CN115531402A - 人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用 - Google Patents
人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用 Download PDFInfo
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- CN115531402A CN115531402A CN202211395657.3A CN202211395657A CN115531402A CN 115531402 A CN115531402 A CN 115531402A CN 202211395657 A CN202211395657 A CN 202211395657A CN 115531402 A CN115531402 A CN 115531402A
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Abstract
本发明公开了人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用，通过建立异硫氰酸苯酯(APIT)诱导大鼠急性胆汁淤积型肝炎模型，探讨人参皂苷Rd对胆汁淤积性肝病的治疗效果及作用机制，结果显示，人参皂苷Rd能够缓解胆汁淤积性肝病症状，主要表现为降低血清ALT、ALP、Tbil、γ‑GT水平，恢复胆汁排泄量，抑制肝脏炎症因子表达水平，为临床治疗胆汁淤积性肝病提供了一种疗效确切且副作用小的新的药物。
Description
技术领域
本发明涉及中药技术领域，具体涉及人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用。
背景技术
胆汁淤积性肝病是由各种原因引起的胆汁生成、分泌和排泄障碍，不能主动经胆小管排至肠腔，在肝内淤积，反流入血，而引起的一系列器质性损害、代谢失调和功能紊乱的肝胆系统疾病。胆汁淤积性肝病的发生原因较复杂，病因主要包括遗传、免疫、变性、感染、结石及肿瘤等。如不及时有效治疗，甚至可能进展为肝纤维化、肝硬化、肝衰竭和肝肿瘤。流行病学证据显示，我国胆汁淤积性肝炎的发生率占慢性肝病患者的10%以上。目前临床上主要的治疗药物有熊去氧胆酸（UDCA）、S-腺苷蛋氨酸、考来烯酸胺、奥贝胆酸和贝特类药等，其中UDCA是临床推荐一线药物，主要目的是改善由于胆汁淤积所致的临床症状和肝脏损伤。然而，临床疗效尚无法令人满意，约有30%的患者对UDCA无效，且UDCA起效缓慢，较为昂贵，临床上急需更有效的药物。
人参皂苷Rd(Ginsenoside Rd，G-Rd)是一种四环三萜类化合物，是从三七、人参中提取的人参皂苷类物质。目前已有研究报道，人参皂苷Rd能激活AMPK和SIRT1，从而调节氧化应激和细胞凋亡，并改善糖尿病驱动的血管损伤。还有研究报道，人参皂苷Rd能通过诱导p62驱动的有丝分裂介导的NLRP3炎症小体失活来改善结肠炎。还有研究报道，人参皂苷Rd通过表皮生长因子受体信号轴抑制结直肠癌的转移。由此可见，人参皂苷Rd有抗炎、抗癌、抗氧化、抗细胞凋亡等多种生物活性，并且在治疗糖尿病和急性缺血性中风等疾病方面效果显著。
然而，人参皂苷Rd对于胆汁淤积性肝病的治疗效果及其作用机制尚未见报道。
发明内容
鉴于此，本发明的目的在于提供人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用。
