Abstract
中国传统药材辽东楤木［Aralia elata （Miq.） Seem.］又称龙牙楤木，具有“补气安神，强精滋肾，祛风活血”的功效，用于治疗神经衰弱、阳虚气弱、肾气不足、脾阳虚衰之水湿停滞、消渴、跌打损伤等症。楤木皂苷类化合物是其发挥药理作用的主要物质基础。辽东楤木具有广泛的现代药理学作用，主要包括通过调控离子稳态及抑制炎症发挥抗心肌缺血和缓解继发性心肌缺血再灌注损伤的作用；通过抑制肿瘤细胞增殖促进肿瘤细胞凋亡及增强机体免疫来发挥抗肿瘤作用；通过调控机体糖脂代谢发挥降血糖、调血脂药理作用；以及保肝护肝、神经保护和抗炎、镇痛作用。未来，辽东楤木药理作用机制的深入研究将有利于促进其开发及利用。本文综述了国内外近二十年来对辽东楤木的相关研究，并提出了针对辽东楤木的药理研究新思路，旨在为同行提供参考。
Keywords: 辽东楤木, 龙牙楤木, 辽东楤木皂苷, 心血管系统, 抗肿瘤药, 综述
Abstract
The traditional Chinese medicine Aralia elata (Miq.) Seem., also known as Aralia mandshurica, has the effect of “tonifying Qi and calming the mind, strengthening the essence and tonifying the kidneys, and dispelling wind and invigorating blood circulation”. It is used in the treatment of neurasthenia, Yang deficiency and Qi deficiency, kidney Qi deficiency, spleen Yang deficiency, water-dampness stagnation, thirst, and bruises. Aralia elata saponins are the main components for the pharmacological effects. From the perspective of modern pharmacological science, Aralia elata has a wide range of effects, including anti-myocardial ischaemia and alleviation of secondary myocardium ischemic reperfusion injury by regulating ionic homeostasis, anti-tumor activity by inhibiting proliferation, promoting apoptosis and enhancing immunity, hypoglycemia and lipid lowering effects by regulating glucose and lipid metabolism, and hepato-protective, neuroprotective, anti-inflammatory/analgesic effects. The studies on pharmacological mechanisms of Aralia elata will be conducive to its development and application in the future. This article reviews the research progress of Aralia elata domestically and internationally in the last two decades and proposes new directions for further research.
Keywords:
Aralia elata (Miq.) Seem, Aralia mandshurica,
Aralia elata saponin, Cardiovascular system, Anti-neoplastics, Review
辽东楤木［Aralia elata（Miq.）Seem.］又称龙牙楤木，为五加科（Araliaceae）楤木属（Aralia Linn.）多年生落叶灌木植物，在我国黑龙江、吉林中部和辽宁东北部地区资源丰富、栽培技术成熟且有大量人工种植［1］。辽东楤木作为楤木类药材最早记载于唐代孙思邈的《千金方》。随着现代科学的进步，人们尝试通过现代药理学方法对辽东楤木的药理作用进行研究。目前，研究者已从辽东楤木的根、茎、叶中分离得到多种活性化合物，主要包括皂苷类化合物、黄酮类化合物、糖类化合物、脂肪类化合物、氨基酸类化合物及无机元素等，其中皂苷类化合物作为主要的药效物质研究较多［2］。辽东楤木提取物及其活性成分在心血管系统、抗肿瘤、降血糖、调血脂、保肝护肝、神经保护、抗炎和镇痛等诸多方面具有显著的药理学活性。本文阐述了辽东楤木的药理学作用及其分子机制，不仅可以为其开发、利用提供理论依据，同时也为临床上多种疾病的治疗提供潜在的候选药物。
1. 对心血管系统的药理作用
随着溶栓治疗和经皮冠脉介入术的发展，心肌缺血梗死的抢救成功率得到一定提升，但不可避免的是因心肌缺氧/复氧后带来的MIRI。辽东楤木在心血管系统的药理研究相对较早且深入，主要包括对抗心肌缺血、缓解继发性MIRI等作用。
1. 1 辽东楤木恢复心肌缺血时的离子稳态平衡
无机金属离子广泛参与细胞各项生命活动，如维持细胞膜电位的平衡、参与生化反应、肌肉收缩、信号转导等，因此离子稳态对于维持细胞生命的稳定至关重要。心肌缺血时，由于缺氧和供能不足，导致心肌细胞出现钾离子、钙离子、铁离子的严重失衡，进而造成心肌功能减弱伴心肌细胞死亡。研究发现，辽东楤木能够恢复上述离子的稳态平衡。首先，辽东楤木总皂苷能促进mitoKATP的开放，通过钾离子的外流来减少因缺氧导致的线粒体膜去极化，从而抑制MPTP的开放，发挥缺血预适应的保护作用，增强细胞对缺氧和氧化应激的抵抗能力，同时抑制线粒体途径的细胞凋亡［3-4］。其次，辽东楤木能维持细胞内钙离子稳态，增加心肌收缩力，缓解钙超载。辽东楤木总皂苷可增大MIRI后的钙瞬变幅度、速度，并降低稳态钙静息值、缩短收缩期细胞内钙离子上升到50.0%最高值的时间、减缓胞内钙瞬变衰减率，起到正性肌力作用［5-6］，同时恢复MIRI后钙镁ATP酶、钠钾ATP酶、SERCA的活性并降低钙调神经磷酸酶的活性，使辽东楤木总皂苷通过减轻钙超载、阻断内质网应激中的PERK通路，从而抑制CHOP依赖的促细胞凋亡程序［7-8］。来源于辽东楤木的三种单体Elatoside C、Araloside C、Calenduloside E分别通过不同的机制维持细胞内钙离子稳态。Elatoside C通过激活RISK途径和SAFE途径，同时增加SERCA2活性，减少内质网钙离子耗竭导致的钙超载，从而缓解内质网应激［9-10］。而在缺氧/复氧处理的H9c2心肌细胞中，Araloside C不但上调了HSP90的表达水平，同时也能通过氢键的形成稳定对接到HSP90的ATP/ADP结合域中，从而维持钙离子瞬变并抑制钙超载导致的内质网应激［11-12］。Calenduloside E可显著上调BAG3的表达而促进细胞自噬，并通过细胞自噬减少L型钙通道的含量从而缓解因MIRI导致的心肌细胞钙超载，抑制心肌细胞的钙依赖性凋亡［13-14］。此外，通过网络药理学策略，辽东楤木总皂苷及其成分楤木皂苷A可通过NR3C1/p53/SLC7A11通路来对抗铁离子依赖的活性氧增多所致细胞铁死亡［15-16］。基于以上研究可知，辽东楤木可以通过逆转心肌细胞钾离子、钙离子、铁离子的稳态失衡产生抗心肌缺血的作用。
1.2. 辽东楤木可抑制MIRI后多种途径介导的炎症反应
