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柴胡皂苷A的药理活性和作用机制研究现状及进展

  • 肖丽霞1

    机 构：

    1. 兰州大学第二临床医学院,甘肃 兰州 730030

    ×
  • ，周辉年2

    机 构：

    2. 兰州大学第二医院,甘肃 兰州 730030

    ×
  • ，龙勃2

    机 构：

    2. 兰州大学第二医院,甘肃 兰州 730030

    ×
  • ，焦作义2

    机 构：

    2. 兰州大学第二医院,甘肃 兰州 730030

    ×

1. 兰州大学第二临床医学院,甘肃 兰州 730030；
2. 兰州大学第二医院,甘肃 兰州 730030；

Advances on the pharmacological activity and mechanism of saikosaponin A

  • Xiao Lixia1

    Affiliation：

    1. Second College of Clinical Medicine, Lanzhou University, Lanzhou 730030 , Gansu, China

    ×
  • ，Zhou Huinian2

    Affiliation：

    2. Lanzhou University Second Hospital, Lanzhou 730030 , Gansu, China

    ×
  • ，Long Bo2

    Affiliation：

    2. Lanzhou University Second Hospital, Lanzhou 730030 , Gansu, China

    ×
  • ，Jiao Zuoyi2

    Affiliation：

    2. Lanzhou University Second Hospital, Lanzhou 730030 , Gansu, China

    ×

1. Second College of Clinical Medicine, Lanzhou University, Lanzhou 730030 , Gansu, China；
2. Lanzhou University Second Hospital, Lanzhou 730030 , Gansu, China；

通讯作者:

焦作义(1977-),男,甘肃天水人,博士生导师,主要从事消化系肿瘤的基础和转化研究。E-mail:jiaozy@lzu.edu.cn

中图分类号:R966,R-1

文献标识码:A

文章编号:2096-8965(2021)04-0060-07

DOI:10.12287/j.issn.2096-8965.20210408

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目录contents

    摘要

    柴胡皂苷A （Saikosaponin A, SSA） 在中华人民共和国药典 （国家药典委员会2020年版） 中被规定为评价柴胡质量的标记化合物之一。目前对于柴胡及其方剂的临床应用已经比较广泛，但是对于其主要活性成分SSA的药理活性和作用机制的研究仍处于探索阶段。研究显示SSA在体内外均具有生物活性，尤其是在抗炎、抗肿瘤、免疫调节、神经调节与抗病毒等方面。本文旨在结合文献资料深入探讨SSA的体内外药理活性及作用机制，为其今后的进一步开发与临床应用提供参考。

    Abstract

    Saikosaponin A (SSA) is specified as one of the labeled compounds for evaluating the quality of Bupleurum in the Pharmacopoeia of the People's Republic of China (the 2020 edition of the Chinese Pharmacopoeia Commission). Since its discovery, SSA has been found to play an important role in treating diverse diseases via a variety of mechanisms. This review summarizes the current research status and prospects of activities of SSA, providing novel insights into the limitations of current studies. In addition, it discusses whether SSA can be applied in clinical therapy and the possible mechanisms by which SSA may facilitate therapy. The research is significant to understand the potentials of SSA in the development of SSA-based therapeutic strategies and clinical practice.

  • SSA（C 42H 68O 13）（见图1） 是柴胡和银柴胡的主要活性成分之一，属于皂苷衍生物，其结构骨架为五环三萜类齐墩果烷型[1]，相对分子质量780.99g/mol。SSA对于炎性疾病[2]、肿瘤[3]、免疫系统疾病[4]、神经系统疾病[5]、病毒感染性疾病[6] 等皆具有药理活性。目前，SSA在用于过敏性鼻炎、子宫内膜炎、肺炎、胰腺炎、胰腺纤维化、心肌纤维化、肝纤维化、脑损伤、肾损伤、肝损伤、缺血再灌注损伤、银屑病、肥胖症、乳腺癌、过敏性哮喘、假性过敏反应、抑郁、焦虑、癫痫疾病的作用机制研究相对多，为未来可能的临床转化研究奠定了基础。

