CN116672338B - 蟛蜞菊内酯在制备治疗系统性红斑狼疮药物中的应用 - Google Patents
蟛蜞菊内酯在制备治疗系统性红斑狼疮药物中的应用 Download PDFInfo
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Abstract
本发明公开了蟛蜞菊内酯在制备治疗系统性红斑狼疮药物中的应用,蟛蜞菊内酯作为一种caspase 11的抑制剂,可明显降低狼疮小鼠肾脏中caspase 11和gasdermin D的表达,抑制细胞焦亡,并减轻肾脏病理。另外,本发明还证实了蟛蜞菊内酯对脾脏B细胞成熟、分化具有较好的抑制作用,能降低免疫系统活跃程度,从而抑制狼疮小鼠的免疫亢进,改善狼疮症状,包括降低血清抗dsDNA抗体滴度、减轻脾脏肿大、改善肾脏病理、提高存活率等。因此,蟛蜞菊内酯有可能开发成新型抗SLE药物,具有良好的市场应用前景。
Description
技术领域
本发明属于医药领域,具体涉及蟛蜞菊内酯在制备治疗系统性红斑狼疮药物中的应用。
背景技术
系统性红斑狼疮(Systemic lupus erythematosus,SLE)是一种以免疫系统异常激活和自身抗体增多为特征的自身免疫性疾病,可累及多个器官或系统。我国估计有超过100万SLE患者,而女性高达113/10万人,且有逐年递增的趋势。SLE的病因复杂,涉及遗传、感染、环境等多种因素,且其临床表现、严重程度和血清学异常存在极大的异质性。患者表现出一系列临床表型,可累及皮肤、关节、肾脏、血管系统、神经和血液系统。如不及时治疗可产生肾功能衰竭等致死性损害。SLE目前可用的治疗方法有限,主要以糖皮质激素、抗疟药、免疫抑制剂为主。
糖皮质激素是治疗SLE的一线药物,有助于提高SLE患者的远期生存率,但易产生药物依赖,长期使用可能会造成多种近期及远期不良反应,包括消化道溃疡、白内障、骨质疏松、和冠状动脉疾病等。非选择性免疫抑制剂虽然有效,但不能实现治愈,而且长期使用毒副作用大。因此,亟需开发更多有效疗法,为SLE的治疗提供新选择。
蟛蜞菊内酯(Wedelolactone,WDL)是从蟛蜞菊、墨旱莲中提取的香豆素类化合物。蟛蜞菊内酯具有许多不同的生物活性,有保肝、抗免疫抑制、抗炎症、促骨分化、抗癌等药理作用。然而,蟛蜞菊内酯对SLE的治疗作用尚未报道。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供蟛蜞菊内酯在制备治疗系统性红斑狼疮药物中的应用。
为了解决上述技术问题,本发明公开了下述技术方案:
第一方面,本发明公开了蟛蜞菊内酯在制备治疗系统性红斑狼疮产品中的应用。
其中,所述产品为下调caspase表达水平,抑制细胞焦亡,或抑制B细胞分化的产品。
其中,所述产品为caspase抑制剂和/或细胞焦亡抑制剂。
第二方面,本发明公开了一种治疗系统性红斑狼疮的药物,所述药物的活性成分包括蟛蜞菊内酯。
第三方面,本发明公开了一种caspase抑制剂,所述caspase抑制剂的活性成分包括蟛蜞菊内酯。
第四方面,本发明公开了一种细胞焦亡抑制剂,所述细胞焦亡抑制剂的活性成分包括蟛蜞菊内酯。
第五方面,本发明公开了蟛蜞菊内酯在制备抑制B细胞分化药物中的应用。
第六方面,本发明公开了上述caspase抑制剂、细胞焦亡抑制剂或抑制B细胞分化药物在制备治疗系统性红斑狼疮药物中的应用。
第七方面,本发明公开了以蟛蜞菊内酯为活性成分的药物或药物组合物或药物制剂,所述药物或药物组合物或药物制剂包括治疗有效量的蟛蜞菊内酯,以及药学上可接受的辅料。
第八方面,本发明公开了上述第七方面所述药物或药物组合物或药物制剂在制备具有以下任意一种或多种功能产品中的应用;
i,治疗系统性红斑狼疮;优选为减轻脾脏肿大,降低抗dsDNA抗体水平,减轻肾脏炎症浸润,减轻肾小球肿大,提高存活率,或前述任意多种功能;
ii,抑制caspase11的表达或抑制gasdermin D的表达;
iii,抑制细胞焦亡;
iv,抑制B细胞分化。
本发明中,所述细胞焦亡为系统性红斑狼疮引起的细胞焦亡。
本发明中,所述产品包括药物。
有益效果:与现有技术相比,本发明具有以下优势:
本发明选取蟛蜞菊内酯为研究对象,在体内和体外水平上证明其对系统性红斑狼疮的作治疗作用及其作用机制。本发明首次发现,在MRL/lpr狼疮小鼠中,caspase 11和gasdermin D蛋白介导的细胞焦亡水平显著升高,蟛蜞菊内酯作为一种caspase 11的抑制剂,可明显降低狼疮小鼠肾脏中caspase 11和gasdermin D的表达,抑制细胞焦亡,并减轻肾脏病理。另外,本发明还证实了蟛蜞菊内酯对脾脏B细胞成熟、分化具有较好的抑制作用,能降低免疫系统活跃程度,从而抑制狼疮小鼠的免疫亢进,改善狼疮症状,包括降低血清抗dsDNA抗体滴度、减轻脾脏肿大、改善肾脏病理、提高存活率等。因此,蟛蜞菊内酯有可能开发成新型抗SLE药物,具有良好的市场应用前景。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1是蟛蜞菊内酯对MRL/lpr小鼠血清抗dsDNA抗体滴度的降低作用;***表示p<0.001。