辽东楤木总皂苷可显著抑制CD40L/CD40信号通路，从而减少血小板CD40L/CD40信号的活化，抑制GPⅡb/Ⅲa介导的血小板聚集和黏附，缓解血栓形成和血管堵塞而导致的无复流现象。辽东楤木总皂苷还可显著抑制巨噬细胞、中性粒细胞的CD40L/CD40信号通路的激活，从而抑制白细胞产生的大量活性氧以及多种炎症因子，缓解氧化应激和炎症反应［17-18］。此外，辽东楤木总皂苷通过激活PI3K-Akt信号通路抑制NLRP3炎症小体通路，从而缓解MIRI继发的炎症反应以及炎症引发的心肌细胞死亡［19］。局部炎症反应失控和内皮细胞的损伤可使细胞黏附分子的表达增多，从而导致心室重塑［20-21］。然而辽东楤木总皂苷虽然能够显著缓解因氧化应激导致的MIRI，但对细胞黏附分子生成所引起的心室重塑无显著性作用［22-23］。综上，辽东楤木可以通过多种抗炎机制抑制炎症引发的心肌细胞死亡，但对炎症继发的心室重塑无影响。
早期研究主要围绕辽东楤木通过抗氧化等实现对心肌细胞损伤的保护作用，随着对辽东楤木药效物质基础及其作用机制的不断认识，发现辽东楤木总皂苷和多种单体成分可通过恢复离子稳态平衡和抑制炎症反应显著缓解心肌缺血以及心肌缺血继发的MIRI。此外，辽东楤木可以通过影响血液成分，如多种离子水平、血液流变学以及机体炎症反应，对症治疗心肌缺血及MIRI“气虚血瘀”、“浊邪”，从而实现“补气安神，强精滋肾，祛风活血”之功效［24-26］。未来，对于辽东楤木在心血管系统的药理作用需要利用新的技术方法及新的机制来不断进行阐释，从而为其应用提供良好的基础。
2. 抗肿瘤作用
目前，抗肿瘤治疗药物主要包括放化疗以及靶向治疗药物等，开发具有高效低毒、多靶点且能够显著提高肿瘤患者治愈率的新药物具有重要意义。辽东楤木具有良好的抗肿瘤作用，有望成为临床抗肿瘤的候选药物。
2.1. 抗呼吸、消化系统肿瘤作用
研究发现，辽东楤木的有效组分辽东楤木叶总皂苷可以通过下调COX-2的表达明显抑制裸鼠A549肺癌细胞体外移植瘤的生长，降低肿瘤组织的微血管密度［27］。此外，从辽东楤木的根部提取得到的单体多糖AER-A3和叶中提取得到的三种三萜皂苷Congmuyenosides C~E均能抑制A549肺癌细胞的增殖［28-29］。研究发现，辽东楤木叶总皂苷可以明显上调H22肝癌细胞荷瘤小鼠p53和PCNA的表达，从而引起细胞周期阻滞，其药效与30 mg/kg环磷酰胺相当［30］。此外，辽东楤木多糖对SMMC-7721肝癌细胞显示出体外抑制活性，可提高荷瘤小鼠脾脏和胸腺质量以及增加淋巴细胞数且呈浓度依赖性，增加NK细胞和巨噬细胞活性，表明辽东楤木多糖在抑制肿瘤增殖的同时可通过增强机体的免疫能力抵抗肿瘤［31-32］。辽东楤木叶总皂苷能够有效抑制人BGC胃癌细胞增殖并诱导其凋亡，但具体分子机制不清楚［33］。辽东楤木叶总皂苷可显著抑制HT-29结肠癌细胞增殖并促进其凋亡且呈剂量依赖性，同时通过下调Polo样激酶1的表达，阻滞HT-29细胞于G0/G1期［34］。辽东楤木叶总皂苷对HT-29结肠癌细胞荷瘤裸鼠的肿瘤生长具有显著的抑制作用，其中150 mg/kg辽东楤木叶总皂苷与20 mg/kg 5-氟尿嘧啶的抑制率相当，其体内抑瘤机制与抑制TLR-4/NF-κB信号通路以及下调IL-1、肿瘤坏死因子-α的表达有关［35］。
在辽东楤木单体成分中，AER-A3和Congmuyenosides C~E均能抑制HepG2肝癌细胞增殖［28-29］。此外，研究发现来源于辽东楤木的一种蛋白质Aralin对MIA PaCa-2胰腺癌细胞、MKN45胃腺癌细胞、HepG2肝癌细胞都具有显著的抗肿瘤活性［36］。Aralin作为一种Ⅱ型核糖体失活蛋白通过其RNA N-糖苷酶结构域切割28S rRNA的N-糖苷键抑制核糖体蛋白活性和作用于高密度脂蛋白的受体高密度脂蛋白结合蛋白来发挥抑制肿瘤生长和促进肿瘤细胞凋亡的作用［37-38］。
以上研究表明，辽东楤木对呼吸、消化系统肿瘤均具有显著的抗肿瘤作用，且其抗肿瘤药效物质基础主要为总皂苷类物质，而其抗肿瘤作用机制主要与诱导肿瘤细胞凋亡、抑制肿瘤细胞增殖有关。
2.2. 抗乳腺癌及妇科肿瘤作用
辽东楤木叶总皂苷对人乳腺癌细胞MCF-7具有剂量依赖性的增殖抑制作用和促细胞凋亡作用。随药物浓度增加，辽东楤木的G0/G1期阻滞作用增强；同时辽东楤木通过线粒体凋亡通路（包括三条MAPK信号通路即JNK信号通路、ERK1/2信号通路、p38MAPK信号通路）及内质网应激通路共同促进MCF-7细胞的凋亡［39-40］。此外，辽东楤木与5-氟尿嘧啶联合使用对MCF-7乳腺癌荷瘤小鼠的抑瘤率明显高于单独使用，其增效机制可能与免疫调节有关；同时，辽东楤木又可明显减轻5-氟尿嘧啶对免疫器官和骨髓的毒性作用［41-42］。此外，辽东楤木叶总皂苷对耐顺铂的SKOV3卵巢癌细胞株具有剂量依赖性的抑制作用，其机制主要包括下调肺耐药蛋白的表达以及抑制NF-κB介导的炎症反应［43］。对辽东楤木单体成分抗妇科肿瘤的研究发现，Congmuyenosides C~E对SKOV3卵巢癌细胞具有抗肿瘤作用［29］。同时，Aralin通过上一节所述机制对OVK18卵巢癌细胞和HeLa宫颈癌细胞均具有抑制作用［36-38］。以上研究表明，辽东楤木在体内外对乳腺癌均具有显著的抑制作用，与化疗药物合用时具有增效减毒的作用。同时，对卵巢癌尤其是耐顺铂的SKOV3卵巢癌细胞株同样具有显著的抑制作用，可见辽东楤木在乳腺及妇科肿瘤治疗中的潜在价值。
上述辽东楤木抗肿瘤作用机制总结如附表1所示。辽东楤木具有较为广谱的抗肿瘤作用，而对其确切的抗肿瘤机制研究是促进其开发利用的关键。研究发现，辽东楤木总皂苷、皂苷单体、多糖、蛋白质对多种肿瘤均具有抑制作用，并初步确认了辽东楤木有效成分化学结构与其生物活性的相关性。目前，辽东楤木抗肿瘤作用机制主要包括以下几方面：①抑制肿瘤生长，促进其凋亡；②增强机体免疫力；③具有增效减毒功效。以上对其现代药理学的研究与传统中医药抗肿瘤的治则“扶正驱邪”相一致。
3. 调节代谢作用
3.1. 降血糖作用
辽东楤木具有良好的降血糖作用。研究发现，辽东楤木果实水煎液对四氧嘧啶破坏胰岛β细胞的1型糖尿病模型具有明显的降血糖作用，可增加血清中胰岛素含量并降低胰高血糖素含量［44］。进一步研究显示，辽东楤木对正常动物以及链脲佐菌素等造成的高血糖模型均具有浓度依赖性的降血糖作用。
此外，在糖尿病进展的后期，由于代谢异常、内分泌紊乱、免疫功能异常，常继发心血管系统疾病、肾损伤、神经损伤、视网膜病变。辽东楤木对糖尿病造成的并发症也具有良好的疗效。辽东楤木总皂苷可减缓糖尿病性心肌病早期阶段的进展［46］；可抑制因糖尿病导致的白内障形成，对视网膜神经节细胞具有良好的神经保护作用，主要是通过下调OGT、SREBP-1的表达、改善胰岛素抵抗、减少NF-κB p65亚基的N-乙酰糖基化修饰等方式抑制视网膜神经节细胞的凋亡［47-49］。
综上所述，辽东楤木具有优良的降血糖作用，还具有预防和缓解糖尿病造成的继发性疾病的作用。辽东楤木这种兼顾降血糖及减缓糖尿病并发症的双重作用，在临床治疗中具有明显的优势，但目前对其药效物质基础的研究以及降血糖关键作用机制的研究尚不充分，还须进一步研究以利于未来更好地开发利用。
3.2. 调血脂作用
辽东楤木具有调血脂、改善胰岛素抵抗、抗脂肪肝、预防动脉粥样硬化等作用。在调血脂、改善胰岛素抵抗方面，辽东楤木提取物在体外实验中显著降低HepG2细胞中的总胆固醇水平且呈剂量依赖性，在体内实验中改善高脂饮食诱导的非酒精性脂肪肝的胰岛素抵抗［50-51］。他汀类药物的靶点为HMG-CoA还原酶，贝特类药物的靶点为PPAR，而辽东楤木可以同时作用于以上两个靶点。辽东楤木提取物一方面可以激活Akt/GLUT4通路从而下调SREBP-1c等脂肪合成基因，并上调PPARα等脂肪分解基因；另一方面可以抑制HMG-CoA还原酶的活性，最终阻断胆固醇代谢通路、抑制游离胆固醇的合成［50-51］。在抗脂肪肝方面，辽东楤木皂苷能够降低因长期高脂饮食导致的肝脂肪指数，上调肝脂肪酶的表达，具有降低血液中总胆固醇、三酰甘油、低密度脂蛋白的作用［52］。在抗动脉粥样硬化方面，Elatoside C可以通过增加FoxO1的表达水平诱导自噬来减轻氧化低密度脂蛋白诱导的HUVEC损伤，而Calenduloside E则通过靶向Hsp90AB1减少了氧化低密度脂蛋白诱导的HUVEC氧化损伤及凋亡，提示Elatoside C和Calenduloside E可成为治疗动脉粥样硬化的潜在药物［53-55］。综上，辽东楤木具有良好的调血脂作用，未来这可能是辽东楤木研究的重要方向之一。