  • 图1 SSA的化学结构

  • 图2 SSA的抗炎机制

  • 1 抗炎活性

  • 炎症反应存在于诸多疾病中，药物的抗炎活性研究颇为重要。研究显示SSA的抗炎活性在柴胡皂苷中最强，针对其抗炎活性的研究也最多，其抗炎核心机制 （见图2） 可以总结为SSA通过减弱IκBα 的磷酸化和p65NF-κB由胞质入核来抑制NF-κB信号通路的激活[7]。相关研究团队对SSA的抗炎活性的研究各有侧重，详细研究内容见表1。

  • 2 抗肿瘤活性

  • SSA作为一种中药提取物，在多种疾病的抗炎过程中具有重要作用，同样对机体免疫系统也具有调节作用，而炎症、免疫和肿瘤发生发展具有较多交互作用，同时由于SSA具有低毒特性，因此在抗肿瘤研究中引起了较多关注 （见图3）。Zhao等[26] 研究发现，SSA可以通过IL-12/STAT4途径使Th1/Th2平衡向Th1移动来缓解乳腺癌；而Wang等[3] 发现， SSA可通过CXCR4/SDF-1、 Akt/mTOR、 PI3K/Akt途径缓解三阴性乳腺癌的发生发展。随着临床化疗药物大剂量、长时程应用的增加，化疗药物敏感性降低和多药耐药问题日趋明显，有研究显示SSA通过细胞凋亡途径可以增敏顺铂[27]，并可以通过下调Wnt/β-catenin信号通路逆转肺癌细胞A549对顺铂的耐药性[28]，改善包括阿霉素、长春新碱、紫杉醇在内的化疗药物的多药耐药性[29]。虽然化疗能够有效抑制肿瘤，但是化疗后患者容易出现骨髓抑制导致的中性粒细胞减少，最新研究表明，SSA可以通过CBL-ERK1/2通路明显逆转环磷酰胺诱导的中性粒细胞减少[30]。对SSA的结构进行更深入的研究后发现，SSA的C-16、C-23位 α 构型羟基可促进其细胞毒性作用，有效杀伤人肝癌细胞系HepG2及Hep3B、人乳腺癌细胞系Bcap-37及MCF-7和人肺腺癌细胞系A549[31]。目前关于SSA的抗肿瘤活性仅在乳腺癌中有较深入的机制研究，SSA对其他肿瘤的抗肿瘤活性的作用机制仍不清楚，有待继续深入探索。

  • 表1 SSA的抗炎活性

  • 3 免疫调节活性

  • SSA的免疫调节活性与T细胞密切相关。SSA可直接抑制T细胞的增殖和活化，导致细胞周期停滞在G0/G1期，并通过线粒体途径诱导凋亡，从而在Sprague-Dawley大鼠中显示其免疫调节作用[32]； 也可通过抑制NF-κB通路间接减少Th2和Th17细胞因子的产生，从而改善卵清蛋白诱导的小鼠过敏性鼻炎[8] 和大鼠过敏性哮喘[33]。

  • 除T细胞外，SSA还可通过Mas相关基因Mrg⁃ prx2途径减少钙离子内流和人肥大细胞LAD2脱颗粒来抑制化合物诱导的不依赖于IgE的假过敏反应[4]；通过Wnt/β-catenin通路促进骨髓基质细胞的成骨分化，间接调节造血干细胞形成[34]，进而影响免疫系统。由此可见，针对SSA免疫调节活性的研究较少 （见图3），可供参考的机制尚不全面。

  • 图3 SSA的抗肿瘤、免疫调节、神经调节机制

  • 4 神经调节活性

  • 最新研究表明，SSA通过p-CREB/BDNF通路改善脑缺血后抑郁样行为并抑制海马神经元凋亡[5]。此前也有诸多研究表明，SSA可通过改善下丘脑-垂体-肾上腺轴的失调以减少神经炎症并促进脑源性神经营养因子表达[35]、上调PRRT2的表达水平和海马中多巴胺的含量[36]，以及通过mTOR信号通路[37] 改善各种原因所致的抑郁症状。抑郁和焦虑可谓一体两面，通过mTOR信号通路亦可缓解慢性皮质激素导致的焦虑作用[37]。