优选地，本发明所述的胆汁淤积性肝病为胆汁淤积性肝炎，更优选为异硫氰酸苯酯APIT诱导的急性胆汁淤积型肝炎。
本发明所述的人参皂苷Rd可以通过人参或三七中提取纯化得到，也可以通过市购获得。
本发明通过异硫氰酸苯酯(APIT)诱导大鼠急性胆汁淤积型肝炎模型，结果显示，人参皂苷Rd对APIT诱导的胆汁淤积所导致的Tbil、ALT、ALP和γ-GT活性升高有显著的抑制作用，对APIT诱导的肝细胞损伤、炎症细胞浸润以及胆汁排泄量的抑制也有显著的改善，表明人参皂苷Rd对APIT诱导的胆汁淤积型肝炎具有较好的治疗作用；且人参皂苷Rd对APIT诱导的胆汁淤积所导致的IL-1β、TNF-α和IL-6 mRNA水平升高有显著的抑制作用，对NOS、COX-2、IL-18、NLRP3的蛋白水平升高也有显著的改善，表明人参皂苷Rd对APIT诱导的胆汁淤积型肝炎具有良好的抗炎作用，为临床治疗胆汁淤积性肝病提供更有利的药效学依据。
本发明还提供了一种预防或治疗胆汁淤积性肝病的药物，包含有效含量的人参皂苷Rd和药学上可接受的载体。本发明预防或治疗胆汁淤积性肝病的药物可经本领域常规方法制备成适宜的剂型。优选的，所述药物的剂型为片剂、胶囊剂、粉剂、注射剂、散剂、糖浆剂、丸剂、合剂或颗粒剂。
所述药学上可接受的载体包括但不限于填充剂、崩解剂、甜味剂、润滑剂、助悬剂、防腐剂、粘合剂等等，其用量为本领域常规用量。
本发明与现有技术相比，具有如下优异效果：
本发明提供了人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的新用途，通过建立异硫氰酸苯酯(APIT)诱导大鼠急性胆汁淤积型肝炎模型，探讨人参皂苷Rd对胆汁淤积性肝病的治疗效果及作用机制，结果显示，人参皂苷Rd能够缓解胆汁淤积性肝病症状，主要表现为降低血清ALT、ALP、Tbil、γ-GT水平，恢复胆汁排泄量，抑制肝脏炎症因子表达水平，为临床治疗胆汁淤积性肝病提供了一种疗效确切且副作用小的新的药物。
附图说明
图1为人参皂苷Rd对胆汁淤积大鼠病理学变化的影响。
具体实施方式
下面通过具体实施方式来进一步说明本发明，以下实施例为本发明具体的实施方式，但本发明的实施方式并不受下述实施例的限制。
本发明实施例所采用的试药或试剂如下：
人参皂苷Rd（批号：S27663，购自上海源叶生物科技有限公司）；
熊去氧胆酸（批号：s25093，购自上海源叶生物科技有限公司）；
人参皂苷Rd的剂量为6.25 mg/kg、12.5 mg/kg、25 mg/kg、50 mg/kg，给药剂量为20ml/kg。
人参皂苷Rd为固体粉末状，人参皂苷Rd的施用方法为：溶于总体积1%的DMSO，震摇充分溶解后加水配置成0.3125 mg/ml、0.625 mg/ml、1.25 mg/ml、2.5 mg/ml的溶液。
急性胆汁淤积性肝病由异硫氰酸苯酯(APIT)诱导（液态，每1ml含1.13g）由橄榄油稀释至110 mg/kg。
熊去氧胆酸作为阳药组，剂量为 50 mg/kg, 溶于总体积1%的DMSO，震摇充分溶解后加蒸馏水配置成2.5 mg/ml的溶液。
下述各实验例证明本发明所述的技术效果。
实施例1：人参皂苷Rd对胆汁淤积性肝病中的保护作用
1、实验材料
清洁级雄性SD大鼠，体重200±20g，由吴氏实验动物提供，在塑料笼具内分笼饲养，自由摄食与饮水7天，使其适应环境。
2、实验方法
本实验例应用异硫氰酸苯酯(APIT)建立大鼠急性肝内胆汁淤积型肝炎模型，研究人参皂苷Rd对该模型大鼠的治疗作用。
2.1实验分组
