CN113476437A - 刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用 - Google Patents
刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用 Download PDFInfo
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- CN113476437A CN113476437A CN202110913195.9A CN202110913195A CN113476437A CN 113476437 A CN113476437 A CN 113476437A CN 202110913195 A CN202110913195 A CN 202110913195A CN 113476437 A CN113476437 A CN 113476437A
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Abstract
本发明公开了刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用,属于生物医药领域。本发明利用刺芒柄花素缓解胰腺水肿,降低血清淀粉酶和血清脂肪酶的含量,缓解腺泡细胞损伤及炎症浸润,缓解急性胰腺炎所致结肠杯状细胞损伤及炎症浸润,减少胰腺、结肠中促炎细胞因子的释放。本发明将刺芒柄花素用于制备治疗急性胰腺炎及其相关疾病的药物、药物组合物中,拓宽了刺芒柄花素的应用领域。
Description
技术领域
本发明属于生物医药领域,特别涉及刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用。
背景技术
急性胰腺炎是目前一种发病率持续增高的自身免疫性疾病,起病急,病情进展快,是胰酶消化胰腺及其周围组织所引起的急性炎症,主要表现为胰腺呈水肿、出血及坏死。发病原因以胆道系统疾病、酗酒和暴饮暴食、手术与损伤、感染、高脂血症等为主,AP常累及胰周组织,触发炎症瀑布样级联反应从而引起全身炎症反应综合征(SIRS)和多器官功能障碍综合征(MODS)。据调查,大约20%的AP患者会发展为中度或严重的急性胰腺炎,出现胰腺及胰腺周围组织或器官坏死,或两者兼有,死亡率高达20-40%,给患者家庭及社会带来了巨大的负担,但是目前急性胰腺炎的发病机制尚未完全明确,因此也尚无根治疗法存在。研究发现,肠道炎症、肠屏障的损坏与急性胰腺炎严重程度密切相关。肠道屏障功能障碍直接导致肠道细菌和内毒素发生移位,引起肠源性内毒素血症,导致腹腔、胰腺及胰腺周围组织发生严重感染,不仅对胰腺造成“二次打击”,还可能进一步引发SIRS和MODS。
发明内容
为了解决上述问题,本发明提供了一种新方式,利用刺芒柄花素来防治急性胰腺炎。刺芒柄花素是一种从日常食用的黄芪、大豆、苦参、苜蓿等食物中提取的异黄酮。本发明利用化合物刺芒柄花可有效缓解小鼠胰腺水肿情况,降低血清淀粉酶和血清脂肪酶水平和缓解中性粒细胞浸润,缓解腺泡细胞损伤及炎症浸润,缓解结肠杯状细胞损伤和炎性浸润,减少胰腺、结肠促炎细胞因子的释放。本发明拓宽了刺芒柄花素的使用范围,提供了一种有效的、新的、无毒副作用的防治急性胰腺炎的方法。
本发明提供了刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用。
在本发明的一种实施方式中,所述刺芒柄花素的结构如下所示:
本发明提供了一种用于防治急性胰腺炎的药物,所述药物中包含刺芒柄花素。
在本发明的一种实施方式中,所述药物的剂型包括汤剂、丸剂、散剂、膏剂、丹剂、酒剂、糖浆剂、浸膏剂、锭剂、棒剂、栓剂、曲剂、炙剂。
在本发明的一种实施方式中,所述药物的剂型还包括片剂、冲剂、袋泡剂、口服液剂、胶囊剂、滴丸剂、合剂、酊剂、气雾剂、膜剂、针剂、注射剂。
在本发明的一种实施方式中,所述药物还含有医学上可接受的辅料。
在本发明的一种实施方式中,所述医学上可接受的辅料包括黏合剂、填充剂、崩解剂、润滑剂、抗氧剂、矫味剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂。
在本发明的一种实施方式中,黏合剂包括羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶。
在本发明的一种实施方式中,增溶剂包括淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸。
在本发明的一种实施方式中,崩解剂包括琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠。
