CN115105497A - 10,11-脱氢弯孢霉菌素在抑制nlrp3活化中的用途 - Google Patents
10,11-脱氢弯孢霉菌素在抑制nlrp3活化中的用途 Download PDFInfo
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- CN115105497A CN115105497A CN202210783628.8A CN202210783628A CN115105497A CN 115105497 A CN115105497 A CN 115105497A CN 202210783628 A CN202210783628 A CN 202210783628A CN 115105497 A CN115105497 A CN 115105497A
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- dehydrocurvularin
- nlrp3
- activation
- inflammasome
- beta
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Abstract
本发明属于生物医药技术领域，具体公开一种10,11‑脱氢弯孢霉菌素在抑制NLRP3活化中的用途。10,11‑脱氢弯孢霉菌素对NLRP3炎症小体具有特异性抑制作用，且通过抑制NEK7‑NLRP3的相互作用来抑制NLRP3炎症小体的激活，还可以抑制NLRP3炎症小体的组装。
Description
技术问题
本发明属于生物医药技术领域，具体公开一种10,11-脱氢弯孢霉菌素在抑制NLRP3活化中的用途。
背景技术
NLRP3炎症小体是一种胞质蛋白复合物，由先天免疫受体NLRP3、ASC和caspase-1组成。危险和病原体相关的分子模式可以驱动NLRP3炎性小体的组装和激活，导致促炎细胞因子IL-1β和IL-18的释放。K离子外排、ROS水平升高、线粒体损伤和溶酶体破裂与NLRP3炎症小体激活相关。NLRP3炎症小体的过度激活与多种炎症疾病的发生相关，包括动脉粥样硬化、阿尔茨海默病、结肠炎、败血症和2型糖尿病，这意味着需要抑制NLRP3炎症小体才能很好地控制这些疾病。因此，NLPR3炎症小体称为炎症性疾病的潜在靶点。最近，一些小分子化合物，包括β-羟基丁酸酯、MCC950、冬凌草素、冬凌草毒素、pristimerin和曲尼司特，已被证明通过抑制NLRP3炎症小体发挥抗炎作用。故新型NLPR3炎症小体抑制剂的发现对NLPR3相关的疾病具有重要的临床意义。
10,11-脱氢弯孢霉菌素是一种天然的苯二醇内酯，是许多真菌的次生代谢产物。研究表明，10,11-脱氢弯孢霉菌素具有广泛的抗癌活性，包括细胞周期阻滞、血管生成和侵袭抑制。除了诱导对癌细胞的细胞毒性外，10,11-脱氢弯孢霉菌素还具有抗氧化和抗炎活性。同样，研究表明，10,11-脱氢弯孢霉菌素通过抑制NF-κB和MAPK信号通路抑制促炎细胞因子的释放和炎症反应。此外，10,11-脱氢弯孢霉菌素在败血症和结肠炎中发挥了广泛的保护作用。但10,11-脱氢弯孢霉菌素是否可以抑制NLRP3炎症小体的活化尚未见报道。
发明内容
鉴于以上技术问题，本发明提供以下技术方案：
本发明提供一种10,11-脱氢弯孢霉菌素在抑制NLRP3活化中的用途。
优选地，所述10,11-脱氢弯孢霉菌素用于制备NLRP3活化抑制剂。
优选地，所述10,11-脱氢弯孢霉菌素用于制备抑制NLRP3活化的药物。
优选地，所述10,11-脱氢弯孢霉菌素用于制备治疗和/或预防NLRP3异常活化相关疾病的药物。
优选地，所述NLRP3异常活化相关疾病为动脉粥样硬化、阿尔茨海默病、结肠炎、腹膜炎、败血症、痛风、风湿性关节炎、帕金森多发性硬化症或2型糖尿病中的至少一种。
优选地，所述10,11-脱氢弯孢霉菌素用于制备IL-1β及IL-18表达抑制剂。
本发明还提供一种治疗和/或预防NLRP3异常活化相关疾病的药物，其包括所述10,11-脱氢弯孢霉菌素，以及药学上可接受的辅料或载体。