4. 保肝护肝作用
肝脏中的氧化应激是导致肝脏损伤的重要因素，因此，具有缓解肝脏氧化应激相关作用的药物可以抑制多种因素导致的肝脏损伤［56］。研究发现，辽东楤木的乙醇提取物能够缓解因苯并［a］芘导致的肝损伤，降低氧化应激，恢复肝脏的脂代谢能力［57］。在大鼠过度训练动物模型的研究中发现，辽东楤木醇提取物可通过抑制肝脏中氧化物质过度生成导致肝损伤［58］。研究发现，辽东楤木叶总皂苷可以显著降低四氯化碳、D-半乳糖胺诱导的急性肝损伤，其机制可能是诱导肝细胞内酶系统，从而促进肝细胞的核酸、蛋白质、糖原的合成，保护肝细胞膜的正常结构而起到改善肝损伤的作用［59］。辽东楤木总皂苷还可以缓解四氯化碳诱导的大鼠肝纤维化，表明辽东楤木皂苷具有抗肝纤维化作用［60］。另有研究发现，辽东楤木总皂苷可通过减少内质网应激关键蛋白肌醇依赖性激酶1α的磷酸化，抑制其介导的JNK和NF-κB信号通路的激活，从而发挥治疗非酒精性脂肪性肝炎的作用［61］。
综上，辽东楤木不同药用部位的提取物及有效组分均具有肝脏保护作用，其护肝作用与维持肝脏的氧化还原稳态有关。肝脏作为人体关键的代谢器官，维护其功能对于患者至关重要。护肝药物合并治疗药物使用具有增效减毒的功效，可以提高患者的治疗耐受性。然而，目前临床上可以用于配合长期服药患者合并使用的护肝药物匮乏，辽东楤木有望为临床护肝治疗提供新的方法。
5. 神经保护作用
已有研究发现，辽东楤木具有显著的神经保护作用。辽东楤木活性组分研究发现，辽东楤木总皂苷能够明显抑制脑内单胺氧化酶B活性，缓解因单胺氧化酶B活性异常带来的过氧化物生成过多而导致的神经元损伤［62］。而对辽东楤木根皮醇提取物研究发现，提取物可能通过提高海马组织抗氧化能力缓解因过度运动导致海马BDNF上调及NGF下调，从而在调节突触发育、突触可塑性、学习记忆、神经保护方面具有重要作用［63-68］。另有研究发现，辽东楤木的乙醇提取物可提高脑内乙酰胆碱含量，抑制乙酰胆碱酯酶的活性；辽东楤木还可通过提高脑超氧化物歧化酶含量，降低丙二醛含量减少氧化应激，促进Akt磷酸化，防止JNK、τ蛋白的过度磷酸化，抑制慢性酒精暴露诱导的神经细胞凋亡［69-70］。
辽东楤木的单体皂苷也具有神经保护作用。Wang等［71］发现，Eclalbasaponin Ⅰ可明显减少因过氧化氢诱导的氧化应激，其抗氧化机制与诱导保护性自噬及显著抑制细胞凋亡有关。此外，Eclalbasaponin Ⅰ可活化MAPK家族信号通路中的p38、ERK通路，其保护作用能够被p38、ERK抑制剂显著逆转；但对JNK通路影响不大。
综上，辽东楤木可以影响小鼠脑内单胺氧化酶B活性，而该酶的活性与神经系统退行性疾病密切相关，提示辽东楤木可能具有神经保护作用。辽东楤木发挥神经保护以及神经营养作用的机制可能与其抗氧化作用及调控NGF和BDNF相关。随着对辽东楤木神经保护作用机制的不断阐明，辽东楤木有望为神经系统退行性疾病这一临床难题的解决提供新的方案。
6. 抗炎、镇痛作用
辽东楤木总皂苷或其提取物具有良好的抗炎活性。研究发现，辽东楤木的乙醇提取物可抑制巨噬细胞的炎性介质合成，抑制细菌脂多糖对巨噬细胞的激活，并抑制COX-2、iNOS和NF-κB的活性，因而可显著减少巨噬细胞炎性细胞因子的合成，从而发挥抗炎作用［72］。且辽东楤木总皂苷可显著减轻醋酸所致内脏疼痛并降低由二甲苯所致实验小鼠耳廓的肿胀程度，显示出较强的抗炎镇痛作用［73］。对其确切的抗炎有效成分研究发现，八种辽东楤木单体皂苷Elatoside A，Elatoside C，Tarasaponin Ⅴ，Congmuyanoside Ⅴ、Ⅹ、Ⅺ、Ⅻ和ⅩⅤ可显著降低fMLP诱导的人中性粒细胞超氧化物生成，其中Congmuyanoside Ⅴ、Ⅻ和ⅩⅤ可显著降低花生四烯酸诱导的人中性粒细胞超氧化物生成［74-75］。而上述单体皂苷可能是通过下调中性粒细胞酪氨酸激酶、丝氨酸/苏氨酸激酶的活性，同时抑制p47phox、p67phox、rac的细胞膜易位，抑制超氧化物生成，进而发挥其抗炎药效［74-76］。另有研究表明，来源于辽东楤木的一种齐墩果酸OA可抑制细菌脂多糖诱导的raw 264.7细胞炎性细胞因子合成，其机制与OA抑制NF-κB抑制蛋白α的磷酸化，减少NF-κB核易位，从而下调COX-2和iNOS的基因表达有关；此外，OA还抑制MAPK家族信号通路，降低ERK1/2、p38和JNK的磷酸化水平，因此具有显著的抗炎效应［77］。
上述研究表明，辽东楤木抗炎作用的研究主要集中在抑制超氧化物的生成以及传统的抗炎通路NF-κB等抗炎机制。而未来加快对于相对匮乏且迟滞的辽东楤木的抗炎及镇痛作用机制研究，利于进一步促进中药材辽东楤木的产业化应用。
7. 结语
辽东楤木作为我国东北地区一种药食同源的传统中药材，具有抗心血管疾病、抗肿瘤、降血糖、调血脂以及抗炎、镇痛等广泛的药理学作用。对辽东楤木的深入研究有望将其开发成为临床候选药物。目前对辽东楤木药理作用的研究多聚焦于提取物及总皂苷的药理活性研究，而其确切的药效物质基础以及关键的药理作用机制研究仍处于停滞阶段，且多数已发现的药理活性的作用机制尚未完全阐明，阻碍了其进一步开发利用。为了进一步加快辽东楤木的开发利用，未来针对辽东楤木的研究可重点关注以下研究方向。
（1）探究辽东楤木确切药效物质基础。药效物质的深入研究是传统中药材进行现代化研究的基础，因此，优化其有效成分的提取分离方法，尤其是利用现代技术手段如多组学/系统生物学方法充分认识其药效物质基础及药理作用是目前辽东楤木研究的重要内容。
（2）基于整体观的辽东楤木现代药理学研究。整体观是指将药物进入体内后针对不同疾病的最终药效作为考察药物效用的方法，是对药物效用认识的一种新观点，也是克服其药效物质基础研究尚不确切情况下的可行性研究思路。采用新的具有整体观的药理学研究手段是对其进行药理机制研究的关键所在，而采用血清药理学这一实验方法结合组学技术，实现整体性与高通量相结合的研究便是对中药复杂成分进行机制研究的有效手段，是辽东楤木未来重要的研究方向之一。
（3）针对不同疾病采用 “有效成分配伍”使用。有效成分配伍是指将药物发挥效用的不同成分相互配合使用的过程，通过有效成分配伍从而取长补短、多效协同。例如将辽东楤木的抗肿瘤有效成分与辽东楤木护肝有效成分以及镇痛有效成分进行适当配伍，可以实现辽东楤木发挥抗肿瘤药效的同时，缓解因抗肿瘤药物的肝脏损伤作用引起的抗肿瘤药效的下降，此外，合用辽东楤木镇痛有效成分也可缓解肿瘤患者的癌痛，从而达到“一药多效”的协同作用［78］。因此，未来随着对辽东楤木药效物质基础研究的充分，辽东楤木有效成分的配伍将具有剂量、药效毒性以及不同成分之间化学反应的可控，进而实现生产的质量可控，从而为辽东楤木的现代化研究及应用提供新思路。
Supplementary information
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1008-9292-2023-52-5-616-s001.docx (14.7KB, docx)
Acknowledgments
研究得到国家级大学生创新创业训练计划（20221 3021030）支持。感谢陈莹、王昱宸、周洲、许航玮、朱曼莉在稿件审阅修改中提供帮助
Acknowledgments
This study was supported by the National Undergraduate Training Program for Innovation and Entrepreneurship (202213021030). We thank CHEN Ying, WANG Yuchen, ZHOU Zhou, XU Hangwei and ZHU Manli for reviewing and revising the manuscript
［缩略语］
