CN116270678A - 连翘酯苷a在制备缓解肠道炎症药物中的应用 - Google Patents
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Abstract
本发明公开了连翘酯苷A在制备缓解肠道炎症药物中的应用，涉及医药技术领域，其技术方案要点是：连翘酯苷A通过上调beclin1、LC3II/LC3I激活自噬小体，降低NLRP3炎症小体信号通路NLRP3、cleavedcaspase1、cleavedIL‑1β蛋白表达量，降低p62蛋白表达含量，降低血清中DAO以及D‑LA水平缓解肠道炎症。患者在使用甲氨蝶呤(MTX)治疗肿瘤的同时会引起肠道炎症，使用连翘酯苷A后能够通过修复肠道屏障功能以及调控自噬小体抑制NLRP3炎症小体活性降低肠道通透性，还可以减少肠道组织炎性细胞浸润、腺体扩张、缓解黏膜层绒毛结构紊乱等，达到缓解肠道炎症的效果。
Description
技术领域
本发明涉及医药技术领域，更具体地说，它涉及连翘酯苷A在制备缓解肠道炎症药物中的应用。
背景技术
肠道是机体最大的消化器官，同时也是重要的免疫器官之一。肠粘膜完整性是维持机体正常功能的关键。当机体受到严重创伤或其他应激时，会引起肠道粘膜损伤等病理生理的发生，并通过激活机体免疫反应，导致大量炎性介质产生和释放，最终引发肠道炎症甚至全身炎症反应。化疗药物虽然对癌细胞有毒，但也可引起严重的不良反应。其中，肠黏膜炎(Intestinalmucositis，IM)是主要的胃肠道副作用之一。化疗引起的IM发生率约为40％，尤其是使用甲氨蝶呤(Methotrexate，MTX)、5-氟尿嘧啶(5-Fu)、阿糖胞苷等化疗药物时，肠黏膜炎的患病率可高达90％。到目前为止没有有效治疗MTX引起的肠黏膜炎的方法。研究表明，自噬(autophagy)在调控炎症反应，调节免疫方面发挥着重要作用，自噬的缺损是诱发炎症反应及炎症性疾病的重要机制之一。木犀科植物连翘的干燥果实中提取的连翘酯苷A(ForsythiasideA，FTA)在抑制炎症反应方面能够发挥重要作用。因此本发明旨在研究连翘酯苷A通过调控自噬缓解化疗药物引发的肠黏膜炎。
发明内容
本发明的目的是提供连翘酯苷A在制备缓解肠道炎症药物中的应用，以解决上述技术问题。
本发明的上述技术目的是通过以下技术方案得以实现的：连翘酯苷A在制备缓解肠道炎症药物中的应用，所述连翘酯苷A用于治疗肠道炎症药物的制备。
本发明进一步设置为：所述连翘酯苷A通过上调beclin1、LC3II/LC3I激活自噬小体，抑制NLRP3炎症小体信号通路表达。
本发明进一步设置为：所述连翘酯苷A通过降低p62蛋白表达含量，降低血清中DAO以及D-LA水平缓解肠道炎症。
本发明进一步设置为：所述连翘酯苷A通过降低NLRP3、cleaved caspase1、cleavedIL-1β蛋白表达量缓解肠道炎症。
综上所述，本发明具有以下有益效果：能够通过修复肠道屏障功能以及调控自噬小体抑制NLRP3炎症小体活性降低肠道通透性，还可以减少肠道组织炎性细胞浸润、腺体扩张、缓解黏膜层绒毛结构紊乱等，达到缓解肠道炎症的效果。
附图说明
图1是本发明实施例中FTA对血液中DAO和D-lactate影响(与对照组比较，##p<0.01；与MTX组比较,**p<0.01)；
图2是本发明实施例中FTA对beclin1和LC3II/LC3I蛋白表达量的影响(与MTX组比较，*p<0.05，**p<0.01)；
图3是本发明实施例中FTA对p62蛋白表达量的影响(与对照组比较，##p<0.01；与MTX组比较,**p<0.01)；