大鼠36只，随机分为正常对照（Con）组、模型（TAA）组、熊去氧胆酸阳药（UDCA）组、人参皂苷Rd 6.25 mg/kg给药组、人参皂苷Rd 12.5 mg/kg给药组和人参皂苷Rd 25 mg/kg给药组。
2.2给药方法
各给药组按20ml/kg的剂量灌胃给药，正常对照组、模型组给予同等体积生理盐水，每天一次，给药6天，灌药第6天后除正常对照组外，其余各组大鼠均灌胃给予APIT110mg/kg，所有大鼠在给予APIT后8小时，进行胆排泄试验测定2h胆汁流量；然后，腹主动脉取血制备血清，取左叶肝脏置于10％甲醛溶液中固定备用。
3、实验数据检测与处理
3.1检测指标
3.1.1血清指标测定
大鼠腹主动脉取血后，血液样本室温静止30min以上，3000 rpm 离心10 min，然后取上清液得到血清样本。然后按照试剂盒说明书进行操作，检测各组血清中谷丙转氨酶（ALT）、碱性磷酸酶（ALP）水平、血清总胆红素 (Tbil)、谷酰转移酶(γ-GT)活性。
3.1.2肝病理组织学观察
大鼠肝脏用10％中性甲醛固定，石蜡包埋，4-5μm切片，二甲苯脱蜡，梯度乙醇脱水，常规HE染色，乙醇脱水，二甲苯透明，树脂封固，使用显微镜观察。
3.1.3胆排泄实验
大鼠腹腔注射乌拉坦1g /kg麻醉，胆总管插管，用预先称重并加入1mol/L的KH2PO4 100μL的离心管，冰块上收集胆汁。
3.2统计学分析
采用SPSS 26.0软件进行数据处理，统计方法选择单因素方差分析。
4.实验结果
人参皂苷Rd对胆汁淤积大鼠血清生化指标的影响如表1所示，对胆汁排泄量的影响如表2所示，对胆汁淤积大鼠肝组织病理学变化的影响如图1所示。
表1 人参皂苷Rd对胆汁淤积大鼠血清生化指标的影响 
###表示和正常对照组相比P<0 .001， ##表示和正常对照组相比P<0 .01，
***表示和模型对照组相比P<0 .001，**表示和模型对照组相比P<0 .01，*表示和模型对照组相比P<0 .05。
表2 人参皂苷Rd对胆汁淤积大鼠胆汁排泄量的影响
###表示和正常对照组相比P<0 .001，
**表示和模型对照组相比P<0.01，*表示和模型对照组相比P<0.05。
ALT是反应肝功能的血清学标志，Tbil、ALP和γ-GT是肝内胆汁淤积的血清学标志。由表1和表2可知，模型组Tbil、ALP、γ-GT和ALT活性明显升高，胆汁排泄量显著减少；由图1可知，模型组出现炎性浸润和肝细胞坏死现象；表明大鼠急性肝内胆汁淤积型肝炎模型造模成功。
并且由表1和表2可知，熊去氧胆酸和人参皂苷Rd对APIT诱导的胆汁淤积所导致的Tbil、ALT、ALP和γ-GT活性升高有显著的抑制作用，对APIT诱导的肝细胞损伤、炎症细胞浸润以及胆汁排泄量的抑制也有显著的改善。
5、实验结论
人参皂苷Rd对APIT诱导的胆汁淤积型肝炎具有较好的治疗作用。
实施例2：人参皂苷Rd对胆汁淤积性肝病中炎症指标的影响
1、实验材料
清洁级雄性SD大鼠，体重200±20g，由吴氏实验动物提供，在塑料笼具内分笼饲养，自由摄食与饮水7天，使其适应环境。
2、实验方法
本实验例应用异硫氰酸苯酯(APIT)建立大鼠急性肝内胆汁淤积型肝炎模型，研究人参皂苷Rd对该模型大鼠的治疗作用。
2.1实验分组
大鼠36只，随机分为正常对照（Con）组、模型（TAA）组、熊去氧胆酸（UDCA）组、人参皂苷Rd12.5 mg/kg给药组、人参皂苷Rd25 mg/kg给药组和人参皂苷Rd 50mg/kg给药组。
2.2给药方法