心肌缺血再灌注损伤（myocardium ischemic reperfusion injury，MIRI）；腺苷三磷酸（adenosine triphosphate，ATP）；线粒体ATP敏感性钾通道（mitochondrial ATP sensitive potassium channel，mitoKATP）；线粒体膜通透性转换孔（mitochondrial permeability transition pore，MPTP）；类蛋白激酶内质网激酶（protein kinase-like endoplasmic reticulum kinase，PERK）；肌质网/内质网钙ATP酶（sarcoplasmic/endoplasmic reticulum Ca2+-ATPase，SERCA）；C/EBP同源蛋白（C/EBP homologous protein，CHOP）；再灌注损伤挽救激酶（reperfusion injury salvage kinase，RISK）；存活激活因子增强（survivor activating factor enhancement，SAFE）；热休克蛋白（heat shock protein，HSP）；Bcl-2结合抗凋亡基因（Bcl-2 associated athanogenes，BAG）；环氧合酶（cyclooxygenase，COX）；增殖细胞核抗原（proliferating cell nuclear antigen，PCNA）；核因子κB（nuclear factor-κB，NF-κB）；促分裂原活化的蛋白激酶（mito-genactivated protein kinase，MAPK）；Jun激酶（Jun kinase，JNK）；胞外信号调节激酶（extracellular signal-regulated kinase，ERK）；氧连氮-乙酰葡萄糖胺转移酶（O-linked N-acetylglu-cosamine transferase，OGT）；固醇调节元件结合蛋白（sterol regulatory element binding protein，SREBP）；β-羟-β-甲戊二酸单酰辅酶A（β-hydroxy-β-methylglutaryl-CoA，HMG-CoA）；过氧化物酶体增殖物激活受体（peroxisome proliferators activated receptor，PPAR）；人脐静脉内皮细胞（human umbilical vein endothelial cell，HUVEC）；脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）；神经生长因子（nerve growth factor，NGF）；诱生型一氧化氮合酶（inducible nitric oxide synthase，iNOS）；3-O-β-D-吡喃葡萄糖基（1→3）-α-L-吡喃鼠李糖基（1→2）-α-L-阿拉伯吡喃糖苷［3-O-β-D-glucopyranosyl（1→3）-α-L-rhamnopyranosyl（1→2）-α-L-arabinopyranoside，OA］
利益冲突声明
所有作者均声明不存在利益冲突
Conflict of Interests
The authors declare that there is no conflict of interests
参考文献（References）
1.邹淑君, 贾力维, 吕邵娃, 等. 基于谱-效关系的辽东楤木叶质量评价研究[J]. 中草药, 2023, 54(7): 2172-2181. 37381898 [Google Scholar]; ZOU Shujun, JIA Liwei, Shaowa LYU, et al.
Quality evaluation of Aralia elata leaves based on spectrum-effect relationship[J]. Chinese Traditional and Herbal Drugs, 2023, 54(7): 2172-2181. (in Chinese) [Google Scholar]
2.刘季田媛. 辽东楤木不同药用部位活性、成分分离及含量测定研究[D]. 哈尔滨: 黑龙江中医药大学, 2017. [Google Scholar]; LIU Jitianyuan. Study on activity, constituent isolation and content determination of different medicinal parts from Aralia Elata
[D]. Harbin: Heilongjiang University of Chinese Medicine, 2017. (in Chinese) [Google Scholar]
3.谭玉婷, 鲁卫星, 赵俊男. 龙牙楤木总皂苷对缺血再灌注损伤大鼠心肌细胞线粒体细胞色素C和膜电位的影响及其作用机制[J]. 西部中医药, 2016, 29(12): 9-12. 10.3969/j.issn.1004-6852.2016.12.003 [DOI] [Google Scholar]; TAN Yuting, LU Weixing, ZHAO Junnan. Study of effects and function mechanism of aralosides on mito-chondrial cytochrome C and membrane potential of IRI rat cardiac muscle cells[J]. Western Journal of Traditional Chinese Medicine, 2016, 29(12): 9-12. (in Chinese)
10.3969/j.issn.1004-6852.2016.12.003. 10.3969/j.issn.1004-6852.2016.12.003 [DOI] [Google Scholar]
4.陈婵娟. 基于心肌mitoKATP通道龙牙楤木总皂苷对大鼠缺血再灌注心脏的作用及机制研究[D]. 北京: 北京中医药大学, 2014. [Google Scholar]; CHEN Chanjuan. Study on the effect and mechanism of total saponins of Aralia elata on ischemia reperfusion heart in rats based on myocardial mitoKATP channel[D]. Beijing: Beijing University of Chinese Medicine, 2014. (in Chinese) [Google Scholar]
5.WANG M, XU X, XU H, et al.
Effect of the total saponins of Aralia elata (Miq) Seem on cardiac contractile function and intracellular calcium cycling regulation[J]. J Ethnopharmacol, 2014, 155(1): 240-247. 10.1016/j.jep.2014.05.024 [DOI] [PubMed] [Google Scholar]
6.张妙笛, 孙桂波, 徐惠波, 等. 龙牙楤木总皂苷对缺血/再灌注心肌细胞收缩功能和钙瞬变的影响[J]. 中国中药杂志, 2015, 40(12): 2403-2407. 10.4268/cjcmm20151227 [DOI] [PubMed] [Google Scholar]; ZHANG Miaodi, SUN Guibo, XU Huibo, et al.
Effect of aralosides to contraction function and calcium transient of ischemia/reperfusion myocardial cells[J]. China Journal of Chinese Materia Medica, 2015, 40(12): 2403-2407. (in Chinese)
10.4268/cjcmm20151227. 10.4268/cjcmm20151227 [DOI] [PubMed] [Google Scholar]
7.WANG R, YANG M, WANG M, et al.
