CN114209736B - 黄花倒水莲总皂苷的应用 - Google Patents
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Abstract
本发明公开了黄花倒水莲总皂苷在制备治疗自身免疫性肝炎药物或保健品中的应用,其中,所述黄花倒水莲总皂苷按下述方法制备:将黄花倒水莲水提取液上大孔树脂柱,用水及含水乙醇洗脱,收集60~70v/v%乙醇洗脱液,经回收溶剂后干燥即得。申请人的实验结果表明,黄花倒水莲总皂苷可以有效地调节自身免疫性肝炎模型小鼠的免疫系统,缓解其脾脏的肿大,抑制肝脏炎症的发生,可用于制备治疗自身免疫性肝炎的药物或保健品。
Description
技术领域
本发明涉及植物提取物的应用,具体涉及黄花倒水莲总皂苷在制备治疗自身免疫性肝炎药物或保健品中的应用。
背景技术
黄花倒水莲(Polygala fallax Hemsl.)为远志科远志属灌木或小乔木,又名假黄花远志、黄花参、倒吊黄、吊吊黄、念健、一身保暖、鸭仔兜等,其生长于山谷林下水旁荫湿处,在我国江西、福建、湖南、广东、广西和云南等省均有分布。其根入药,性平,味甘、微苦,具有补气血、健脾利湿、活血调经之功效,可用于治疗病后体虚、腰膝酸痛、跌打损伤及抗衰老等,为瑶、苗、壮等少数民族的常用药物。近年来,黄花倒水莲的药用价值逐渐被重视,对其化学成分与药理活性的研究取得了较大进展,如:
公布号为CN1382476A的发明专利指出,黄花倒水莲水煎液或水溶性成分可用于制备治疗梅尼埃病的药物。
公布号为CN1431221A的发明专利指出,黄花倒水莲总皂苷(PTS)具有降脂作用,其中PTS是将黄花倒水莲水提取液上大孔树脂(D101、HP20、AB8等)柱,用水及含水乙醇梯度洗脱,收集60~70%(v/v)乙醇洗脱液,经浓缩、干燥而得。
公布号为CN112043749A的发明专利指出,黄花倒水莲提取物(包括水提取物和乙醇提取物)能够改善溃疡性结肠炎小鼠动物模型的体重、饮食量以及脾脏和胸腺系数、降低疾病活动指数(DAI)、增加结肠长度,表明黄花倒水莲提取物对溃疡性结肠炎具有治疗作用。
郭继远等(中国天然药物,2006年7月第4卷第4期,303-307)指出,黄花倒水莲总苷(PTS)对由四氯化碳与氨基半乳糖造成的急性肝损伤具有治疗作用;对酒精精脂肪肝有保护作用,PTS改善了模型的脂质代谢并降低了自由基引起的氧化作用。
自身免疫性肝炎是由自身免疫反应异常介导的,慢性、进行性地累及肝实质的炎症性疾病,其临床特征表现为不同程度的血清转氨酶升高、高γ-球蛋白血症和自身抗体阳性,组织学特征是以淋巴细胞、浆细胞浸润为主的界面性肝炎,严重病例可快速进展为肝硬化和肝衰竭。该病在世界范围内均有发生,在欧美国家发病率相对较高。但是,近年来,我国报道的病例数呈现出明显的上升趋势。自身免疫性肝炎的治疗难度大,且预后不良,如治疗不及时,可导致门静脉高压与肝功能不全,甚至发展为肝硬化、肝衰竭,因此,应当引起足够的重视。目前,自身免疫性肝炎治疗药物以免疫抑制剂和肾上腺皮质类固醇类为主,可改善生化指标,抑制肝脏炎症,防止肝损伤,但患者需长期用药,容易产生耐药性,且药物毒副作用大,停药后面临着较高的复发风险。目前尚未见有将黄花倒水莲总皂苷用于改善自身免疫性肝炎症状、延缓病情发展方面的相关报道。
发明内容
本发明要解决的技术问题是提供黄花倒水莲总皂苷在制备治疗自身免疫性肝炎药物或保健品中的应用。
本发明的技术方案为:黄花倒水莲总皂苷在制备治疗自身免疫性肝炎的药物或保健品中的应用,其中,所述黄花倒水莲总皂苷按下述方法制备:将黄花倒水莲水提取液上大孔树脂柱,用水及含水乙醇洗脱,收集60~70%(v/v)乙醇洗脱液,经回收溶剂后干燥即得。
上述技术方案中,黄花倒水莲水提取液采用现有常规技术获得;所述的大孔树脂为现有技术中用于分离纯化皂苷的常规选择,如D101、HP20、AB8等;收集所得的60~70%(v/v)乙醇洗脱液优选采用真空回收溶剂,之后进行冷冻干燥以得到黄花倒水莲总皂苷。
上述技术方案中,所述黄花倒水莲总皂苷中皂苷的含量通常≥55%(总皂苷含量测定方法参见:刘友平等,分光光度法测定不同产地远志总皂甙的含量,《成都中医药大学学报》,2000年,23(2):46-47)。
具体地,黄花倒水莲总皂苷是通过调节免疫系统,抑制炎症反应来实现治疗自身免疫性肝炎。
具体的应用方法为:取黄花倒水莲总皂苷,加入或不加入药用辅料,按常规方法制备成各种药物制剂;或者是取黄花倒水莲皂苷组分,加入或不加入辅料,按常规方法制备成保健品。