  • 除了在抗焦虑和抗抑郁方面发挥作用，还有研究发现，SSA可通过减弱海马神经元的自发性癫痫样放电并上调电压门控型钾通道介导的A型电压门控钾电流来缓解癫痫症状[38]，还通过下调多巴胺转运蛋白和增强自发性高血压大鼠的脑源性神经营养因子表达减轻多动障碍的症状[39]。Maccioni等[40] 先后发现，SSA可通过激活γ-氨基丁酸B受体降低大鼠对酒精的自我摄取，并通过5-羟色胺2C受体降低暴饮暴食大鼠对黄油或巧克力饼干的进食[41]。 SSA由于其显著的药理活性和低毒高效的作用机制，有望成为治疗神经系统疾病的新药物（见图3）。

  • 5 抗病毒活性

  • 新型冠状病毒肺炎发生后，Yan等[6] 应用分子对接研究发现，SSA与SARS-CoV-2ACEⅡ受体具有高亲和力，并可抑制M蛋白酶以发挥抗2019-nCoV作用。当然，Cheng等[42] 也证明SSA可通过减弱病毒的附着和侵入以显著抑制HCoV-229E病毒感染。受新冠肺炎的影响，近两年对于冠状病毒的研究众多，遗憾的是，尚未发现显著有效的治疗药物。

  • 6 总结及展望

  • SSA是柴胡皂苷A~D中一种结构明确、研究最深入的小分子植物提取物，尤其在抗炎、抗肿瘤、免疫调节、神经调节和抗病毒等相关研究中对其作用机制进行了深入细致的探索。截止目前，在SSA抗炎方面的研究成果最为丰富，例如通过Nrf2/NF-κB分别改善铅诱导的肾损伤和LPS诱导的子宫内膜炎，以及通过Nrf2/HO-1可改善氧-葡萄糖剥夺/复氧刺激的脑缺血缺氧损伤和通过Keap1/Nrf2-ARE可改善牛黄胆酸钠诱导的急性重症胰腺炎；还可通过IL-6/ROR-γt/STAT3/IL-17/NF-κB诸多通路缓解卵清蛋白诱发的过敏性鼻炎，通过PPAR-γ/NF-κB改善高脂饮食和牛黄胆酸钠诱导的高脂血症性胰腺炎，通过NLRP3/NF-κB改善LPS诱导的急性肺损伤，通过SIRT1/NF-κB改善福尔马林诱导的急性炎性小鼠足肿胀，通过NOD2/NF-κB缓解CCl4 诱导的肝损伤，通过ERK/NF-κB改善肥胖症，通过NF-κB通路也可治疗咪喹莫特诱导的银屑病和香烟烟雾导致的肺炎。此外，SSA亦可通过抑制核内HMGB1释放入血改善缺血再灌注损伤，通过AMPK/mTOR减缓胰腺纤维化，通过TGFβ/smad和Wnt/β-catenin减缓心肌纤维化、通过固有线粒体途径缓解肝纤维化，通过ERK1/2/p38MAPK和JNK/p38MAPK改善动脉粥样硬化，通过MAPK缓解外伤性脑损伤。同时，由于SSA具有低毒副作用，其抗炎研究在临床转化中也被广泛关注，尤其是韩国在2014年就对SSA治疗胃病进行了多药物联合实验，获得良好的研究成果并申报了发明专利。纵观现有研究，SSA针对各类疾病均有较好的疗效，且相应的分子机制也较为明确，但是这些研究目前仍停留在细胞和细胞系异种移植模型 （Cell line De⁃ rived Xenograft，CDX） 水平，需要更好的临床前类器官模型和人源性肿瘤异种移植模型 （Patient De⁃ rived Xenograft，PDX） 进行验证。SSA具有的抗炎、抗肿瘤、免疫调节、神经调节和抗病毒活性，为治疗包括肿瘤在内的诸多疾病提供了新的方案。期望在未来的研究中能够将SSA的基础研究向临床研究转化，使其真正成为造福患者的良药，体现天然产物的重要价值。

  • 参考文献

    • [1] YANG Y Y,TANG Y Z,FAN C L,et al.Identification and determination of the saikosaponins in Radix bupleuri by accelerated solvent extraction combined with rapid-resolution LC-MS[J].J Sep Sci,2010,33(13):1933-1945.