Total saponins of Aralia Elata (Miq) seem alleviate calcium home-ostasis imbalance and endoplasmic reticulum stress-related apoptosis induced by myocardial ischemia/reperfusion injury[J]. Cell Physiol Biochem, 2018, 50(1): 28-40. 10.1159/000493954 [DOI] [PubMed] [Google Scholar]
8.宋欣丽. 龙牙楤木总皂苷抗MIRI机制研究及中成药防治MIRI的系统评价[D]. 北京: 北京中医药大学, 2021. [Google Scholar]; SONG Xinli. Study on the anti MIRI mechanism of total saponins of Aralia elata and systematic evaluation of traditional chinese patent medicines and simple preparations in the prevention and treatment of MIRI[D]. Beijing: Beijing University of Chinese Medicine, 2021. (in Chinese) [Google Scholar]
9.WANG M, MENG X B, YU Y L, et al.
Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation[J]. Apoptosis, 2014, 19(12): 1727-1735. 10.1007/s10495-014-1039-3 [DOI] [PubMed] [Google Scholar]
10.WANG M, SUN G B, ZHANG J Y, et al.
Elatoside C protects the heart from ischaemia/reperfusion injury through the modulation of oxidative stress and intra-cellular Ca2+ homeostasis[J]. Int J Cardiol, 2015, 185: 167-176. 10.1016/j.ijcard.2015.03.140 [DOI] [PubMed] [Google Scholar]
11.WANG M, TIAN Y, DU Y Y, et al.
Protective effects of Araloside C against myocardial ischaemia/reperfusion injury: potential involvement of heat shock protein 90[J]. J Cell Mol Med, 2017, 21(9): 1870-1880. 10.1111/jcmm.13107 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.DU Y, WANG M, LIU X, et al.
Araloside C prevents hypoxia/reoxygenation-induced endoplasmic reticulum stress via increasing heat shock protein 90 in H9C2 cardiomyocytes[J]. Front Pharmacol, 2018, 9: 180. 10.3389/fphar.2018.00180 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.WANG R, WANG M, ZHOU J, et al.
Calenduloside E suppresses calcium overload by promoting the interaction between L-type calcium channels and Bcl2-associated athanogene 3 to alleviate myocardial ischemia/reperfusion injury[J]. J Adv Res, 2021, 34: 173-186. 10.1016/j.jare.2020.10.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.WANG R, WANG M, LIU B, et al.
Calenduloside E protects against myocardial ischemia-reperfusion injury induced calcium overload by enhancing autophagy and inhibiting L-type Ca2+ channels through BAG3[J]. Biomed Pharmacother, 2022, 145: 112432. 10.1016/j.biopha.2021.112432 [DOI] [PubMed] [Google Scholar]
15.梁芳, 鲁卫星, 周天琪, 等. 龙牙楤木总皂苷及楤木皂苷A对缺氧/复氧诱导的AC16心肌细胞铁死亡的影响[J]. 环球中医药, 2022, 15(6): 970-975. 10.3969/j.issn.1674-1749.2022.06.009 [DOI] [Google Scholar]; LIANG Fang, LU Weixing, ZHOU Tianqi, et al.
Effects of aralosides and araloside A on hypoxia/reoxygenation-induced ferroptosis in AC16 cells[J]. Global Traditional Chinese Medicine, 2022, 15(6): 970-975. (in Chinese)
10.3969/j.issn.1674-1749.2022.06.009. 10.3969/j.issn.1674-1749.2022.06.009 [DOI] [Google Scholar]
16.梁芳, 鲁卫星, 周天琪, 等. 基于NR3C1/p53/SLC7A11通路探讨龙牙楤木总皂苷及其成分楤木皂苷A对缺氧/复氧诱导的心肌细胞铁死亡的影响[J]. 中国中医药信息杂志, 2022, 29(5): 63-68. [Google Scholar]; LIANG Fang, LU Weixing, ZHOU Tianqi, et al.
Effects of aralosides and its component araloside A on hypoxia/reoxygenation induced ferroptosis of myocardial cells based on NR3C1/p53/SLC7A11 pathway[J]. Chinese Journal of Information on Traditional Chinese Medicine, 2022, 29(5): 63-68. (in Chinese) [Google Scholar]
17.崔现军. 龙牙楤木总甙对大鼠心肌缺血再灌注CD40L表达的影响[D]. 北京: 北京中医药大学, 2008. [Google Scholar]; CUI Xianjun. Effects of aralosides to CD40L expression during rat myocardial ischemia reperfusion[D]. Beijing: Beijing University of Chinese Medicine, 2008. (in Chinese) [Google Scholar]
18.崔现军, 李明, 鲁卫星. 龙牙楤木总皂苷对大鼠心肌缺血再灌注CD40L表达的影响[J]. 北京中医药大学学报, 2010, 33(5): 323-326, 361. [Google Scholar]; CUI Xianjun, LI Ming, LU Weixing. Influence of aralosides on CD40L expression in rats with myocardial ischemia and reperfusion[J]. Journal of Beijing University of Traditional Chinese Medicine, 2010, 33(5): 323-326, 361. (in Chinese) [Google Scholar]
19.SUN L, LU W X, LI H, et al.
Total saponins of Aralia elata (Miq.) Seem. alleviate myocardial ischemia-reperfusion injury by promoting NLRP3-inflammasome inactivation via PI3K/Akt signaling[J]. Kaohsiung J Med Sci, 2023, 39(3): 290-301. 10.1002/kjm2.12627 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.WEIL B R, NEELAMEGHAM S. Selectins and immune cells in acute myocardial infarction and post-infarction ventricular remodeling: pathophysiology and novel treatments[J]. Front Immunol, 2019, 10: 300. 10.3389/fimmu.2019.00300 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.SAGER H B, HULSMANS M, LAVINE K J, et al.
Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure[J]. Circ Res, 2016, 119(7): 853-864. 10.1161/circresaha.116.309001 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.鲁卫星, 李明, 王婷. 龙牙楤木总皂苷对大鼠心肌缺血再灌注损伤保护机制的研究[J]. 中华中医药杂志, 2011, 26(3): 554-556. [Google Scholar]; LU Weixing, LI Ming, WANG Ting. Study of protection mechanism of aralosides on myocardial ischemia/reper-fusion injury in rats[J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2011, 26(3): 554-556. (in Chinese) [Google Scholar]
23.王婷. 龙牙楤木总皂甙对大鼠心肌缺血再灌注损伤sVCAM-1表达及MDA、SOD影响的研究[D]. 北京: 北京中医药大学, 2009. [Google Scholar]; WANG Ting. Effects of aralosides on sVCAM-1 expression and the MDA&SOD in rats with myocardial ischemia/reperfusion injury[D]. Beijing: Beijing University of Chinese Medicine, 2009. (in Chinese) [Google Scholar]
24.徐舒婷, 方晓艳, 王萍, 等. 基于中西医临床病证特点的冠心病心绞痛动物模型分析[J]. 中药药理与临床, 2023, 39(4): 92-96. [Google Scholar]; XU Shuting, FANG Xiaoyan, WANG Ping, et al.
Animal models of coronary heart disease angina pectoris: an analysis based on clinical characteristics of tradi-tional chinese and western medicine[J]. Pharmacology and Clinics of Chinese Materia, 2023, 39(4): 92-96. (in Chinese) [Google Scholar]
25.李鹏飞, 徐寒莹, 李双娣, 等. 基于“浊邪”探讨铁死亡与心肌缺血再灌注损伤的相关性[J]. 吉林中医药, 2023, 43(2): 129-134. [Google Scholar]; LI Pengfei, XU Hanying, LI Shuangdi, et al.
Discussion on the correlation between ferroptosis and myocardial ischemia reperfusion injury based on the theory of “turbid pathogen”[J]. Jilin Journal of Chinese Medicine, 2023, 43(2): 129-134. (in Chinese) [Google Scholar]
26.李兆钰. 不稳定性心绞痛热毒证及益气解毒法抗动脉粥样硬化的作用机制研究[D]. 济南: 山东中医药大学, 2022. [Google Scholar]; LI Zhaoyu. Study on heat-toxic syndrome of unstable angina and mechanism of anti-atherosclerosis with the method of replenishing Qi and detoxification[D]. Jinan: Shandong University of Traditional Chinese Medicine, 2022. (in Chinese) [Google Scholar]
27.王丽岩, 肖洪彬, 张秀萍, 等. 辽东楤木叶总皂苷(ETS)对裸鼠A549体外移植瘤抑制率及瘤体相关蛋白COX-2表达影响的实验研究[J]. 中医药学报, 2010, 38(6): 30-32. 10.3969/j.issn.1002-2392.2010.06.012 [DOI] [Google Scholar]; WANG Liyan, XIAO Hongbin, ZHANG Xiuping, et al.