图4是本发明实施例中FTA对NLRP3炎症小体相关蛋白表达量的影响(与对照组比较，##p<0.01；与MTX组比较,*p<0.05，**p<0.01)；
图5是本发明实施例中自噬抑制后，FTA对肠道组织形态的影响；
图6是本发明实施例中自噬抑制后，FTA对NLRP3炎症小体相关蛋白表达量的影响(与FTA高剂量组比较，#p<0.05，##p<0.01)。
具体实施方式
以下结合附图1-6对本发明作进一步详细说明。
实施例：连翘酯苷A在制备缓解肠道炎症药物中的应用，如图1所示，连翘酯苷A能够降低血清中DAO以及D-LA水平。如图2、图3、图4、图5和图6所示，连翘酯苷A能够上调beclin1、LC3II/LC3I激活自噬小体，抑制NLRP3炎症小体信号通路表达，降低NLRP3、cleavedcaspase1、cleavedIL-1β蛋白表达量，降低p62蛋白表达含量。如图5所示连翘酯苷A可以减少肠道组织炎性细胞浸润、腺体扩张、缓解黏膜层绒毛结构紊乱等。综合以上结果FTA能够通过激活自噬小体抑制NLRP3炎症小体信号通路缓解MTX诱导的肠道炎症。
将健康6-8周龄200-220g雄性SD大鼠随机分为五组，每组6只：对照组，模型组，连翘酯苷A低组(40mg/kg)，连翘酯苷A高组(80mg/kg)，3-MA(15mg/kg3-MA)+连翘酯苷A高组(80mg/kg)。实验持续时间为7天。模型组前3天腹腔注射7mg/kg/dMTX建立小肠炎模型，后4天然后灌喂等量的生理盐水。连翘酯苷A低组(40mg/kg)和连翘酯苷A高组(80mg/kg)前3天腹腔注射7mg/kg/dMTX并且分别灌喂40和80mg/kg连翘酯苷A，后四天两组分别只灌喂40和80mg/kg连翘酯苷A。3-MA+连翘酯苷A高组(80mg/kg)前3天腹腔注射7mg/kg/dMTX和15mg/kg3-MA，并且灌喂80mg/kg连翘酯苷A，后4天只灌喂80mg/kg连翘酯苷A。对照组灌喂等量的生理盐水。从实验开始记录每组大鼠的采食量和最终体重。在第7天灌喂后24h，采用腹腔注射2％戊巴比妥钠麻醉大鼠。收集血液和小肠组织。然后用Elisa法检测血液中D-乳酸(D-lactate)的浓度和二胺氧化酶(diamineoxidase，DAO)的活性。Westernblot检测小肠组织中LC3I，LC3II，Beclin1，p62，NLRP3，cleavedcaspase1(p20)，cleavedIL-1β(p17)的表达量。HE法检测小肠病理变化。
本具体实施例仅仅是对本发明的解释，其并不是对本发明的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本发明的权利要求范围内都受到专利法的保护。
Claims (4)
1.连翘酯苷A在制备缓解肠道炎症药物中的应用，其特征是：包括，所述连翘酯苷A用于治疗肠道炎症药物的制备。
2.根据权利要求1所述的连翘酯苷A在制备缓解肠道炎症药物中的应用，其特征是：所述连翘酯苷A通过上调beclin1、LC3II/LC3I激活自噬小体，抑制NLRP3炎症小体信号通路表达。
3.根据权利要求1所述的连翘酯苷A在制备缓解肠道炎症药物中的应用，其特征是：所述连翘酯苷A通过降低p62蛋白表达含量，降低血清中DAO以及D-LA水平缓解肠道炎症。
4.根据权利要求1所述的连翘酯苷A在制备缓解肠道炎症药物中的应用，其特征是：所述连翘酯苷A通过降低NLRP3、cleaved caspase1、cleaved IL-1β蛋白表达量缓解肠道炎症。
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