在本发明的一种实施方式中,润滑剂包括滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠。
在本发明的一种实施方式中,所述药物还含有药用载体。
在本发明的一种实施方式中,所述药用载体包括微囊、微球、纳米粒和脂质体。
本发明提供了刺芒柄花素在制备用于缓解胰腺水肿的药物中的应用。
本发明提供了刺芒柄花素在制备用于缓解胰腺组织的中性粒细胞浸润的药物中的应用。
本发明提供了刺芒柄花素在制备用于缓解腺泡细胞损失及炎症浸润的药物中的应用。
本发明提供了刺芒柄花素在制备用于减少胰腺组织中促炎细胞因子释放的药物中的应用。
本发明提供了刺芒柄花素在制备用于缓解急性胰腺炎中结肠的杯状细胞损伤及炎症浸润的药物中的应用。
本发明提供了刺芒柄花素在制备用于减少急性胰腺炎中结肠组织中促炎细胞因子释放的药物中的应用。
本发明提供了刺芒柄花素在制备用于缓解雨蛙素诱导的急性胰腺炎的药物中的应用。
本发明的有益效果为:
本发明提供了刺芒柄花素在治疗急性胰腺炎药物中的新用途,刺芒柄花素对缓解胰腺水肿,降低血清淀粉酶和血清脂肪酶的含量,缓解腺泡细胞损伤及炎症浸润,缓解急性胰腺炎所致结肠杯状细胞损伤及炎症浸润,减少胰腺、结肠中促炎细胞因子的释放。刺芒柄花素可以用于治疗急性胰腺炎及其相关疾病中的药物、药物组合物中,拓宽了刺芒柄花素的应用领域。
附图说明
图1为刺芒柄花素应用于急性胰腺炎小鼠后胰腺水肿和中性粒细胞浸润、血清淀粉酶、脂肪酶的结果图。其中,CON表示对照组,CAE表示炎症模型组,CAE+FOR表示刺芒柄花素灌胃后的模型处理组。*:P<0.05,**:P<0.01,***:P<0.001,****:P<0.0001。
图2为刺芒柄花素应用于急性胰腺炎小鼠后胰腺组织的病理变化图。*:P<0.05,**:P<0.01,***:P<0.001。
图3为刺芒柄花素应用于急性胰腺炎小鼠后胰腺的细胞因子表达情况结果图。*:P<0.05,**:P<0.01,***:P<0.001。
图4为刺芒柄花素应用于急性胰腺炎小鼠后结肠组织的病理变化图。*:P<0.05,**:P<0.01,***:P<0.001。
图5为刺芒柄花素应用于急性胰腺炎小鼠后结肠的细胞因子表达情况结果图。*:P<0.05,**:P<0.01,***:P<0.001。
具体实施方式
化合物信息:刺芒柄花素(Formononetin)的分子式是C16H12O4,CAS号485-72-3,购买自上海阿拉丁生化科技股份有限公司。
实施例1急性胰腺炎模型的建立
将8周龄左右的20-23g雌性C57BL/6J小鼠随机分为对照组(CON),炎症模型组(CAE),刺芒柄花素预处理组(CAE+FOR),每组8只,提供可控的饲养条件。采用腹腔注射雨蛙素的方式诱导急性胰腺炎模型。将雨蛙素溶于生理盐水中,向小鼠腹腔注射雨蛙素(50mg/kg),每1h注射1次,共注射10次,CON组小鼠给予等体积生理盐水。刺芒柄花素预处理组是造模前每天用刺芒柄花素溶于1%的DMSO中进行灌胃,剂量为100mg/kg,灌胃时间是7天,其余两组小鼠灌胃等量1%的DMSO。最后一针注射后3小时向小鼠注射致死剂量的戊巴比妥钠并快速收集血液、胰腺等样品。
实施例2刺芒柄花素可以缓解急性胰腺炎小鼠胰腺水肿、中性粒细胞的浸润以及降低血清淀粉酶、脂肪酶的升高
胰腺水肿程度是能够反映急性胰腺炎的严重程度最直观的指标之一。水肿的诱因主要是急性胰腺炎发生时胰腺中大量免疫细胞的募集和浸润。在这些大量浸润的免疫细胞中,中性粒细胞的活化在急性胰腺炎病理过程中发挥着重要作用。髓过氧化物酶是中性粒细胞释放的一种重要酶类,其酶活水平可间接反映中性粒细胞的活性及浸润情况。剪取部分新鲜胰腺组织,剥离脂肪后用滤纸轻轻吸拭胰腺组织表面的水分,置于预先称过质量的锡箔纸上,用分析天平称量湿重。随后将胰腺组织包裹于锡纸内并将其放置在80℃烘箱中烘干水分,48小时后再次用分析天平称量干重。以湿重和干重的质量差与湿重的比值来衡量胰腺的水肿程度。胰腺髓过氧化物酶测定采用髓过氧化物酶试剂盒。如图1所示,与CON组相比,CAE组胰腺发生明显水肿,同时胰腺髓过氧化物酶水平也大幅度升高。而CAE+FOR组比CAE组水肿程度明显减少,胰腺髓过氧化物酶水平有所下降,表明刺芒柄花素预处理对胰腺水肿有有效的缓解作用,同时能缓解胰腺中性粒细胞的浸润。
血清淀粉酶和血清脂肪酶是临床上诊断AP的重要指标。AP发生时,由于胰腺腺泡细胞遭到破坏,胰腺分泌的淀粉酶和脂肪酶大量进入血液,导致血清淀粉酶和血清脂肪酶升高。收集新鲜血液于血清分离管,室温静置30min,经离心(4℃,3000g,15min)后得到血清样品,然后分别用淀粉酶试剂盒、脂肪酶试剂盒来测定,如图1所示,与CON组小鼠相比,CAE组小鼠血清淀粉酶和血清脂肪酶水平显著升高。而刺芒柄花素预处理可以显著降低急性胰腺炎小鼠的血清淀粉酶和血清脂肪酶水平。