优选地，所述药物的剂型为口服制剂或注射制剂。
对比现有技术，本发明的有益效果为：
1、本发明提供了10,11-脱氢弯孢霉菌素在抑制NLRP3活化中的用途。经过试验证明，10,11-脱氢弯孢霉菌素对NLRP3炎症小体具有特异性抑制作用，且通过抑制NEK7-NLRP3的相互作用来抑制NLRP3炎症小体的激活，还可以抑制NLRP3炎症小体的组装；同时，碳碳双键是10,11-脱氢弯孢霉菌素抑制NLRP3炎症小体必不可少的。
2、10,11-脱氢弯孢霉菌素通过抑制NLRP3炎症小体活性，从而抑制体内炎症的发生，而由于NLRP3炎症小体异常活化与多种炎症性疾病有关，故10,11-脱氢弯孢霉菌素可以作为治疗NLRP3驱动疾病的候选药物。
附图说明
图1是10,11-脱氢弯孢霉菌素对尼日利亚菌素刺激后的BMDMs中caspase-1及IL-1β的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；**p<0.01，***p<0.001；
图2是10,11-脱氢弯孢霉菌素对尼日利亚菌素诱导的IL-18的影响；**p<0.01，***p<0.001；
图3是10,11-脱氢弯孢霉菌素对TNF-α的影响；
图4是10,11-脱氢弯孢霉菌素对LPS诱导的小鼠腹腔巨噬细胞中caspase-1及IL-1β的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；**p<0.01，***p<0.001；
图5是10,11-脱氢弯孢霉菌素对LPS诱导的BMDCs中caspase-1及IL-1β的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；**p<0.01，***p<0.001；
图6是10,11-脱氢弯孢霉菌素对激动剂Mock、ATP、MSU及Nigericin诱导的caspase-1及IL-1β的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；**p<0.01，***p<0.001；
图7是10,11-脱氢弯孢霉菌素对鼠伤寒沙门氏菌感染诱导的NLRC4炎症小体的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；***p<0.001；
图8是10,11-脱氢弯孢霉菌素对poly(dA:dT)转染诱导AIM2炎症小体的影响；A、蛋白免疫印迹分析图，B、上清液中IL-1β含量；***p<0.001；
图9是内源性免疫沉淀(IP)和Westernblot分析NEK7-NLRP3和NLRP3-ASC的相互作用；A、NLRP3和NEK7的相互作用；B、NLRP3与ASC的相互作用；
图10是HEK-293T细胞中VSV-NLRP3与Flag-NEK7相互作用的Co-IP分析；
图11是Co-IP分析VSV-NLRP3与Flag-NLRP3在HEK-293T细胞中的相互作用；
图12是Co-IP和Westernblotting分析VSV-NLRP3和Flag-ASC在HEK-293T细胞中的相互作用；
图13是10,11-脱氢弯孢霉菌素对NLRP3炎症小体激活的不可逆的抑制作用；A、Westernblotting分析上清液中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和caspase-1，B、上清液中IL-1β含量；*p<0.05，***p<0.001；
图14是二硫苏糖醇和谷胱甘肽阻止10,11-脱氢弯孢霉菌素对NLRP3炎症小体的抑制作用；A、Westernblotting分析上清液中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和caspase-1，B、上清液中IL-1β含量；***p<0.001；
图15是无C＝C双键的10,11-脱氢弯孢霉菌素的结构式；DCV：10,11-脱氢弯孢霉菌素；R-DCV：还原型10,11-脱氢弯孢霉菌素；