The experimental study of Aralia Elata Seem leaves to nude mouse A549 explantation lump suppression rate and lump body associated protein COX-2 expression influence[J]. Acta Chinese Medicine and Pharma-cology, 2010, 38(6): 30-32. (in Chinese)
10.3969/j.issn.1002-2392.2010.06.012. 10.3969/j.issn.1002-2392.2010.06.012 [DOI] [Google Scholar]
28.XIA Y G, ZHU R J, SHEN Y, et al.
A high methyl ester pectin polysaccharide from the root bark of Aralia elata: structural identification and biological activity[J]. Int J Biol Macromol, 2020, 159: 1206-1217. 10.1016/j.ijbiomac.2020.05.117 [DOI] [PubMed] [Google Scholar]
29.KUANG H X, WANG Z B, WANG Q H, et al.
Triterpene glucosides from the leaves of Aralia elata and their cytotoxic activities[J]. Chem Biodivers, 2013, 10(4): 703-710. 10.1002/cbdv.201200087 [DOI] [PubMed] [Google Scholar]
30.尹丽颖, 边晓燕, 肖洪彬, 等. 辽东楤木叶总皂苷对H22荷瘤小鼠p53及PCNA蛋白表达的影响[J]. 中医药学报, 2010, 38(1): 18-20. 10.3969/j.issn.1002-2392.2010.01.007 [DOI] [Google Scholar]; YIN Liying, BIAN Xiaoyan, XIAO Hongbin, et al.
Effects of total saponins from Aralia elata leaves on the expression of p53 and PCNA protein in H22 tumor-bearing mice[J]. Acta Chinese Medicine and Phar-macology, 2010, 38(1): 18-20. (in Chinese)
10.3969/j.issn.1002-2392.2010.01.007. 10.3969/j.issn.1002-2392.2010.01.007 [DOI] [Google Scholar]
31.王丽君, 石莉萍. 龙牙楤木多糖诱导人肝癌SMMC-7721细胞凋亡机制研究[J]. 中国免疫学杂志, 2010, 26(12): 1082-1085. 10.3969/j.issn.1000-484X.2010.12.006 [DOI] [Google Scholar]; WANG Lijun, SHI Liping. AEPS induces apoptosis in SMMC-7721 hepatocellular cancer cells and its mechanism[J]. Chinese Journal of Immunology, 2010, 26(12): 1082-1085. (in Chinese)
10.3969/j.issn.1000-484X.2010.12.006. 10.3969/j.issn.1000-484X.2010.12.006 [DOI] [Google Scholar]
32.王丽君, 姜虹. 龙牙楤木多糖抗肿瘤活性及对荷瘤小鼠免疫功能的影响[J]. 中国免疫学杂志, 2011, 27(2): 130-134. 10.3969/j.issn.1000-484X.2011.02.008 [DOI] [Google Scholar]; WANG Lijun, JIANG Hong. Antitumor activity of polysaccharide from Aralia elata Seem and the effect on immune functions in tumor-bearing mice[J]. Chinese Journal of Immunology, 2011, 27(2): 130-134. (in Chinese)
10.3969/j.issn.1000-484X.2011.02.008. 10.3969/j.issn.1000-484X.2011.02.008 [DOI] [Google Scholar]
33.尹丽颖, 仲丽丽, 边晓燕, 等. 辽东楤木叶总皂苷对人胃癌BGC细胞凋亡的影响[J]. 中医药学报, 2012, 40(3): 12-14. 10.3969/j.issn.1002-2392.2012.03.005 [DOI] [Google Scholar]; YIN Liying, ZHONG Lili, BIAN Xiaoyan, et al.
Effect of Aralia Elate Seem leaf total saponin on apoptosis of BGC in human gastric cancer[J]. Acta Chinese Medicine and Pharmacology, 2012, 40(3): 12-14. (in Chinese)
10.3969/j.issn.1002-2392.2012.03.005. 10.3969/j.issn.1002-2392.2012.03.005 [DOI] [Google Scholar]
34.尹丽颖, 李凤金, 边晓燕, 等. 辽东楤木叶总皂苷对结肠癌HT-29细胞的生长抑制作用及机制研究[J]. 中国药理学通报, 2013, 29(11): 1545-1548. 10.3969/j.issn.1001-1978.2013.11.017 [DOI] [Google Scholar]; YIN Liying, LI Fengjin, BIAN Xiaoyan, et al.
Growth inhibitory effect of total saponins from leaves of Aralia elata Seem on human colon cancer and its related mechanism[J]. Chinese Pharmacological Bulletin, 2013, 29(11): 1545-1548. (in Chinese)
10.3969/j.issn.1001-1978.2013.11.017. 10.3969/j.issn.1001-1978.2013.11.017 [DOI] [Google Scholar]
35.尹丽颖, 肖洪彬, 敖鹏, 等. 辽东楤木叶总皂苷对荷结肠癌细胞裸鼠移植瘤TLR-4/NF-κB信号通路及炎性因子的影响[J]. 中国实验方剂学杂志, 2018, 24(24): 152-157. [Google Scholar]; YIN Liying, XIAO Hongbin, AO Peng, et al.
Effect of total saponins in Aralia elata leaves on TLR-4/NF-κB signal pathway and inflammatory factors in xenografts from nude mice bearing human colon cancer cells[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2018, 24(24): 152-157. (in Chinese) [Google Scholar]
36.TOMATSU M, OHNISHI-KAMEYAMA M, SHIBAM-OTO N. Aralin, a new cytotoxic protein from Aralia elata, inducing apoptosis in human cancer cells[J]. Cancer Lett, 2003, 199(1): 19-25. 10.1016/s0304-3835(03)00348-3 [DOI] [PubMed] [Google Scholar]
37.TOMATSU M, KONDO T, YOSHIKAWA T, et al.
An apoptotic inducer, aralin, is a novel type Ⅱ ribosome-inactivating protein from Aralia elata
[J]. Biol Chem, 2004, 385(9): 819-827. 10.1515/bc.2004.107 [DOI] [PubMed] [Google Scholar]
38.OTSUKA H, GOTOH Y, KOMENO T, et al.
Aralin, a type Ⅱ ribosome-inactivating protein from Aralia elata, exhibits selective anticancer activity through the processed form of a 110-kDa high-density lipoprotein-binding protein: a promising anticancer drug[J]. Biochem Biophys Res Commun, 2014, 453(1): 117-123. 10.1016/j.bbrc.2014.09.067 [DOI] [PubMed] [Google Scholar]
39.李凤金, 毕明刚, 武爽, 等. 辽东楤木叶总皂苷抗人乳腺癌作用的研究[J]. 中国药理学通报, 2013, 29(12): 1663-1667. 10.3969/j.issn.1001-1978.2013.12.009 [DOI] [Google Scholar]; LI Fengjin, BI Minggang, WU Shuang, et al.