    • [2] SONG Y Y,SUN H W,GAO S Y,et al.Saikosaponin A attenuates lead-induced kidney injury through activating Nrf2 signaling pathway[J].Comp Biochem Physiol C Toxicol Pharmacol,2021,242:108945.

    • [3] WANG Y,ZHAO L,HAN X H,et al.Saikosaponin A inhibits triple-negative breast cancer growth and metastasis through downregulation of CXCR4[J].Frontiers in Oncology,2019,9:1487.

    • [4] WANG N,CHE D L,ZHANG T,et al.Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo[J].Biochemical Pharmacology,2018,148:147-154.

    • [5] WANG A R,MI L F,ZHANG Z L,et al.Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia through p-CREB/BDNF pathway[J].Behavioural Brain Research,2021,403:113138.

    • [6] YAN Y M,SHEN X,CAO Y K,et al.Discovery of anti-2019-nCoV agents from Chinese patent drugs via docking screening [J].Preprints,2020.

    • [7] LU C N,YUAN Z G,ZHANG X L,et al.Saikosaponin A and its epimer Saikosaponin D exhibit anti-inflammatory activity by suppressing activation of NF-κB signaling pathway[J].International Immunopharmacology,2012,14(1):121-126.

    • [8] 何静,王珏岚,邹福兰,等.柴胡皂苷A上调HO-1对新生大鼠神经 OGD/R 损伤的影响[J].郑州大学学报(医学版),2021,56(4):525-529.

    • [9] PIAO C H,SONG C H,LEE E J,et al.Saikosaponin A ameliorates nasal inflammation by suppressing IL-6/ROR-γt/STAT3/IL-17/NF-κB pathway in OVA-induced allergic rhinitis[J].Chemico-biological Interactions,2020,315:108874.

    • [10] WANG X Y,YANG G F.Saikosaponin A attenuates neural injury caused by ischemia/reperfusion[J].Trans-lational Neuroscience,2020,11(1):227-235.

    • [11] CUI L H,LI C X,ZHUO Y Z,et al.Corrigendum to "Saikosaponin A inhibits the activation of pancreatic stellate cells by suppressing autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway"[J].Biomedicine & Pharmacotherapy,2020,130:110685.

    • [12] CUI L H,LI C X,ZHUO Y Z,et al.Saikosaponin A inhibits the activation of pancreatic stellate cells by suppressing autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway[J].Biomedicine & Pharmacotherapy,2020,128:110216.

    • [13] FENG P P,XU Y F,TONG B Y,et al.Saikosaponin A attenuates hyperlipidemic pancreatitis in rats via the PPAR-γ/NF-κB signaling pathway[J].Experimental and Therapeutic Medicine,2020,19(2):1203-1212.

    • [14] LI J,HAN J F,LV J,et al.Saikosaponin A-induced gut microbiota changes attenuate severe acute pancreatitis through the activation of Keap1/Nrf2-ARE antioxidant signaling[J].Oxidative Medicine and Cellular Longevity,2020,2020:9217219.

    • [15] LIU M,ZHANG G F,NAQVI S,et al.Cytotoxicity of Saikosaponin A targets HEKα cell through apoptosis induction by ROS accumulation and inflammation suppression via NF-κB pathway[J].International Immun-opharmacology,2020,86:106751.

    • [16] WANG J,WANG W W,PANG Y T.Saikosaponin A inhibits LPS-induced endometritis in mice through activating Nrf2 signaling pathway[J].Inflammation,2018,41(4):1508-1514.

    • [17] DU Z A,SUN M N,HU Z S.Saikosaponin A ameliorates LPS-induced acute lung injury in mice[J].Inflammation,2018,41(1):193-198.

