.
目的:探讨雷公藤甲素(TP)诱导伊马替尼耐药的K562/G01细胞的凋亡作用及机制。方法采用四甲基偶氮唑盐(MTT)法测定不同浓度TP作用的K562/G01细胞增殖抑制情况,流式细胞术检测细胞凋亡率,实时荧光定量PCR法检测bcr-abl、XIAP、MDM2、p53等mRNA的表达。结果10、20、40、80、100 nmol/L TP作用12、24、48 h,K562/G01细胞增殖受到抑制,呈时间-剂量依赖性;20、40 nmol/L TP分别作用K562/G01细胞12 h和24 h,细胞凋亡率呈时间-剂量依赖性;TP能降低bcr-abl、XIAP、MDM2 mRNA的表达,升高p53 mRNA的表达。结论TP可抑制K562/G01细胞增殖,诱导凋亡,其机制可能是通过XIAP-MDM2-p53通路相关基因的表达影响K562/G01细胞的增殖及凋亡。
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[38] 王伟,王坤.雷公藤甲素通过ERK通路诱导肺癌A549细胞自噬[J].中国病理生理杂志,2016,32(9):1551-1555.
<p><strong>目的:</strong>研究雷公藤甲素(tripchlorolide,TP)对肺癌A549细胞活力及自噬的影响,并初步探讨其作用机制。<strong>方法:</strong>应用TP作用于肺癌A549细胞后,MTT法检测细胞活力;吖啶橙染色(AO)法在荧光显微镜下观察细胞自噬状态;GFP-LC3质粒转染实验观察细胞胞质中绿色点状聚集的自噬小体;Western blot法检测自噬相关蛋白LC3-Ⅱ的表达情况及有关的信号通路ERK蛋白水平的变化。<strong>结果:</strong>TP可以显著抑制肺癌A549细胞的增殖(<em>P</em>&lt;0.05),并呈一定的剂量-时间依赖关系。TP作用于肺癌A549细胞48 h后,细胞内酸性滤泡染成亮红色荧光比例增多。GFP-LC3转染实验结果显示在100 nmol/L TP处理后,细胞胞质中出现绿色点状聚集的自噬小体,而正常培养组极少细胞有自噬小体形成;同时转染GFP-control质粒的细胞在100 nmol/L TP处理及正常培养条件下均未观察到点状聚集的自噬小体产生。TP作用于肺癌A549细胞48 h后,与对照组相比,100 nmol/L TP组LC3-Ⅱ蛋白表达水平显著升高(<em>P</em>&lt;0.01),同时p-ERK/ERK蛋白水平也显著升高(<em>P</em>&lt;0.01);与100 nmol/L TP组相比,TP+3-MA组LC3-Ⅱ蛋白表达水平显著下降(<em>P</em>&lt;0.01),同时p-ERK/ERK蛋白水平也显著下降(<em>P</em>&lt;0.01)。<strong>结论:</strong>TP可显著抑制肺癌A549细胞活力并诱导细胞发生自噬,这种作用可能与影响ERK的磷酸化有关。</p>
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[39] ZHAO F,HUANG W,ZHANG Z,et al.Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells[J].Oncotarget,2016,7(5):5366-5382.
Abstract Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4-2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKK-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKK-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.
DOI:10.18632/oncotarget.6783      PMID:26734992      URL    
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[40] XIE C Q,ZHOU P,ZUO J,et al.Triptolide exerts pro-apoptotic and cell cycle arrest activity on drug-resistant human lung cancer A549/Taxol cells via modulation of MAPK and PI3K/Akt signaling pathways[J].Oncol Lett,2016,12(5):3586-3590.