Total saponins from leaves of Aralia elata Seem exhibit antitumor effects on human breast cancer in vitro and vivo
[J]. Chinese Pharmacological Bulletin, 2013, 29(12): 1663-1667. (in Chinese)
10.3969/j.issn.1001-1978.2013.12.009. 10.3969/j.issn.1001-1978.2013.12.009 [DOI] [Google Scholar]
40.李凤金. 辽东楤木叶总皂苷抗人乳腺癌作用及其毒性研究[D]. 哈尔滨: 黑龙江中医药大学, 2016. [Google Scholar]; LI Fengjin. The anti-tumor effects of total saponins from Aralia Elata leaves on human breast cancer and potential toxicity[D]. Harbin: Heilongjiang University of Chinese Medicine, 2016. (in Chinese) [Google Scholar]
41.张毅. 辽东楤木叶总皂苷对5-FU治疗乳腺癌小鼠的减毒作用研究[D]. 哈尔滨: 黑龙江中医药大学, 2015. [Google Scholar]; ZHANG Yi. The attenuated action of the total saponine of Aralia Elata Seem leaveson tumor-bearing mice treaded with fluorouracil[D]. Harbin: Heilongjiang University of Chinese Medicine, 2015. (in Chinese) [Google Scholar]
42.翟慧颖. 辽东楤木叶总皂苷联合5-FU对乳腺癌作用的研究[D]. 哈尔滨: 黑龙江中医药大学, 2015. [Google Scholar]; ZHAI Huiying. Synergistic anticancer effect of the total saponine of Aralia Elata Seem leaves combined with 5-fluorouracil in vitro
[D]. Harbin: Heilongjiang University of Chinese Medicine, 2015. (in Chinese) [Google Scholar]
43.王春梅, 薛晓鸥, 张广美. 辽东楤木协同顺铂抑制SKOV3-DDP生长的作用及机理[J]. 中医药信息, 2013, 30(3): 24-28. 10.3969/j.issn.1002-2406.2013.03.011 [DOI] [Google Scholar]; WANG Chunmei, XUE Xiaoou, ZHANG Guangmei. Cooperative effect of Aralia Elata (Miq.) Seem with cisplatin and the possible mechanism[J]. Information on Traditional Chinese Medicine, 2013, 30(3): 24-28. (in Chinese)
10.3969/j.issn.1002-2406.2013.03.011. 10.3969/j.issn.1002-2406.2013.03.011 [DOI] [Google Scholar]
44.徐岩, 鲁绍华, 雷影, 等. 龙牙楤木果实水煎液对小鼠降血糖作用的实验研究[J]. 吉林农业, 2018, 2018(23): 70-71. 29628746 [Google Scholar]; XU Yan, LU Shaohua, LEI Ying, et al.
Experimental study on hypoglycemic effect of Aralia elata fruit decoction on mice[J]. Agriculture of Jilin, 2018, 2018(23): 70-71. (in Chinese) [Google Scholar]
45.宋少江, 徐绥绪, 曹颖林. 辽东楤木总皂苷降血糖作用研究[J]. 中药研究与信息, 2005, 7(5): 7-9. 10.3969/j.issn.1673-4890.2005.05.003 [DOI] [Google Scholar]; SONG Shaojiang, XU Suixu, CAO Yinglin. Hypoglycemic effect of saponins from Aralia elata (Miq.) Seem[J]. Modern Chinese Medicine, 2005, 7(5): 7-9. (in Chinese)
10.3969/j.issn.1673-4890.2005.05.003. 10.3969/j.issn.1673-4890.2005.05.003 [DOI] [Google Scholar]
46.XI S, ZHOU G, ZHANG X, et al.
Protective effect of total aralosides of Aralia elata (Miq) Seem (TASAES) against diabetic cardiomyopathy in rats during the early stage, and possible mechanisms[J]. Exp Mol Med, 2009, 41(8): 538-547. 10.3858/emm.2009.41.8.059 [DOI] [PMC free article] [PubMed] [Google Scholar]
47.KIM Y S, KIM M, CHOI M Y, et al.
Aralia elata (Miq) Seem extract decreases O-GlcNAc transferase expression and retinal cell death in diabetic mice[J]. J Med Food, 2017, 20(10): 989-1001. 10.1089/jmf.2016.3891 [DOI] [PubMed] [Google Scholar]
48.SHIN S H, LOVE D C, HANOVER J A. Elevated O-GlcNAc-dependent signaling through inducible mOGT expression selectively triggers apoptosis[J]. Amino Acids, 2011, 40(3): 885-893. 10.1007/s00726-010-0719-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
49.KIM S J, KIM M J, CHOI M Y, et al.
Aralia elata inhibits neurodegeneration by downregulating O-GlcNAcylation of NF-κB in diabetic mice[J]. Int J Ophthalmol, 2017, 10(8): 1203-1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.HWANG K A, HWANG Y J, KIM G R, et al.
Extracts from Aralia elata (Miq) Seem alleviate hepatosteatosis via improving hepatic insulin sensitivity[J]. BMC Complement Altern Med, 2015, 15: 347. 10.1186/s12906-015-0871-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
51.HWANG K A, HWANG Y J, SONG J. Cholesterol-lowering effect of Aralia elata (Miq.) Seem via the activation of SREBP-2 and the LDL receptor[J]. J Chin Med Assoc, 2017, 80(10): 630-635. 10.1016/j.jcma.2017.06.007 [DOI] [PubMed] [Google Scholar]
52.朱晓冉. 龙牙楤木皂苷的制备及降血脂功能的研究[D]. 哈尔滨: 东北林业大学, 2019. [Google Scholar]; ZHU Xiaoran. Preparation of saponins from Aralia Elata and its antihyperlipidemic function[D]. Harbin: Northeast Forestry University, 2019. (in Chinese) [Google Scholar]
53.LUO Y, MENG X, ZHOU P, et al.
Elatoside C protects against ox-LDL-induced HUVECs injury by FoxO1-mediated autophagy induction[J]. Biochim Biophys Acta Mol Basis Dis, 2017, 1863(6): 1654-1665. 10.1016/j.bbadis.2017.01.017 [DOI] [PubMed] [Google Scholar]
54.TIAN Y, WANG S, SHANG H, et al.
The proteomic profiling of calenduloside E targets in HUVEC: design, synthesis and application of biotinylated probe BCEA[J]. Rsc Advances, 2017, 7(11): 6259-6265. 10.1039/c6ra25572h [DOI] [Google Scholar]
55.WANG S, TIAN Y, ZHANG J Y, et al.
Targets fishing and identification of Calenduloside E as Hsp90AB1: design, synthesis, and evaluation of clickable activity-based probe[J]. Front Pharmacol, 2018, 9: 532. 10.3389/fphar.2018.00532 [DOI] [PMC free article] [PubMed] [Google Scholar]
56.薛瑾, 陈应强. Nrf2/HO-1信号通路在肝脏相关疾病中的研究进展[J]. 南昌大学学报(医学版), 2022, 62(3): 88-92. [Google Scholar]; XUE Jin, CHEN Yingqiang. Research progress of Nrf2/HO-1 signaling pathway in liver-related diseases[J]. Journal of Nanchang University (Medical Sciences), 2022, 62(3): 88-92. (in Chinese) [Google Scholar]
57.CHUNG C K, JUNG M E. Ethanol fraction of Aralia elata Seemann enhances antioxidant activity and lowers serum lipids in rats when administered with benzo(a)pyrene[J]. Biol Pharm Bull, 2003, 26(10): 1502-1504. 10.1248/bpb.26.1502 [DOI] [PubMed] [Google Scholar]
58.王庆福, 衣雪洁. 辽东楤木对过度训练大鼠肝脏氧化损伤的预防作用[J]. 沈阳体育学院学报, 2007, 26(4): 63-65. 10.3969/j.issn.1004-0560.2007.04.021 [DOI] [Google Scholar]; WANG Qingfu, YI Xuejie. Prevention of the Aralia Elata (Miq.) against oxidative damage of rat’s liver during overtraining[J]. Journal of Shenyang Sport University, 2007, 26(4): 63-65. (in Chinese)
10.3969/j.issn.1004-0560.2007.04.021. 10.3969/j.issn.1004-0560.2007.04.021 [DOI] [Google Scholar]
59.王丽岩, 肖洪彬, 王鸣慧. 辽东楤木叶总皂苷抗急性肝损伤的实验研究[J]. 中医药信息, 2009, 26(2): 29-30, 93. 10.3969/j.issn.1002-2406.2009.02.012 [DOI] [Google Scholar]; WANG Liyan, XIAO Hongbin, WANG Minghui. Empirical study on anti-acute hepatic injury of Aralia Elate Seem leaf total saponin[J]. Information on Traditional Chinese Medicine, 2009, 26(2): 29-30, 93. (in Chinese)
10.3969/j.issn.1002-2406.2009.02.012. 10.3969/j.issn.1002-2406.2009.02.012 [DOI] [Google Scholar]
60.任美萍, 李华, 刘艳, 等. 辽东楤木皂苷对大鼠肝纤维化的影响[J]. 中药药理与临床, 2013, 29(4): 88-90. [Google Scholar]; REN Meiping, LI Hua, LIU Yan, et al.