    • [18] CHEN R J,GUO X Y,CHENG B H,et al.Saikosaponin A inhibits cigarette smoke-induced oxidant stress and inflammatory responses by activation of Nrf2[J].Inflammation,2018,41(4):1297-1303.

    • [19] LIU Y,GAO L,ZHAO X,et al.Saikosaponin A protects from pressure overload-induced cardiac fibrosis via inhibiting fibroblast activation or endothelial cell EndMT [J].International Journal of Biological Sciences,2018,14(13):1923-1934.

    • [20] CHEN C H,CHEN M F,HUANG S J,et al.Saikosaponin A induces apoptosis through mitochondria-dependent pathway in hepatic stellate cells[J].The American Journal of Chinese Medicine,2017,45(2):351-368.

    • [21] YANG L,LIU J,QI G.Mechanism of the effect of saikosaponin on atherosclerosis in vitro is based on the MAPK signaling pathway[J].Molecular Medicine Reports,2017,16(6):8868-8874.

    • [22] MAO X,MIAO G,TAO X,et al.Saikosaponin A protects TBI rats after controlled cortical impact and the underlying mechanism[J].American Journal of Translational Research,2016,8(1):133-141.

    • [23] MA Y,BAO Y R,WANG S,et al.Anti-inflammation effects and potential mechanism of saikosaponins by regulating nicotinate and nicotinamide metabolism and arachidonic acid metabolism[J].Inflammation,2016,39(4):1453-1461.

    • [24] ZHAO H Y,LI S P,ZHANG H S,et al.Saikosaponin A protects against experimental sepsis via inhibition of NOD2-mediated NF-κB activation[J].Experimental and Therapeutic Medicine,2015,10(2):823-827.

    • [25] KIM S O,PARK J Y,JEON S Y,et al.Saikosaponin A,an active compound of Radix bupleuri,attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-κB signaling pathways[J].International Journal of Molecular Medicine,2015,35(4):1126-1132.

    • [26] ZHAO X,LIU J Y,GE S S,et al.Saikosaponin A inhibits breast cancer by regulating Th1/Th2 balance[J].Frontiers in Pharmacology,2019,10:624.

    • [27] WANG Q,ZHENG X L,YANG L,et al.Reactive oxygen species-mediated apoptosis contributes to chemosen-sitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells[J].J Exp Clin Cancer Res,2010,29(1):159.

    • [28] 何艺韵,殷亦男,曾海荣,等.柴胡皂苷A通过 Wnt/β-catenin通路改变A549/DDP细胞耐药性[J].中国实验方剂学杂志,2021,27(11):83-88.

    • [29] YE R P,CHEN Z D.Saikosaponin A,an active glycoside from Radix bupleuri,reverses P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells and HepG2/ADM cells[J].Xenobiotica,2017,47(2):176-184.

    • [30] QI X T,LIU J,LI X Y,et al.Saikosaponin A contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway[J].Phytomedicine,2021,82:153444.

    • [31] LI D Q,WU J,LIU L Y,et al.Cytotoxic triterpenoid glycosides(saikosaponins)from the roots of Bupleurum Chinense[J].Bioorg Med Chem Lett,2015,25(18):3887-3892.

    • [32] SUN Y,CAI T T,ZHOU X B,et al.Saikosaponin A inhibits the proliferation and activation of T cells through cell cycle arrest and induction of apoptosis[J].International Immunopharmacology,2009,9(7-8):978-983.

    • [33] BUI T T,PIAO C H,SONG C H,et al.Bupleurum chinense extract ameliorates an OVA-induced murine allergic asthma through the reduction of the Th2 and Th17 cytokines production by inactivation of NF-κB pathway[J].Biomed Pharmacother,2017,91:1085-1095.

    • [34] HUANG W,ZHENG X,YANG X,et al.Stimulation of osteogenic differentiation by Saikosaponin A in bone marrow stromal cells via WNT/β-Catenin pathway[J].Calcified Tissue International,2017,100(4):392-401.

    • [35] CHEN X Q,CHEN S J,LIANG W N,et al.Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress[J].Neuroscience Letters,2018,662:283-289.