进一步的,本发明还提供一种以黄花倒水莲总皂苷为有效成分制备的治疗自身免疫性肝炎的药物或保健品。所述药物或保健品的剂型可以是药学上可接受的剂型,如胶囊剂、片剂或颗粒剂等常规剂型。
申请人通过动物实验发现,黄花倒水莲总皂苷可以有效地调节自身免疫性肝炎模型小鼠的免疫系统,缓解其脾脏的肿大,抑制肝脏炎症的发生,可用于制备治疗自身免疫性肝炎的药物或保健品。
具体实施方式
下面结合实验进一步说明黄花倒水莲总皂苷(以下简称为PTS)在调节免疫系统、抑制炎症反应的作用。
一、PTS的制备及动物实验方案
1、PTS的制备
1)取干燥的黄花倒水莲根1kg,粉碎至50目,用相当于药材15倍重量的水浸泡3h,煎煮并保持微沸状态1h。过滤,滤渣保持微沸状态再煎煮2次,每次1h,合并3次滤液,得黄花倒水莲水提取液。
2)黄花倒水莲水提取液上D101大孔树脂柱吸附,依次用蒸馏水、20%(v/v)乙醇、70%(v/v)乙醇洗脱。收集70%(v/v)乙醇洗脱液,减压浓缩,冷冻干燥,即得PTS。根据文献(刘友平等,分光光度法测定不同产地远志总皂甙的含量,《成都中医药大学学报》,2000年,23(2):46-47)中的方法测定所得样品中皂苷的含量,结果为61.3±4.8%。
2、PTS对自身免疫性肝炎小鼠脾脏的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,称量小鼠体重。颈椎脱臼处死小鼠,取脾脏,称量脾脏重量,计算脾脏指数,公式为:脾脏指数=脾脏重量/体重×100%,采用单因素方差分析进行差异性统计。
3、PTS对自身免疫性肝炎小鼠肝脏的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,称量小鼠体重。颈椎脱臼处死小鼠,取肝脏,称量肝脏重量,计算肝脏指数,公式为:肝脏指数=肝脏重量/体重×100%,采用单因素方差分析进行差异性统计。
4、PTS对自身免疫性肝炎小鼠血清中ALT的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,颈椎脱臼处死小鼠后立即摘眼球取血,制备血清。用武汉伊莱瑞特公司生产的谷丙转氨酶(ALT)检测试剂盒(货号:E-BC-K235-M),测定各组小鼠血清中的ALT活性,采用单因素方差分析进行差异性统计。
5、PTS对自身免疫性肝炎小鼠血清中AST的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,颈椎脱臼处死小鼠后立即摘眼球取血,制备血清。用武汉伊莱瑞特公司生产的谷草转氨酶(AST)检测试剂盒(货号:E-BC-K236-M),测定各组小鼠血清中的AST活性,采用单因素方差分析进行差异性统计。
6、PTS对自身免疫性肝炎小鼠肝脏中IL-6表达的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,颈椎脱臼处死小鼠。取肝脏,按1:9(g/mL)比例加入生理盐水,充分匀浆。离心10分钟(13000g,4℃),取上清液。用武汉伊莱瑞特公司生产的白细胞介素6(IL-6)检测试剂盒(货号:E-EL-M0044c),测定上清液中的IL-6浓度;用BCA法测定上清液中的蛋白质浓度。采用单因素方差分析进行差异性统计。
7、PTS对自身免疫性肝炎小鼠肝脏中TNF-α表达的影响
从湖南斯莱克景达实验动物有限公司购买SPF级雄性昆明小鼠52只,适应性饲养7天。随机挑取2只小鼠,颈椎脱臼处死,取肝脏,按1:9(g/mL)的比例加入生理盐水,充分匀浆后,离心10分钟(4000g,4℃)。取上清液,即为同基因肝抗原。按1:1(v/v)的比例,将同基因肝抗原与完全弗氏佐剂混合均匀,使其充分乳化,即成免疫剂。随机挑取40只小鼠造模,腹腔注射免疫剂(1mL/只),完成第一次免疫。7天后,按照相同方法进行加强免疫,得到自身免疫性肝炎小鼠模型。正常对照组小鼠8只均同期腹腔注射生理盐水(1mL/只)。
采用随机分组方法,将造模小鼠分为5组:模型组、PTS低剂量组(50mg/kg/d)、PTS中剂量组(100mg/kg/d)、PTS高剂量组(200mg/kg/d)和阳性对照组(100mg/kg/d联苯双酯滴丸),每组8只。造模结束当天开始灌胃给药(0.1m L/10g),正常对照组和模型组给予同等剂量生理盐水,每日1次,连续14天。