Study on Aralia saponins in preventing rats liver fibrosis[J]. Pharma-cology and Clinics of Chinese Materia Medica, 2013, 29(4): 88-90. (in Chinese) [Google Scholar]
61.LUO Y, DONG X, YU Y, et al.
Total aralosides of Aralia elata (Miq) seem (TASAES) ameliorate nona-lcoholic steatohepatitis by modulating IRE1α-mediated JNK and NF-κB pathways in ApoE－/－ mice[J]. J Ethno-pharmacol, 2015, 163: 241-250. 10.1016/j.jep.2015.01.017 [DOI] [PubMed] [Google Scholar]
62.师海波, 孙英莲, 刘威, 等. 龙牙楤木总甙对小鼠B型单胺氧化酶及蛋白质合成的影响[J]. 中药药理与临床, 1999, 15(6): 20-21. [Google Scholar]; SHI Haibo, SUN Yinglian, LIU Wei, et al.
Effects of Aralia elata total glycosides on MAO-B and protein synthesis in mice[J]. Pharmacology and Clinics of Chinese Materia Medica, 1999, 15(6): 20-21. (in Chinese) [Google Scholar]
63.常波, 贾斯媛, 史娇娇, 等. 辽东楤木根皮醇提取物和人参茎叶总皂苷对过度训练大鼠海马BDGF和NGF mRNA表达的影响[J]. 沈阳体育学院学报, 2013, 32(3): 67-71. 10.3969/j.issn.1004-0560.2013.03.017 [DOI] [Google Scholar]; CHANG Bo, JIA Siyuan, SHI Jiaojiao, et al.
Empirical study of A. elata and ginsenosides extracts on the BDGF, NGF mRNA expression of hippocampus tissue in the overtraining rat[J]. Journal of Shenyang Sport University, 2013, 32(3): 67-71. (in Chinese)
10.3969/j.issn.1004-0560.2013.03.017. 10.3969/j.issn.1004-0560.2013.03.017 [DOI] [Google Scholar]
64.WANG C S, KAVALALI E T, MONTEGGIA L M. BDNF signaling in context: from synaptic regulation to psychiatric disorders[J]. Cell, 2022, 185(1): 62-76. 10.1016/j.cell.2021.12.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
65.NOTARAS M, VAN DEN BUUSE M. Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders[J]. Mol Psychiatry, 2020, 25(10): 2251-2274. 10.1038/s41380-019-0639-2 [DOI] [PubMed] [Google Scholar]
66.COLUCCI-D’AMATO L, SPERANZA L, VOLPICELLI F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurode-generation and brain cancer[J]. Int J Mol Sci, 2020, 21(20): 7777. 10.3390/ijms21207777 [DOI] [PMC free article] [PubMed] [Google Scholar]
67.PIIRSOO M, KALJAS A, TAMM K, et al.
Expression of NGF and GDNF family members and their receptors during peripheral nerve development and differentiation of Schwann cells in vitro
[J]. Neurosci Lett, 2010, 469(1): 135-140. 10.1016/j.neulet.2009.11.060 [DOI] [PMC free article] [PubMed] [Google Scholar]
68.TERADA Y, MORITA-TAKEMURA S, ISONISHI A, et al.
NGF and BDNF expression in mouse DRG after spared nerve injury[J]. Neurosci Lett, 2018, 686: 67-73. 10.1016/j.neulet.2018.08.051 [DOI] [PubMed] [Google Scholar]
69.王桂云, 张淑芹, 董琦. 龙牙楤木嫩芽生品对小鼠脑及肝SOD及MDA的影响[J]. 中国林副特产, 2003, 2003(64): 10. 10.3969/j.issn.1001-6902.2003.01.008 [DOI] [Google Scholar]; WANG Guiyun, ZHANG Shuqin, DONG Qi. Effects of Aralia mandshurica bud on SOD and MDA in brain and liver of mice[J]. Forest By-Product and Speciality in China, 2003, 2003(64): 10. (in Chinese)
10.3969/j.issn.1001-6902.2003.01.008. 10.3969/j.issn.1001-6902.2003.01.008 [DOI] [Google Scholar]
70.KWON B S, KIM J M, PARK S K, et al.
Chronic alcohol exposure induced neuroapoptosis: diminishing effect of ethyl acetate fraction from Aralia elata
[J]. Oxid Med Cell Longev, 2019, 2019: 7849876. 10.1155/2019/7849876 [DOI] [PMC free article] [PubMed] [Google Scholar]
71.WANG W, YAO G D, SHANG X Y, et al.
Eclalba-saponin Ⅰ from Aralia elata (Miq.) Seem. reduces oxidative stress-induced neural cell death by autophagy activation[J]. Biomed Pharmacother, 2018, 97: 152-161. 10.1016/j.biopha.2017.10.106 [DOI] [PubMed] [Google Scholar]
72.LEE J H, JEONG C S. Suppressive effects on the biosynthesis of inflammatory mediators by Aralia elata extract fractions in macrophage cells[J]. Environ Toxicol Pharmacol, 2009, 28(3): 333-341. 10.1016/j.etap.2009.05.009 [DOI] [PubMed] [Google Scholar]
73.刘纪成, 吕志强, 蒙雪婵, 等. 龙牙楤木总皂苷含量测定及其抗炎镇痛活性评价[J]. 生物资源, 2017, 39(2): 130-134. [Google Scholar]; LIU Jicheng, Zhiqiang LYU, MENG Xuechan, et al.
Determination of total saponin content of Aralia elata (Miq.) Seem and evaluation of its antiinflammation and analgesic effects[J]. Biotic Resources, 2017, 39(2): 130-134. (in Chinese) [Google Scholar]
74.WANG Z, SONG S, LU H, et al.
Effect of three triterpenoid compounds isolated from root bark of Aralia elata on stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation of p47phox and p67phox to cell membrane in human neutrophil[J]. Clin Chim Acta, 2003, 336(1-2): 65-72. 10.1016/s0009-8981(03)00326-7 [DOI] [PubMed] [Google Scholar]
75.YAGI-CHAVES S N, LIU G, YAMASHITA K, et al.
Effect of five triterpenoid compounds isolated from root bark of Aralia elata on stimulus-induced superoxide generation, tyrosyl or serine/threonine phosphorylation and translocation of p47phox, p67phox, and rac to cell membrane in human neutrophils[J]. Arch Biochem Biophys, 2006, 446(1): 84-90. 10.1016/j.abb.2005.11.006 [DOI] [PubMed] [Google Scholar]
76.ZHANG M, LIU G, TANG S, et al.
Effect of five triterpenoid compounds from the buds of Aralia elata on stimulus-induced superoxide generation, tyrosyl phosphorylation and translocation of cytosolic compounds to the cell membrane in human neutrophils[J]. Planta Med, 2006, 72(13): 1216-1222. 10.1055/s-2006-951679 [DOI] [PubMed] [Google Scholar]
77.SUH S J, JIN U H, KIM K W, et al.
Triterpenoid saponin, oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-α-L-rhamnopyranosyl (1→2)-α-L-arabinopyranoside (OA) from Aralia elata inhibits LPS-induced nitric oxide production by down-regulated NF-κB in raw 264.7 cells[J]. Arch Biochem Biophys, 2007, 467(2): 227-233. 10.1016/j.abb.2007.08.025 [DOI] [PubMed] [Google Scholar]
78.张帅, 安胜军, 崔清卓, 等. 丹参有效成分最佳配伍对载脂蛋白E－/－小鼠血管外膜成纤维细胞增殖的影响[J]. 世界中医药, 2023, 18(3): 320-323. [Google Scholar]; ZHANG Shuai, AN Shengjun, CUI Qingzhuo, et al.
Effects of optimal compatibility of active components of salvia miltiorrhiza on proliferation of vascular adventitial fibroblasts in ApoE－/－ mice[J]. World Chinese Medicine, 2023, 18(3): 320-323. (in Chinese) [Google Scholar]
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