    • [36] GUO J J,ZHANG F,GAO J F,et al.Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of Saikosaponin A[J].Journal of Cellular and Molecular Medicine,2020,24(1):174-188.

    • [37] SUN X P,LI X L,PAN R,et al.Total Saikosaponins of Bupleurum yinchowense reduces depressive,anxiety-like behavior and increases synaptic proteins expression in chronic corticosterine-treated mice[J].BMC Complementary and Alternative Medicine,2018,18(1):117.

    • [38] HONG Y,DENG N,JIN H N,et al.Saikosaponin A modulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporal lobe epilepsy[J].Drug Design,Development and Therapy,2018,12:2945-2958.

    • [39] LEI S,SUN J C,YIN D Q,et al.Saikosaponin A alleviates symptoms of attention deficit hyperactivity disorder through downregulation of DAT and enhancing BDNF expression in spontaneous hypertensive rats[J].Evidence-based Complementary and Alternative Medicine,2017,2017(2):2695903-2695911.

    • [40] MACCIONI P,LORRAI I,CARAI M A M,et al.Reducing effect of Saikosaponin A,an active ingredient of Bupleurum falcatum,on alcohol self-administration in rats:possible involvement of the GABAB receptor[J].Neuroscience Letters,2016,621:62-67.

    • [41] MACCIONI P,FARA F,GESSA G L,et al.Reducing effect of Saikosaponin A,an active ingredient of Bupleurum falcatum,on intake of highly palatable food in a rat model of overeating[J].Frontiers in Psychiatry,2018,9:369.

    • [42] CHENG P W,NG L T,CHIANG L C,et al.Antiviral effects of saikosaponins on human coronavirus 229E in vitro[J].Clin Exp Pharmacol Physiol,2006,33(7):612-616.

  • 基本信息

    中图分类号: R966,R-1
    文献标识码: A
    DOI: 10.12287/j.issn.2096-8965.20210408
    文章编号: 2096-8965(2021)04-0060-07

    基金信息

    甘肃省科技计划项目(21JR1RA144)；
    兰州大学第二医院“萃英科技创新”计划项目(CY2020-MS10)；

    引用信息

    稿件历史

    收稿日期: 2021-06-08

  • 参考文献

    • [1] YANG Y Y,TANG Y Z,FAN C L,et al.Identification and determination of the saikosaponins in Radix bupleuri by accelerated solvent extraction combined with rapid-resolution LC-MS[J].J Sep Sci,2010,33(13):1933-1945.

    • [2] SONG Y Y,SUN H W,GAO S Y,et al.Saikosaponin A attenuates lead-induced kidney injury through activating Nrf2 signaling pathway[J].Comp Biochem Physiol C Toxicol Pharmacol,2021,242:108945.

    • [3] WANG Y,ZHAO L,HAN X H,et al.Saikosaponin A inhibits triple-negative breast cancer growth and metastasis through downregulation of CXCR4[J].Frontiers in Oncology,2019,9:1487.

    • [4] WANG N,CHE D L,ZHANG T,et al.Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo[J].Biochemical Pharmacology,2018,148:147-154.

    • [5] WANG A R,MI L F,ZHANG Z L,et al.Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia through p-CREB/BDNF pathway[J].Behavioural Brain Research,2021,403:113138.

    • [6] YAN Y M,SHEN X,CAO Y K,et al.Discovery of anti-2019-nCoV agents from Chinese patent drugs via docking screening [J].Preprints,2020.

    • [7] LU C N,YUAN Z G,ZHANG X L,et al.Saikosaponin A and its epimer Saikosaponin D exhibit anti-inflammatory activity by suppressing activation of NF-κB signaling pathway[J].International Immunopharmacology,2012,14(1):121-126.

    • [8] 何静,王珏岚,邹福兰,等.柴胡皂苷A上调HO-1对新生大鼠神经 OGD/R 损伤的影响[J].郑州大学学报(医学版),2021,56(4):525-529.