Multidrug resistance (MDR) is a major obstacle in the effective chemotherapeutic treatment of cancers. Triptolide (TPL) is a diterpenoid isolated from Tripterygium02wilfordii Hook. f., a traditional Chinese medicine. It was demonstrated in our previous study that TPL exerts anti62MDR cancers on various MDR cell lines (including A549/Taxol, MCF627/ADR and Bel7402/562Fu). The present study was designed to investigate its anti62proliferative activity on A549/Taxol cells, and explore the underlying mechanism of action. The anti62proliferative activity of TPL on A549/Taxol cells was assessed by 362(4,562dimethylthiazol62262yl)622,562diphenyltetrazolium bromide (MTT) assay. Its pro62apoptosis and cell cycle arrest activities were analyzed by flow cytometry. Western blot assay was employed to investigate the levels of mitogen-activated protein kinases (MAPKs) and apoptosis62related proteins in cells. TPL efficiently suppressed the proliferation of A549/Taxol cells. Co62treatment with MAPK inhibitors in the MTT assay indicated that the extracellular signal62regulated kinase (ERK) and c62Jun N62terminal kinase (JNK) pathways were involved in the process. Upregulation of p62p38, p62ERK, p62GSK623β, Bax and cleaved caspases623 and 629, and downregulation of p62JNK, p62Akt and Bcl622 were observed upon treatment with TPL in the A549/Taxol cells. The results from flow cytometry assay revealed that TPL induced apoptosis and S62phase arrest in A549/Taxol cells. This occurred as a result of the upregulation of p62ERK and p62GSK623β, and the downregulation of p62JNK and p62Akt, and was responsible for the subsequent anti-proliferative activity.
DOI:10.3892/ol.2016.5099      PMID:27900040      URL    
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[41] CHAUHAN L,JENKIMS G D,BHISE N,et al.Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity[J].BMC Genomics,2015,16(1):483-500.
Background Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses. Results In the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC 50 (p???<???0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity. Conclusions Overall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients.
DOI:10.1186/s12864-015-1614-1      PMID:26121980      URL    
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[42] LI H,PAN G,JIANG Z,et al.Triptolide inhibits human breast cancer MCF-7 cell growth via downregulation of the ER|[alpha]|-mediated signaling pathway[J].Acta Pharmacologica Sinica,2015,36(5):606-613.
To investigate the anticancer mechanisms of triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook F, against human breast cancer cells and the involvement of the estrogen receptor-α (ERα)-mediated signaling pathway in particular.Human breast cancer ERα-positive MCF-7 cells and ERα-negative MDA-MB-231 cells were tested. PrestoBlue assay was used to evaluate the cell viability. The levels of ERα mRNA and protein were detected with real-time PCR and immunoblotting, respectively. Mouse models of MCF-7 or MDA-MB-231 xenograft tumors were treated with triptolide (0.4 mg·kg(-1)·d(-1), po) or a selective estrogen receptor modulator tamoxifen (mg·kg(-1)·d(-1), po) for 3 weeks, and the tumor weight and volume were measured.Triptolide (5-200 nmol/L) dose-dependently inhibited the viability of both MCF-7 and MDA-MB-231 cells, with a more potent inhibition on MCF-7 cells. Knockdown of ERα in MCF-7 cells by siRNA significantly attenuated the cytotoxicity of triptolide, whereas overexpression of ERα in MDA-MB-231 cells markedly enhanced the cytotoxicity. Triptolide dose-dependently decreased the expression of ERα in MCF-7 cells and MCF-7 xenograft tumors. Furthermore, treatment of MCF-7 cells with triptolide inhibited the phosphorylation of ERK1/2 in dose- and time-dependent manners. In the mice xenografted with MCF-7 cells, treatment with triptolide or tamoxifen resulted in significant reduction in the tumor weight and volume. Similar effects were not obtained in the mice xenografted with MDA-MB-231 cells.The anticancer activity of triptolide against ERα-positive human breast cancer is partially mediated by downregulation of the ERα-mediated signaling pathway.
DOI:10.1038/aps.2014.162      PMID:25864647      URL    
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[43] JIANG X,HUANG X C,AO L,et al.Total alkaloids of Tripterygium hypoglaucum (levl.)Hutch inhibits tumor growth both in vitro and in vivo[J].J Ethnopharmac,2014,151(1):292-298.
THHta was effective in inhibiting tumor growth both in vitro and in vivo at less toxic concentrations by inducing apoptosis which suggested it could be developed as a potential anticancer agent.
DOI:10.1016/j.jep.2013.10.045      PMID:24212079      URL    
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[44] LIU T E,ZHANG L,WANG S,et al.Tripterygium glycosi-des induce premature ovarian failure in rats by promoting p53 phosphorylation and activating the serine/threonine kinase 11-p53-p21 signaling pathway[J].Exp Therap Med,2015,10(1):12-18.