实施例3刺芒柄花素可以缓解急性胰腺炎小鼠腺泡细胞损伤及炎症浸润
用H&E染色的方法,将CON组、CAE组、CAE+FOR组胰腺经固定、脱水、染色、脱蜡、透明和封片等主要过程,观察胰腺组织的组织完整性、胰腺水肿程度和炎症细胞浸润程度。如图2,结果显示,CON组胰腺组织结构密实,无明显裂纹。CAE小鼠胰腺组显观察到腺泡细胞存在空泡和死亡情况,炎症细胞浸润,导管扭曲阻塞等情况,胰腺组织损伤明显。而CAE+FOR组较CAE组则有明显的改善作用,说明刺芒柄花素对小鼠急性胰腺炎发挥了保护作用。
实施例4刺芒柄花素可以抑制急性胰腺炎小鼠胰腺组织中促炎细胞因子的释放
采用荧光定量PCR法(qPCR)测定小鼠胰腺组织中促炎因子TNF-α、MCP-1、IL-6、IL-1β的mRNA表达相对含量。组织样品通过使用高通量组织研磨机在Trizol中进行破碎,之后使用氯仿等进行抽提,离心后吸取上清,加入等体积的异丙醇进行沉淀RNA,离心后弃上清,用75%乙醇DEPC进行洗涤所得RNA。对得到的RNA进行浓度和纯度的测量后,使用Takara反转录试剂盒将组织样品中的RNA反转到cDNA。根据mRNA设计的引物在正式实验前需进行qPCR测试其特异性和扩增效率,得到结果后,首先根据熔解曲线判断引物特异性,选择标准为单峰,峰形偏窄,无明显引物二聚体熔解曲线峰。引物验证结果良好后进行正式实验。
使用SYBR Green Mix进行相关基因的扩增检测。扩增程序为:55℃预热30秒;95℃5分钟;接下来循环39次:95℃30秒;58℃30秒;之后进行引物特异性检测,从65℃保持5秒之后每秒上升0.1℃至95℃,观察引物特异性。如上通过对胰腺组织中TNF-α、MCP-1、IL-6、IL-1β的mRNA水平进行检测。如图3,结果显示,与CON组相比,CAE组小鼠胰腺中TNF-α、MCP-1、IL-6、IL-1β的表达显著上调,CAE+FOR组较CAE组细胞因子表达下降,说明刺芒柄花素对小鼠急性胰腺炎发挥了保护作用。
实施例5刺芒柄花素可以缓解急性胰腺炎小鼠结肠杯状细胞损伤及炎症浸润
用H&E染色的方法,将CON组、CAE组、CAE+FOR组结肠经固定、脱水、染色、脱蜡、透明和封片等主要过程,观察结肠组织的组织完整性、结肠水肿程度和炎症细胞浸润程度。如图4,结果显示,CON组肠绒毛和杯状细胞完整,无炎性浸润,而CAE组隐窝内和粘膜层有明显的炎性浸润,肠绒毛变短、杯状细胞不完整,CAE+FOR处理组肠绒毛和杯状细胞明显比CAE组完整,炎性浸润程度也大幅度减小,说明刺芒柄花素对小鼠急性胰腺炎导致的肠道炎症发挥了保护作用。
实施例6刺芒柄花素可以抑制急性胰腺炎小鼠结肠组织中促炎细胞因子的释放
采用荧光定量PCR法(方法同实施例4)测定小鼠结肠组织中促炎因子TNF-α、MCP-1、IL-6、IL-1β的mRNA表达相对含量。如图5,结果显示,与CON组相比,CAE组小鼠结肠中TNF-α、MCP-1、IL-6、IL-1β的表达显著上调,CAE+FOR预处理组较CAE组细胞因子表达下降。说明刺芒柄花素可以有效防治了急性胰腺炎造成的肠道炎症。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.刺芒柄花素在制备用于防治急性胰腺炎类疾病的药物中的应用。
3.一种用于防治急性胰腺炎的药物,其特征在于,所述药物中包含刺芒柄花素。
4.根据权利要求3所述的药物,其特征在于,所述药物的剂型包括汤剂、丸剂、散剂、膏剂、丹剂、酒剂、糖浆剂、浸膏剂、锭剂、棒剂、栓剂、曲剂、炙剂、片剂、冲剂、袋泡剂、口服液剂、胶囊剂、滴丸剂、合剂、酊剂、气雾剂、膜剂、针剂、注射剂。
5.根据权利要求3所述的药物,其特征在于,所述药物还含有医学上可接受的辅料,所述医学上可接受的辅料包括黏合剂、填充剂、崩解剂、润滑剂、抗氧剂、矫味剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂。
6.根据权利要求3所述的药物,其特征在于,所述药物还含有药用载体,药用载体包括微囊、微球、纳米粒和脂质体。
7.刺芒柄花素在制备用于缓解胰腺水肿的药物中的应用。
8.刺芒柄花素在制备用于缓解胰腺组织的中性粒细胞浸润、的药物中的应用。
9.刺芒柄花素在制备用于缓解腺泡细胞损失及炎症浸润的药物中的应用。
10.刺芒柄花素在制备用于减少胰腺组织中促炎细胞因子释放的药物中的应用。
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