    • [9] PIAO C H,SONG C H,LEE E J,et al.Saikosaponin A ameliorates nasal inflammation by suppressing IL-6/ROR-γt/STAT3/IL-17/NF-κB pathway in OVA-induced allergic rhinitis[J].Chemico-biological Interactions,2020,315:108874.

    • [10] WANG X Y,YANG G F.Saikosaponin A attenuates neural injury caused by ischemia/reperfusion[J].Trans-lational Neuroscience,2020,11(1):227-235.

    • [11] CUI L H,LI C X,ZHUO Y Z,et al.Corrigendum to "Saikosaponin A inhibits the activation of pancreatic stellate cells by suppressing autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway"[J].Biomedicine & Pharmacotherapy,2020,130:110685.

    • [12] CUI L H,LI C X,ZHUO Y Z,et al.Saikosaponin A inhibits the activation of pancreatic stellate cells by suppressing autophagy and the NLRP3 inflammasome via the AMPK/mTOR pathway[J].Biomedicine & Pharmacotherapy,2020,128:110216.

    • [13] FENG P P,XU Y F,TONG B Y,et al.Saikosaponin A attenuates hyperlipidemic pancreatitis in rats via the PPAR-γ/NF-κB signaling pathway[J].Experimental and Therapeutic Medicine,2020,19(2):1203-1212.

    • [14] LI J,HAN J F,LV J,et al.Saikosaponin A-induced gut microbiota changes attenuate severe acute pancreatitis through the activation of Keap1/Nrf2-ARE antioxidant signaling[J].Oxidative Medicine and Cellular Longevity,2020,2020:9217219.

    • [15] LIU M,ZHANG G F,NAQVI S,et al.Cytotoxicity of Saikosaponin A targets HEKα cell through apoptosis induction by ROS accumulation and inflammation suppression via NF-κB pathway[J].International Immun-opharmacology,2020,86:106751.

    • [16] WANG J,WANG W W,PANG Y T.Saikosaponin A inhibits LPS-induced endometritis in mice through activating Nrf2 signaling pathway[J].Inflammation,2018,41(4):1508-1514.

    • [17] DU Z A,SUN M N,HU Z S.Saikosaponin A ameliorates LPS-induced acute lung injury in mice[J].Inflammation,2018,41(1):193-198.

    • [18] CHEN R J,GUO X Y,CHENG B H,et al.Saikosaponin A inhibits cigarette smoke-induced oxidant stress and inflammatory responses by activation of Nrf2[J].Inflammation,2018,41(4):1297-1303.

    • [19] LIU Y,GAO L,ZHAO X,et al.Saikosaponin A protects from pressure overload-induced cardiac fibrosis via inhibiting fibroblast activation or endothelial cell EndMT [J].International Journal of Biological Sciences,2018,14(13):1923-1934.

    • [20] CHEN C H,CHEN M F,HUANG S J,et al.Saikosaponin A induces apoptosis through mitochondria-dependent pathway in hepatic stellate cells[J].The American Journal of Chinese Medicine,2017,45(2):351-368.

    • [21] YANG L,LIU J,QI G.Mechanism of the effect of saikosaponin on atherosclerosis in vitro is based on the MAPK signaling pathway[J].Molecular Medicine Reports,2017,16(6):8868-8874.

    • [22] MAO X,MIAO G,TAO X,et al.Saikosaponin A protects TBI rats after controlled cortical impact and the underlying mechanism[J].American Journal of Translational Research,2016,8(1):133-141.

    • [23] MA Y,BAO Y R,WANG S,et al.Anti-inflammation effects and potential mechanism of saikosaponins by regulating nicotinate and nicotinamide metabolism and arachidonic acid metabolism[J].Inflammation,2016,39(4):1453-1461.

    • [24] ZHAO H Y,LI S P,ZHANG H S,et al.Saikosaponin A protects against experimental sepsis via inhibition of NOD2-mediated NF-κB activation[J].Experimental and Therapeutic Medicine,2015,10(2):823-827.

    • [25] KIM S O,PARK J Y,JEON S Y,et al.Saikosaponin A,an active compound of Radix bupleuri,attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-κB signaling pathways[J].International Journal of Molecular Medicine,2015,35(4):1126-1132.