图16是还原型10,11-脱氢弯孢霉菌素对NEK7-NLRP3相互作用的影响；A、内源性NLRP3-NEK7相互作用，B、VSV-NLRP3与Flag-NEK7的相互作用；
图17是还原型10,11-脱氢弯孢霉菌素对caspase-1及IL-1β的影响；A、Westernblotting分析上清液中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和caspase-1，B、上清液中IL-1β含量；***p<0.001；
图18是Co-IP分析HEK-293T细胞中NEK7与WT或C279A突变体NLRP3之间的相互作用；
图19是LPS处理小鼠血清中IL-1β、IL-18的含量；A、IL-1β，B、IL-18；***p<0.001；
图20是LPS处理小鼠血清中TNF-α的含量；
图21是LPS处理小鼠腹腔内IL-1β的含量；***p<0.001；
图22是ELISA检测小鼠腹腔注射MSU晶体后血清和腹腔中IL-1β的含量；A、血清，B、腹腔；**p<0.01，***p<0.001；
图23是Nlrp3+/+和Nlrp3-/-小鼠腹腔注射MSU晶体后腹腔中性粒细胞数量；***p<0.001。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述。但是，本发明可以以许多不同的形式来实现，并不限于本发明所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本发明所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
在本发明中，10,11-脱氢弯孢霉菌素具有如式Ⅰ所示的结构：
本发明实施例涉及10,11-脱氢弯孢霉菌素在抑制NLRP3活化中的用途。
本发明实施例涉及10,11-脱氢弯孢霉菌素在制备治疗和/或预防NLRP3异常活化相关疾病的药物中的用途。
本发明实施例涉及一种治疗和/或预防NLRP3异常活化相关疾病的药物，其包括10,11-脱氢弯孢霉菌素，以及药学上可接受的辅料或载体。
可以理解的是，本发明实施例的药物可以添加不同的药物学可以接受的辅料从而制备成合适的临床剂型，这些临床剂型包括但不限于如下的剂型：片剂、胶囊剂、颗粒剂、散剂、糖浆剂或其他口服液体制剂、丸剂、注射剂。这些药物学可以接受的辅料包括但不限于稀释剂、润湿剂、黏合剂、崩解剂、润滑剂、调节剂、增溶剂、助溶剂、乳化剂、抗氧化剂、防腐剂、pH调节剂、等渗或等张调节剂等。
其中，稀释剂选自淀粉、蔗糖、纤维素类、无机盐类等；润湿剂选自水、乙醇等；黏合剂选自淀粉浆、糊精、糖、纤维素衍生物、明胶、聚维酮、聚乙二醇等；崩解剂选自淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、联羧甲基纤维素钠、交联聚维酮、表面活性剂、跑腾崩解剂等；润滑剂选自滑石粉、硬脂酸钙、硬脂酸镁、十二烷基硫酸镁、微粉硅胶、聚乙二醇等；调节剂选自色素、香料、甜味剂、胶浆剂、矫臭剂等；增溶剂选自吐温类、聚氧乙烯脂肪醇醚类、肥皂类、硫酸化物、磺酸化物等；助溶剂选自有机酸及其盐类、酰胺及胺类化合物、无机盐、聚乙二醇、甘油等；乳化剂选自司盘类、吐温类、卖泽类、苄泽类、甘油脂肪酸酯、高级脂肪酸盐、硫酸化物、磺酸化物、阿拉伯胶、西黄耆胶、明胶、果胶、磷脂、琼脂、海藻酸钠、氢氧化物、二氧化硅、皂土等；抗氧化剂选自亚硫酸盐、焦亚硫酸盐、亚硫酸氢盐、抗坏血酸、没食子酸及其酯类等；防腐剂选自尼泊金类、有机酸及其盐、季铵类化合物、醋酸氯己定、醇类、酚类以及挥发油等；pH调节剂选自盐酸、硫酸、磷酸、酒石酸、醋酸、氢氧化钠、碳酸氢钠、乙二胺、葡甲胺、磷酸盐、醋酸盐、枸橼酸、枸橼酸盐等；等渗或等张调节剂选自葡萄糖、氯化钠、枸橼酸钠、山梨醇以及木糖醇等。
可以理解是，本发明实施例所涉及的药物，基于不同的辅料、制备不同的剂型，相应地，给药方式也可以是多样的。
本发明实施例所用材料及试剂如下：
1、小鼠
所有小鼠都被安置在特定的无病原体条件下的空调房间，所有小鼠均为C57BL/6J背景。所有动物操作均按照《实验动物护理和使用指南》进行，并经伦理委员会批准。