Premature ovarian failure (POF) is a typical pathological disease of the reproductive system in aging females. Infection, inflammation, immune abnormalities, genetic mutation, radiotherapy and chemotherapy can cause POF. Tripterygium glycosides (TGs) are a component extracted from the Chinese herb Tripterygium02wilfordii Hook.02f., also known as Huangteng. Although TGs have been used to treat various diseases, drug resistance and toxicity can affect patients. The aim of the present study was to investigate the mechanism of TG62induced POF in rats. The rats were treated with different concentrations of TG, and pathology assays showed that the TG62induced POF was predominantly composed of interstitial cells in a fibrous matrix with a reduced number of follicles at each stage and an increased number of collapsed oocytes. Furthermore, reverse transcription62quantitative polymerase chain reaction (PCR) and immunohistochemistry assays indicated that the expression levels of serine/threonine kinase0211 (Stk11), p53 p21 and activated caspase623 were elevated significantly in the TG62treated groups. Serine0215 phosphorylation of p53 was also enhanced significantly in the TG62treated groups. In addition, a chromatin immunoprecipitation62PCR assay revealed that the TGs induced p53 activation and enhanced the transcription of p21. In conclusion, TGs induce apoptosis and necrosis in rat ovarian tissues, as well as POF, via p53 phosphorylation and activation of the Stk11-p53-p21 signaling pathway.
DOI:10.3892/etm.2015.2498      PMID:26170905      URL    
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[45] KONG X,ZHANG Y,LIU C,et al.Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade[J].PLoS One,2013,8(10):e77513.
Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA) model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (1109“45 0008g/kg/day) starting on the day 1 after first immunization. The arthritis scores (P<0.05) and the arthritis incidence (P<0.05) of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 1109030445 0008g/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05). Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS09“RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS09“RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-02±, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-0205-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway.
DOI:10.1371/journal.pone.0077513      PMID:3810371      URL    
[本文引用:1]
[46] 申琳,运乃茹.浅述雷公藤研究进展[J].医学信息,2015,28(36):393-394.
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[47] 李春杏,李太生,朱珠,.雷公藤在HIV-1/AIDS辅助治疗方面的研究现状[J].中华中医药杂志,2015,30(8):2857-2861.
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[48] SHAN P,LU Z,YE L,et al.Effect of Tripterygium wilfordii polyglycoside on experimental prostatitis caused by ureaplasma urealyticumin rats[J].Med Sci Moni Int Med J Exp Clin Res,2016,15(22):3722-3726.
Prostatitis is a common and refractory urological disease with complicated etiology.Ureaplasma urealyticum(UU) has a close relationship with human urinary tract infection that can induce nonbacterial prostatitis.Tripterygium wilfordiipolyglycoside (TWP) is a non-steroidal immune inhibitor that causes significant immune suppression and anti-inflammatory effects. Its role in prostatitis caused by UU has not yet been established. The aim of this study was to investigate the effect of TWP on UU-infected prostatitis in a rat model. UU-infected prostatitis SD model rats were randomly divided into 2 groups: the prostatitis group (model group) and the TWP treatment group (treatment group). At 7 days after treatment, prostate weight, leucocyte count, lecithin corpuscles, UU infection rate, and UU microbe count were compared between the 2 groups. Serum inflammatory cytokines TNF-α was determined by ELISA, and ICAM-1 and NF-κB expression were detected. UU infection rate was 80% after modeling. The rat prostate weight and leucocyte count in the model group increased significantly, while lecithin corpuscles decreased. Compared with controls, inflammatory factor TNF-α, ICAM-1, and NF-κB expression were obviously higher (P<0.05). TWP markedly reduced prostate weight and leucocyte count, increased lecithin corpuscles, and decreased UU microbe count and TNF-α, ICAM-1, and NF-κB expression (P<0.05). TWP can inhibit expression of inflammatory factors and may be useful in treating UU-infected prostatitis through reducing UU infection rate.
DOI:10.12659/MSM.897360      PMID:5070633      URL    
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雷公藤
药理作用
合理用药


作者
胡德俊
彭泽燕
何东初