    • [26] ZHAO X,LIU J Y,GE S S,et al.Saikosaponin A inhibits breast cancer by regulating Th1/Th2 balance[J].Frontiers in Pharmacology,2019,10:624.

    • [27] WANG Q,ZHENG X L,YANG L,et al.Reactive oxygen species-mediated apoptosis contributes to chemosen-sitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells[J].J Exp Clin Cancer Res,2010,29(1):159.

    • [28] 何艺韵,殷亦男,曾海荣,等.柴胡皂苷A通过 Wnt/β-catenin通路改变A549/DDP细胞耐药性[J].中国实验方剂学杂志,2021,27(11):83-88.

    • [29] YE R P,CHEN Z D.Saikosaponin A,an active glycoside from Radix bupleuri,reverses P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells and HepG2/ADM cells[J].Xenobiotica,2017,47(2):176-184.

    • [30] QI X T,LIU J,LI X Y,et al.Saikosaponin A contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway[J].Phytomedicine,2021,82:153444.

    • [31] LI D Q,WU J,LIU L Y,et al.Cytotoxic triterpenoid glycosides(saikosaponins)from the roots of Bupleurum Chinense[J].Bioorg Med Chem Lett,2015,25(18):3887-3892.

    • [32] SUN Y,CAI T T,ZHOU X B,et al.Saikosaponin A inhibits the proliferation and activation of T cells through cell cycle arrest and induction of apoptosis[J].International Immunopharmacology,2009,9(7-8):978-983.

    • [33] BUI T T,PIAO C H,SONG C H,et al.Bupleurum chinense extract ameliorates an OVA-induced murine allergic asthma through the reduction of the Th2 and Th17 cytokines production by inactivation of NF-κB pathway[J].Biomed Pharmacother,2017,91:1085-1095.

    • [34] HUANG W,ZHENG X,YANG X,et al.Stimulation of osteogenic differentiation by Saikosaponin A in bone marrow stromal cells via WNT/β-Catenin pathway[J].Calcified Tissue International,2017,100(4):392-401.

    • [35] CHEN X Q,CHEN S J,LIANG W N,et al.Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress[J].Neuroscience Letters,2018,662:283-289.

    • [36] GUO J J,ZHANG F,GAO J F,et al.Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of Saikosaponin A[J].Journal of Cellular and Molecular Medicine,2020,24(1):174-188.

    • [37] SUN X P,LI X L,PAN R,et al.Total Saikosaponins of Bupleurum yinchowense reduces depressive,anxiety-like behavior and increases synaptic proteins expression in chronic corticosterine-treated mice[J].BMC Complementary and Alternative Medicine,2018,18(1):117.

    • [38] HONG Y,DENG N,JIN H N,et al.Saikosaponin A modulates remodeling of Kv4.2-mediated A-type voltage-gated potassium currents in rat chronic temporal lobe epilepsy[J].Drug Design,Development and Therapy,2018,12:2945-2958.

    • [39] LEI S,SUN J C,YIN D Q,et al.Saikosaponin A alleviates symptoms of attention deficit hyperactivity disorder through downregulation of DAT and enhancing BDNF expression in spontaneous hypertensive rats[J].Evidence-based Complementary and Alternative Medicine,2017,2017(2):2695903-2695911.

    • [40] MACCIONI P,LORRAI I,CARAI M A M,et al.Reducing effect of Saikosaponin A,an active ingredient of Bupleurum falcatum,on alcohol self-administration in rats:possible involvement of the GABAB receptor[J].Neuroscience Letters,2016,621:62-67.

    • [41] MACCIONI P,FARA F,GESSA G L,et al.Reducing effect of Saikosaponin A,an active ingredient of Bupleurum falcatum,on intake of highly palatable food in a rat model of overeating[J].Frontiers in Psychiatry,2018,9:369.

    • [42] CHENG P W,NG L T,CHIANG L C,et al.Antiviral effects of saikosaponins on human coronavirus 229E in vitro[J].Clin Exp Pharmacol Physiol,2006,33(7):612-616.

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