CN106389396A - 黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途 - Google Patents
黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途 Download PDFInfo
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Abstract
本发明提供了黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途，可用于防治急性肺损伤与急性呼吸窘迫综合征。使用黄腐酚治疗急性肺损伤或急性呼吸窘迫综合征，具有毒副作用小，临床症状明显，治愈率高。
Description
技术领域
本发明公开了黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途，属于医药领域。
背景技术
黄腐酚（Xanthohumol）是一种从工业酿造啤酒的重要原料之一的啤酒花中提取出的天然的异戊烯黄酮类化合物，具有抗癌、抗病毒、预防及治疗糖尿病、动脉粥样硬化的作用。但目前尚未见黄腐酚用于治疗急性肺损伤的报道。
急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）是指由创伤、输血及感染等多种因素所导致的，以肺间质中大量炎症因子的释放、炎症细胞的聚集及肺水肿为病理生理特征的急性进行性呼吸功能不全或者呼吸衰竭症状，是重症监护中的主要死亡原因。急性肺损伤的发病机制错综复杂，主要涉及炎症反应、氧化应激及炎症小体等多种通路，而且各个通路之间是相互联系、相互影响形成复杂的细胞网络及信号通路网络。正是由于其发病机制的复杂性，尽管多个大型临床试验已经用于探测多种治疗策略（包括使用糖皮质激素、酮康唑、吸入NO或补充的表面活性剂的潜能等，迄今为止仍然没有一个可行、有效的治疗方法降低其死亡率。与现代医学常规治疗手段相比，中草药治疗优势在于可通过多途径、多环节调节机体的免疫反应，从而影响疾病发生的各个因素及全身作用机制。为了寻求更好的治疗方法，已经有很多学者从传统中药的多靶点作用的角度出发，研究中药单体对内毒素引起的急性肺损伤的保护作用及机制，虽然取得了一定的进展，但仍处于起步阶段，具有巨大的发展前景。本发明首次发现黄腐酚通过激活AMPK/AKT/Nrf2信号通路发挥抗氧化、抗炎及抗炎症小体作用，可用于治疗急性肺损伤。
发明内容
本发明公开了黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途。
本发明公开了黄腐酚在制备预防和治疗急性肺损伤药物中的用途。
本发明公开了黄腐酚制备治疗急性呼吸窘迫综合征药物中的用途。
本发明公开了以黄腐酚为活性成分制备治疗急性肺损伤或急性呼吸窘迫综合征的药物可以是药物学上的任何药物制剂。
本发明所述的黄腐酚的分子式为：C21H22O5；分子量354.4
本发明所述的黄腐酚能够对内毒素急性肺损伤小鼠具有较好的治疗作用；
本发明所述的黄腐酚能激活AMPK/AKT/Nrf2信号通路；
本发明所述的黄腐酚能够增强Nrf2调控的抗氧化酶和代谢解毒酶的表达；
本发明所述的黄腐酚能够抑制氧化应激、炎症和炎症小体等相关蛋白的表达；
本发明所述的黄腐酚对急性肺损伤小鼠的治疗作用是依赖于AMPK/AKT/Nrf2信号轴的激活作用；
本发明同时提供了黄腐酚在制备治疗急性肺损伤药物中的应用；
本发明技术方案优选黄腐酚在制备治疗急性肺损伤药物中的应用；
本发明以黄腐酚为活性成分制备治疗急性肺损伤或急性呼吸窘迫综合征的药物可以是药物学上的任何药物制剂；可将黄腐酚和药学上可接受的辅料制备成各种剂型。
本发明优选将黄腐酚制备成注射剂、胶囊、片剂、粉针剂等剂型。
本发明的积极效果在于：提供了黄腐酚新的医用用途，可用于防治急性肺损伤与急性呼吸窘迫综合征。使用黄腐酚治疗急性肺损伤或急性呼吸窘迫综合征，具有毒副作用小，临床症状明显，治愈率高。
附图说明
图1为本发明黄腐酚对急性肺损伤小鼠肺组织病理学改变的保护作用；
图2为本发明黄腐酚对急性肺损伤小鼠肺泡灌洗液中（A）中性粒细胞及(B)炎性细胞因子的抑制作用；
图3 为本发明黄腐酚对急性肺损伤小鼠肺泡灌洗液中ROS产物的抑制作用；
图4为本发明黄腐酚体外对LPS诱导的炎症相关蛋白表达的抑制作用；
图5 为本发明黄腐酚体外对LPS诱导的(A-C)炎症因子和(D)ROS的抑制作用；
图6 为本发明黄腐酚体外对抗氧化应激信号通路及抗氧化酶的激活作用；
图7为本发明黄腐酚对LPS诱导的急性肺损伤小鼠肺组织中Txinp激活和Trx-1消耗，NLRP3炎性小体和的NF-κB炎性信号通路的调节作用；
图8为本发明黄腐酚对急性肺损伤小鼠肺组织中Nrf2、AMPK和GSK3β的蛋白表达的激活作用；
图9为本发明黄腐酚对野生型及Nrf2 -/-急性肺损伤小鼠肺泡灌洗液中(A-C)炎症因子和(D)ROS的抑制作用；