各给药组按20ml/kg的剂量灌胃给药，正常对照组、模型组给予同体积生理盐水，每天一次，给药6天，灌药第6天后除正常对照组外，其余各组大鼠均灌胃给予APIT 110mg/kg，所有大鼠在给予APIT8小时后处死，取肝脏用生理盐水冲洗净表面残留血液并用滤纸擦拭干净后，储存于-80℃备用。
3、实验数据检测与处理
3.1检测指标
3.1.1 RT-qPCR检测炎症因子mRNA的表达程度
取50-100 mg的大鼠肝组织，加入1mLTRIzol，用1 mL注射器反复抽提至均匀混悬，再依次加入氯仿、异丙醇、75%酒精并分别于12000 rpm，4℃离心后获得RNA样本，使用紫外分光光度仪器测量RNA浓度，按照说明书要求配置逆转录体系，于逆转录仪器上制得cDNA样本。按照说明书配置PCR反应体系（DEPC水2 µL、Mix 5 µL、上下游引物各1 µL、cDNA 1 µL）。
PCR扩增反应条件为：95℃预变性30 s，95℃变性10 s，退火60 ℃ 30 s，40个循环。本研究使用相对定量方法，应用 2－ΔΔCt 分析数据。
3.1.2
3.2统计学分析
采用SPSS 26.0软件进行数据处理，统计方法选择单因素方差分析。
4. 实验结果
人参皂苷Rd对胆汁淤积大鼠肝脏中IL-1β、IL-6和TNF-α mRNA水平的影响如表3所示，对胆汁淤积大鼠肝脏中炎性蛋白水平的影响如表4所示。
表3 人参皂苷Rd对胆汁淤积大鼠肝脏中IL-1β、IL-6和TNF-α mRNA水平的影响
###表示和正常对照组相比P<0 .001， #表示和正常对照组相比P<0 .05,
***表示和模型对照组相比P<0 .001，**表示和模型对照组相比P<0 .01，*表示和模型对照组相比P<0 .05。
表4 人参皂苷Rd对胆汁淤积大鼠肝脏中炎性蛋白水平的影响
##表示和正常对照组相比P<0 .01， #表示和正常对照组相比P<0 .05,
***表示和模型对照组相比P<0 .001，*表示和模型对照组相比P<0 .05。
NLRP3是参与炎症反应的关键调节因子，COX-2和iNOS是两种重要的炎性蛋白，IL-18、IL-1β、TNF-α和IL-6是促炎因子，都可以参与炎症反应的发生和放大过程。由表3和表4可知，模型组IL-1β、TNF-α和IL-6 mRNA水平明显升高，iNOS、COX-2、IL-18、NLRP3的蛋白水平明显升高，表明大鼠急性肝内胆汁淤积型肝炎模型中炎症水平升高。
并且由表3和表4可知，熊去氧胆酸和人参皂苷Rd对APIT诱导的胆汁淤积所导致的IL-1β、TNF-α和IL-6 mRNA水平升高有显著的抑制作用，对NOS、COX-2、IL-18、NLRP3的蛋白水平升高也有显著的改善。
5、实验结论
人参皂苷Rd对APIT诱导的胆汁淤积型肝炎具有良好的抗炎作用。
Claims (5)
1.人参皂苷Rd在制备预防或治疗胆汁淤积性肝病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述胆汁淤积性肝病为胆汁淤积性肝炎。
3.根据权利要求2所述的应用，其特征在于，所述胆汁淤积性肝炎为异硫氰酸苯酯APIT诱导的急性胆汁淤积型肝炎。
4.一种预防或治疗胆汁淤积性肝病的药物，其特征在于，包含有效含量的人参皂苷Rd和药学上可接受的载体。
5.根据权利要求4所述的一种预防或治疗胆汁淤积性肝病的药物，其特征在于，所述药物的剂型为片剂、胶囊剂、粉剂、注射剂、散剂、糖浆剂、丸剂、合剂或颗粒剂。
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