2、试剂
Sigma公司购买三磷酸腺苷(ATP)、脂多糖(LPS)、尿酸钠(MSU)晶体、尼日利亚菌素、抗flag抗体和抗vsv抗体。从Santa Cruz Biotechnology公司购买抗nek7、抗asc、抗人IL-1β和抗caspase-1抗体。抗小鼠caspase-1抗体由AdipoGen提供。抗小鼠IL-1β从R&DSystems公司购买。
下面通过具体实施例对本发明进行说明。
实施例1
10,11-脱氢弯孢霉菌素抑制NLRP3炎症小体激活
1、细胞制备与刺激
从骨髓细胞中分离骨髓巨噬细胞(BMDMs)，在含巨噬细胞集落刺激因子(M-CSF,50ng/mL)的RPMI 1640完全培养基中培养。骨髓树突状细胞(BMDCs)来源于骨髓细胞，在RPMI 1640完全培养基中添加粒细胞-巨噬细胞集落刺激因子(GM-CSF,50ng/mL)。
2、NLRP3炎症小体激活
分别用浓度0.5μM、1.0μM、2.0μM的10,11-脱氢弯孢霉菌素(DCV)处理LPS诱导的BMDMs 30分钟，然后用MSU、尼日利亚菌素、ATP分别刺激BMDMs30分钟。Westernblot分析培养上清液(SN)中IL-1β(p17)和caspase-1(p20)及全细胞裂解液(Input)中IL-1β和Pro-Casp-1。
分别用浓度0.5μM、1.0μM、2.0μM的10,11-脱氢弯孢霉菌素处理LPS诱导的小鼠腹腔巨噬细胞，然后用尼日利亚菌素刺激小鼠腹腔巨噬细胞30min。Westernblot分析培养上清液(SN)中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和Pro-Casp-1。
3、统计分析
数据以平均值±标准差表示。采用GraphPad Prism软件进行统计分析。P值<0.05为显著。
4、结果
结果显示，10,11-脱氢弯孢霉菌素以剂量依赖的方式抑制caspase-1的激活和IL-1β的分泌(图1)。10,11-脱氢弯孢霉菌素还抑制了尼日利亚菌素诱导的IL-18的分泌(图2)。然而，10,11-脱氢弯孢霉菌素不影响TNF-α的分泌(图3)，TNF-α是一种炎性小体独立的细胞因子。与这些结果相似，10,11-脱氢弯孢霉菌素还抑制了LPS诱导的小鼠腹腔巨噬细胞(图4)和BMDCs(图5)中caspase-1的激活和IL-1β的分泌。10,11-脱氢弯孢霉菌素还抑制了激动剂Mock(溶剂对照)、ATP、MSU及Nigericin诱导的caspase-1激活和IL-1β分泌(图6)。这些结果表明，10,11-脱氢弯孢霉菌素抑制了细胞内NLRP3炎症小体的激活，并且是一种广泛的NLRP3炎症小体抑制剂。
实施例2
10,11-脱氢弯孢霉菌素特异性抑制NLRP3炎症小体激活
1、NLRP3炎症小体激活
分别用浓度0.5μM、1.0μM、2.0μM的10,11-脱氢弯孢霉菌素处理LPS(200ng/mL)诱导的BMDMs，然后分别用尼日利亚菌素、鼠伤寒沙门氏菌(沙门氏菌)及聚(dA:dT)刺激BMDMs30min。免疫印迹分析SN中IL-1β(p17)和caspase-1(p20)的表达及全细胞裂解液中IL-1β和caspase-1的表达。
2、统计分析
数据以平均值±标准差表示。采用GraphPad Prism软件进行统计分析。P值<0.05为显著。
3、结果
结果表明，10,11-脱氢弯孢霉菌素能够激活鼠伤寒沙门氏菌(Salmonella)感染诱导的NLRC4炎症小体(图7)和poly(dA:dT)转染诱导AIM2炎症小体(图8)。
因此，10,11-脱氢弯孢霉菌素特异性抑制NLRP3炎症小体激活，但不影响NLRC4和AIM2炎症小体。
实施例3
10,11-脱氢弯孢霉菌素抑制NLRP3炎性小体组装
NEK7和NLRP3相互作用是NLRP3的关键过程，NLRP3聚集和ASC募集，导致NLRP3炎症小体组装和激活。为了确定10,11-脱氢弯孢霉菌素是否影响NLRP3炎性小体复合物的形成，本发明检测了NEK7-NLRP3和NLRP3-ASC的相互作用。具体过程如下：