图10为本发明黄腐酚对野生型及Nrf2 -/-急性肺损伤小鼠肺组织中Txinp、NLRP3炎性小体和NF-κB信号通路的抑制作用；
图11为本发明黄腐酚在体外对AMPK、GSK3β以及Nrf2信号通路的激活作用；
图12为本发明黄腐酚加入AMPK及Nrf2抑制剂后，对Nrf2激活作用。
具体实施方式
通过黄腐酚体内对小鼠急性肺损伤的治疗作用试验，体外抗炎、抗氧化活性和对信号通路调节作用试验以及体内外抗炎和抗氧化的作用机制试验证实了黄腐酚可通过激活AMPK/AKT/Nrf2信号轴，发挥治疗急性肺损伤的作用。
实验例1
黄腐酚体内对急性肺损伤小鼠的治疗作用
小鼠急性肺损伤模型建立：60只雄性C57/B小鼠（6～8 周龄，18-20g），随机分6组，每组10只：空白组、LPS（0.5 mg/kg）组、黄腐酚给药组（50 mg/kg），黄腐酚（10、50 mg/kg）+ LPS组、地塞米松（5 mg/kg）+ LPS 组作为阳性对照组。操作方法：首先，生理盐水稀释黄腐酚和地塞米松腹腔注射小鼠，空白组和LPS组腹腔注射等体积的生理盐水。给药1 h后， LPS鼻腔滴注造模，空白组和黄腐酚给药组小鼠鼻腔滴注等体积的生理盐水。在LPS滴注12 h后，处死小鼠，并收集小鼠支气管肺泡灌洗液（BALF）和肺组织，进行相应的指标检测。
实验结果：
黄腐酚对LPS诱导的急性肺损伤小鼠的保护作用参见图1-3，黄腐酚能够显著抑制LPS诱导的急性肺损伤小鼠肺组织病理学改变；抑制体内炎症细胞侵润和炎性细胞因子增多；抑制LPS诱导产生的过多的ROS，对小鼠急性肺损伤发挥保护作用。
实验例2
黄腐酚体外抗炎、抗氧化活性及对信号通路调节作用试验
细胞模型建立：将对数生长期的RAW 264.7细胞铺于96孔培养板中，培养24小时后，加入不同浓度的黄腐酚作用1小时，后给予LPS（1 μg/ml）作用24小时，MTT检测细胞毒性；细胞铺于24孔培养板中， 处理方法同上，（a）收集上清ELISA检测细胞因子，收集细胞WesternBloting检测iNOS、COX-2和HMGB1表达水平；(b)将已配好的DCFH-DA（终浓度：10 μM）加入到每个孔中，置于37 °C温箱中反应30 min后检测ROS产物。
将细胞铺于6孔培养板中，培养24 h后，加入不同浓度黄腐酚处理18 h或黄腐酚（5μM）处理细胞不同时间，收集细胞检测GCLC、GCLM、HO-1、NQO1和Trx-1的蛋白表达。
实验结果：
如图4-6，黄腐酚体外具有显著的抗炎抗氧化活性：黄腐酚能显著抑制LPS诱导炎症相关蛋白表达；显著抑制炎症介质和ROS产物；显著激活抗氧化信号通路及多种抗氧化酶的表达。
实验例3
体内外抗炎和抗氧化作用机制的研究
体内小鼠急性肺损伤模型建立：为了进一步探究黄腐酚对LPS诱导的急性肺损伤保护作用机制，野生型（WT）和Nrf2敲除（Nrf2-/-）小鼠，构建LPS诱导小鼠急性肺损伤模型（建模方法同上），取小鼠的肺组织和肺泡灌洗液（BALF），进行以下相关实验。
实验结果：黄腐酚对急性肺损伤小鼠保护作用机制如图7-10，黄腐酚显著抑制氧化应激诱导的Txinp激活和Trx-1消耗，抑制NLRP3炎性小体和的NF-κB炎性信号通路；显著激活Nrf2、AMPK和GSK3β；显著抑制TNF-α、IL-6、IL-1β和ROS的产生，但在Nrf2 -/-小鼠中抑制作用减弱；Nrf2 -/-小鼠肺组织中，黄腐酚对LPS激活的Txinp、NLRP3炎性小体和NF-κB信号通路的抑制作用，明显减弱。
体外细胞模型建立：相关蛋白检测方法同上。此外，细胞铺于96孔培养板中，培养24 h后，待细胞密度长到70%左右，加入黄腐酚（5 μM）处理细胞（1、3或6小时）后，使用双荧光素酶试剂盒检测ARE活性。细胞铺于6孔培养板中，培养24 h后，加入CC（3 μM，AMPK的抑制剂）处理细胞18小时或加入BT（100 nM，Nrf2的抑制剂）处理细胞1小时后，然后加入黄腐酚（5 μM）处理细胞3小时，收集细胞检测相关蛋白表达情况。
实验结果：
黄腐酚体外抗氧化作用机制如图11-12，黄腐酚体外抗氧化依赖于AMPK/GSK3β/Nrf2信号通路轴。黄腐酚在体外能显著激活AMPK、GSK3β以及Nrf2信号通路；加入AMPK及Nrf2抑制剂后，黄腐酚对Nrf2激活作用消失。
Claims (4)
1.黄腐酚在防治急性肺损伤与急性呼吸窘迫综合征中的用途。
2.黄腐酚在制备预防和治疗急性肺损伤药物中的用途。
3.黄腐酚在制备治疗急性呼吸窘迫综合征药物中的用途。
4.以黄腐酚为活性成分制备治疗急性肺损伤或急性呼吸窘迫综合征的药物可以是药物学上的任何药物制剂。
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| CN112402402A (zh) * | 2020-11-20 | 2021-02-26 | 青岛海洋科学与技术国家实验室发展中心 | 一种黄腐酚在制备新型冠状病毒抑制剂中的应用 |
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