给药14天后,颈椎脱臼处死小鼠。取肝脏,按1:9(g/mL)比例加入生理盐水,充分匀浆。离心10分钟(13000g,4℃),取上清液。用武汉伊莱瑞特公司生产的肿瘤坏死因子α(TNF-α)检测试剂盒(货号:E-EL-M0049c),测定上清液中的TNF-α浓度;用BCA法测定上清液中的蛋白质浓度。采用单因素方差分析进行差异性统计。
二、实验结果
1、PTS对自身免疫性肝炎小鼠脾脏的影响
脾脏是最大的免疫器官,是细胞免疫和体液免疫的中心。如表1所示,自身免疫性肝炎小鼠脾脏指数显著增大(p<0.01),表明脾脏严重增生,继而引起免疫功能异常,导致自身免疫性疾病。用50、100和200mg/kg/d的PTS处理后,脾脏指数随PTS浓度增加而降低(p<0.05),表明PTS可以抑制自身免疫性肝炎小鼠的脾脏增生,调节其免疫系统及免疫功能。
表1 PTS对自身免疫性肝炎小鼠脾脏的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
2、PTS对自身免疫性肝炎小鼠肝脏的影响
如表2所示,自身免疫性肝炎小鼠肝脏指数显著增大(p<0.01),这是由于肝脏增生和水肿所致。用50、100和200mg/kg/d剂量的PTS处理后,肝脏指数逐渐降低(p<0.05),表明PTS可以缓解自身免疫性肝炎小鼠肝脏的增生和水肿。
表2 PTS对自身免疫性肝炎小鼠肝脏的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
3、PTS对自身免疫性肝炎小鼠血清中ALT活性的影响
如表3所示,自身免疫性肝炎小鼠血清中ALT活性显著提升(p<0.01),表明小鼠体内发生了炎症反应。用50、100和200mg/kg/d剂量的PTS处理后,血清中ALT活性逐渐降低(p<0.05),表明PTS可以抑制自身免疫性肝炎小鼠体内的炎症反应。
表3 PTS对自身免疫性肝炎小鼠血清中ALT活性的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
4、PTS对自身免疫性肝炎小鼠血清中AST活性的影响
如表4所示,自身免疫性肝炎小鼠血清中AST活性显著提升(p<0.01),表明小鼠体内发生了炎症反应。用50、100和200mg/kg/d剂量的PTS处理后,血清中AST活性随浓度升高而降低(p<0.05),表明PTS可以抑制自身免疫性肝炎小鼠体内的炎症反应。
表4 PTS对自身免疫性肝炎小鼠血清中AST活性的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
5、PTS对自身免疫性肝炎小鼠肝脏中IL-6表达的影响
如表5所示,自身免疫性肝炎小鼠肝脏组织中IL-6表达量显著上升(p<0.01),表明小鼠肝脏组织中发生了炎症反应。用50、100和200mg/kg/d剂量的PTS处理后,肝脏中IL-6表达量逐渐降低(p<0.05),表明PTS可以抑制自身免疫性肝炎肝脏中的炎症反应。
表5 PTS对自身免疫性肝炎小鼠肝脏中IL-6表达的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
6、PTS对自身免疫性肝炎小鼠肝脏中TNF-α表达的影响
如表6所示,自身免疫性肝炎小鼠血清中TNF-α表达量显著提升(p<0.01),表明小鼠肝脏组织中发生了炎症反应。用50、100和200mg/kg/d剂量的PTS处理后,肝脏组织中TNF-α表达量逐渐降低(p<0.05),表明PTS可以抑制自身免疫性肝炎小鼠肝脏组织中的炎症反应。
表6 PTS对自身免疫性肝炎小鼠肝脏中TNF-α表达的影响
注:与正常对照组比较,##p<0.01;与模型组比较,*p<0.05,**p<0.01
综上所述,PTS具有调节免疫系统,抑制炎症反应的作用,可用于制备治疗自身免疫性肝炎的药物或保健品。
Claims (2)
1.黄花倒水莲总皂苷在制备治疗自身免疫性肝炎药物中的应用,其中,所述黄花倒水莲总皂苷按下述方法制备:将黄花倒水莲水提取液上大孔树脂柱,用水及含水乙醇洗脱,收集60~70v/v%乙醇洗脱液,经回收溶剂后干燥即得。
2.根据权利要求1所述的应用,其特征是,所述黄花倒水莲总皂苷中皂苷的含量≥55%。
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CN110200981A (zh) * | 2019-06-06 | 2019-09-06 | 中国药科大学 | 五环三萜皂苷的医药用途及其药物组合物 |
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