用浓度1.0μM 10,11-脱氢弯孢霉菌素分别处理LPS诱导的BMDMs及HEK-293T细胞(DMEM完全培养基中培养)，再用尼日利亚菌素分别刺激BMDMs及HEK-293T细胞30min。内源性免疫沉淀(IP)和Western blot分析NLRP3与NEK7的相互作用及NLRP3与ASC的相互作用。
结果表明，10,11-脱氢弯孢霉菌素抑制内源性NEK7-NLRP3和NLRP3-ASC的相互作用(图9)，并且阻断了HEK-293T细胞中NEK7和NLRP3的相互作用(图10)。相反，10,11-脱氢弯孢霉菌素处理没有抑制HEK-293T细胞中NLRP3-NLRP3的相互作用(图11)。与此一致的是，10,11-脱氢弯孢霉菌素并没有抑制HEK-293T细胞中NLRP3-ASC的相互作用(图12)。
综上所述，10,11-脱氢弯孢霉菌素通过抑制NEK7-NLRP3的相互作用来抑制NLRP3炎症小体的激活。
实施例4
10,11-脱氢弯孢霉菌素以Michael受体依赖的方式抑制NLRP3炎症小体激活
1、分别用浓度0.5μM、1.0μM、2.0μM的10,11-脱氢弯孢霉菌素处理LPS诱导的BMDMs15分钟，清洗3次以洗去未结合的药物。然后用尼日利亚菌素刺激BMDMs。Westernblot分析SN中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和Pro-Casp-1。
结果显示，洗脱后，10,11-脱氢弯孢霉菌素仍然抑制Caspase-1的激活和IL-1β的分泌(图13)，表明10,11-脱氢弯孢霉菌素对NLRP3炎症小体激活的抑制作用不可逆。
2、本发明研究发现10,11-脱氢弯孢霉菌素的α,β-不饱和羰基可能作为Michael受体并在其功能中发挥重要作用。为了确定10,11-脱氢弯孢霉菌素对NLRP3炎症小体抑制是否重要，用二硫苏糖醇(DTT)或谷胱甘肽(GSH)预处理，具体为：用0.05mM DTT、0.2mM GSH和10,11-脱氢弯孢霉菌素预孵育LPS引物BMDMs，然后用尼日利亚菌素刺激BMDMs。Westernblot分析SN中IL-1β(p17)和caspase-1(p20)及全细胞裂解液中IL-1β和Pro-Casp-1。
结果表明，二硫苏糖醇和谷胱甘肽均可以阻止10,11-脱氢弯孢霉菌素对NLRP3炎症小体的抑制作用(图14)。
3、为了进一步确定碳碳双键(C＝C)是10,11-脱氢弯孢霉菌素抑制NLRP3炎症小体必不可少的，本发明按照实施例1及实施例3中方法使用还原型10,11-脱氢弯孢霉菌进行试验(还原型10,11-脱氢弯孢霉菌的结构式如图15所示)：用还原型10,11-脱氢弯孢霉菌素(2.0μM)处理LPS启动的BMDMs，然后用尼日利亚菌素刺激BMDMs，分析内源性NLRP3-NEK7相互作用。
结果表明，还原型的10,11-脱氢弯孢霉菌素不能抑制NEK7-NLRP3的相互作用(图16)。此外，还原型的10,11-脱氢弯孢霉菌素也不抑制caspase-1的激活或IL-1β的分泌(图17)。
以上结果表明，10,11-脱氢弯孢霉菌素诱导的NLRP3炎症小体激活抑制是Michael受体依赖的。
此外，NLRP3 NACHT结构域的半胱氨酸279负责NLRP3炎症小体的激活。为了确定位于半胱氨酸279上的NLRP3是否对10,11-脱氢弯孢霉菌素诱导的NLRP3炎症小体抑制起关键作用，本发明构建了一个C279ANLRP3突变体。结果发现，虽然C279ANLRP3突变体仍然与NEK7结合，但在10,11-脱氢弯孢霉菌素处理后，NLRP3与NEK7的相互作用没有被抑制(图18)。这些结果表明，10,11-脱氢弯孢霉菌素介导的NLRP3炎症小体失活需要NLRP3的C279。
实施例5
10,11-脱氢弯孢霉菌素可改善体内nlrp3依赖性炎症反应
由于10,11-脱氢弯孢霉菌素在体外抑制NLRP3炎症小体激活，其中LPS驱动NLRP3驱动的IL-1β表达，本发明随后在LPS诱导的全身炎症小鼠模型中检测了10,11-脱氢弯孢霉菌素的治疗效果。具体方法为：
成年雄性C57BL/6J小鼠腹腔注射LPS(20mg/kg)后注射10,11-脱氢弯孢霉菌素(10mg/kg)。4小时后收集腹腔及血液。采用ELISA法测定血清和腹腔灌洗液中IL-1β、IL-18、TNF-α水平。
结果表明，10,11-脱氢弯孢霉菌素显著降低血清中IL-1β和IL-18水平(图19)，而对血清TNF-α水平有轻微影响(图20)。同时，10,11-脱氢弯孢霉菌素能够降低腹腔灌洗液中IL-1β水平(图21)。
为了进一步证实10,11-脱氢弯孢霉菌素能够改善LPS诱导的依赖于NLRP3的全身炎症反应，我们使用NLRP3-/-小鼠，发现10,11-脱氢弯孢霉菌素在NLRP3-/-小鼠中无明显抑制炎症作用(图19～21)。
实施例6
10,11-脱氢弯孢霉菌素对MSU诱导的腹膜炎的治疗效果
MSU通过NLRP3炎症小体依赖的方式增加IL-1β水平并导致大量中性粒细胞内流。因此，我们观察了10,11-脱氢弯孢霉菌素治疗MSU诱导的腹膜炎的效果。具体操作过程为：
成年雄性C57BL/6J小鼠注射10,11-脱氢弯孢霉菌素(10mg/kg)前注射MSU(0.5mg/只)。6h后收集腹腔及血液。测定小鼠中性粒细胞数量，ELISA法测定血清和腹腔灌洗液中IL-1β水平。
结果发现，10,11-脱氢弯孢霉菌素能有效抑制MSU诱导的IL-1β产生和中性粒细胞内流，但在NLRP3-/-小鼠中作用不明显(图22及图23)。
综上所述，10,11-脱氢弯孢霉菌素通过抑制NLRP3炎症小体活性，从而抑制体内炎症的发生。同时，考虑到NLRP3炎症小体激活参与多种炎症性疾病，如动脉粥样硬化、阿尔茨海默病、结肠炎、败血症和2型糖尿病等，故10,11-脱氢弯孢霉菌素可能是一种合适的治疗NLRP3驱动疾病的候选药物。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.一种10,11-脱氢弯孢霉菌素在抑制NLRP3活化中的用途。
2.根据权利要求1所述的用途，其特征在于，所述10,11-脱氢弯孢霉菌素用于制备NLRP3活化抑制剂。
3.根据权利要求1所述的用途，其特征在于，所述10,11-脱氢弯孢霉菌素用于制备抑制NLRP3活化的药物。
4.根据权利要求1所述的用途，其特征在于，所述10,11-脱氢弯孢霉菌素用于制备治疗和/或预防NLRP3异常活化相关疾病的药物。
5.根据权利要求4所述的用途，其特征在于，所述NLRP3异常活化相关疾病为动脉粥样硬化、阿尔茨海默病、结肠炎、腹膜炎、败血症、痛风、风湿性关节炎、帕金森多发性硬化症或2型糖尿病中的至少一种。
6.根据权利要求1～5任一项所述的用途，其特征在于，所述10,11-脱氢弯孢霉菌素用于制备IL-1β及IL-18表达抑制剂。
7.一种治疗和/或预防NLRP3异常活化相关疾病的药物，其特征在于，其包括权利要求1～5任一项所述10,11-脱氢弯孢霉菌素，以及药学上可接受的辅料或载体。
8.根据权利要求7所述的药物，其特征在于，所述药物的剂型为口服制剂或注射制剂。
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| CN109010333A (zh) * | 2018-11-06 | 2018-12-18 | 杭州医学院 | 脱氢弯孢霉素在抑制Hedgehog通路中的应用 |
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| WO2019098461A1 (ko) * | 2017-11-16 | 2019-05-23 | 한국해양과학기술원 | 해양 진균 Penicillium sp. SF-5859 유래 커뷰라린 유형의 대사체를 함유하는 염증질환 예방 또는 치료용 조성물 |
| CN109010333A (zh) * | 2018-11-06 | 2018-12-18 | 杭州医学院 | 脱氢弯孢霉素在抑制Hedgehog通路中的应用 |
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