图2是蟛蜞菊内酯对MRL/lpr小鼠减轻脾脏肿大的作用;**表示p<0.01。
图3是蟛蜞菊内酯减轻MRL/lpr小鼠肾炎的作用;****表示p<0.0001。
图4是蟛蜞菊内酯减轻MRL/lpr小鼠肾脏中caspase 11和gsdermin D表达水平的作用;*表示p<0.05,**表示p<0.01,***表示p<0.001。
图5是蟛蜞菊内酯治疗对小鼠脾脏B细胞亚群的改变;ns表示p>0.05,*表示p<0.05,**表示p<0.01。
图6是蟛蜞菊内酯在体外实验中对小鼠脾脏B细胞分化的影响;ns表示p>0.05,*表示p<0.05,**表示p<0.01。
具体实施方式
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1:蟛蜞菊内酯治疗MRL/lpr狼疮小鼠的作用
1.实验方法
1.1药物准备:将100mg蟛蜞菊内酯粉末溶解于2ml DMSO溶液,得到50mg/ml含蟛蜞菊内酯的DMSO母液。蟛蜞菊内酯组给药溶液按照2%含蟛蜞菊内酯的DMSO母液+40% PEG300+5%吐温-80+53%生理盐水配制得到。对照组采用溶剂对照,由2%不含蟛蜞菊内酯的DMSO+40% PEG 300+5%吐温-80+53%生理盐水配制得到。
1.2小鼠给药:本发明所有使用的小鼠均符合伦理(中国医学科学皮肤病医院伦理委员会,批准文号2022-DW-017)。使用10周龄的MRL/lpr雌鼠,体重30-35g,随机分为2组,每组12只;对照组(溶剂对照),蟛蜞菊内酯(10mg/kg/天)组。采用腹腔注射方式给药,至第19周龄时处死、取材并检测各项指标。
1.3小鼠检测:以首次给药日为起始日,连续观察小鼠临床症状,每2周眶周采血测量血清抗dsDNA自身抗体滴度。19周龄时处死,取小鼠肾脏,制作石蜡切片并进行HE染色,评估小鼠狼疮肾炎严重程度;研磨肾脏组织,提取组织RNA,通过定量q-PCR检测基因表达水平;取小鼠脾脏,研磨至单细胞悬液,并通过流式细胞数检测各免疫细胞亚群情况。
2.实验结果
2.1小鼠血清抗dsDNA抗体滴度的变化
血清抗dsDNA抗体滴度是衡量狼疮活动度的重要指标,疾病活跃程度与抗体滴度成正比。图1(A)是对照组小鼠和蟛蜞菊内酯处理组小鼠的血清抗dsDNA抗体滴度变化。可以看出,在给药前,两组小鼠的抗体滴度水平相当,随着周龄的增大,对照组小鼠的血清抗体滴度逐渐升高,而蟛蜞菊内酯处理组小鼠的血清抗体滴度维持在较低水平。图1(B)是在小鼠19周龄时两组间抗体滴度对比,蟛蜞菊内酯处理组抗体水平显著低于对照组,说明蟛蜞菊内酯具有降低SLE疾病活动度的作用。
2.2小鼠脾脏大小的变化
免疫细胞凋亡相关基因缺陷导致的脾脏肿大、免疫亢进是MRL/lpr小鼠具有狼疮样症状的病理机制,因此脾脏大小可以反应狼疮小鼠的疾病严重程度。图2(A)反映了对照组和蟛蜞菊内酯处理组小鼠的脾脏大小,可以看出蟛蜞菊内酯处理后小鼠的脾脏明显减小。图2(B)为两组小鼠的脾脏重量的组间对比,蟛蜞菊内酯处理组小鼠脾脏重量显著低于对照组。
2.3小鼠肾脏病理的变化
肾脏是SLE最常累及的系统损害之一。狼疮肾炎可有多种病理损害,最常见的是肾小球肾炎。图3(A)展示了C57BL/6(健康小鼠)、MRL/lpr对照组和MRL/lpr蟛蜞菊内酯处理组小鼠的肾脏病理情况。可以看出,MRL/lpr对照组小鼠肾脏有大量炎症细胞浸润、肾小球肿大、系膜增生和新月体形成等肾小球肾炎的病理表现,蟛蜞菊内酯处理后肾脏炎症细胞浸润减轻、肾小球肿大缓解,无明显新月体形成,表明肾脏受累减轻,蟛蜞菊内酯对狼疮肾炎有一定治疗作用。图3(B)展示了三组小鼠狼疮肾炎的肾脏病理活动Austin评分,分数越高,表明狼疮肾炎越重。蟛蜞菊内酯显著降低了狼疮小鼠的Austin评分。
2.4小鼠肾脏中caspase 11和gasdermin D蛋白表达变化
在非经典途径的细胞焦亡过程中,活化的caspase 11剪切激活gasdermin D,使其在胞膜上成孔,导致细胞破裂,释放各种炎症因子、胞内及核内物质。在狼疮的背景下,这些细胞碎片作为自身抗原可进一步激惹免疫系统,从而恶化病情。我们发现在狼疮小鼠的肾脏中,caspase 11和gasdermin D及其活化的剪切体蛋白表达水平较健康C57BL/6小鼠明显升高(图4,A-B),说明狼疮小鼠肾脏中细胞焦亡水平升高。蟛蜞菊内酯治疗后,狼疮小鼠肾脏中caspase 11和gasdermin D的表达水平显著降低(图4,C)。
2.5小鼠脾脏细胞亚群的变化
图5反映了蟛蜞菊内酯对小鼠的脾脏B细胞亚群的影响。可以看出,MRL/lpr对照组小鼠脾脏中B细胞比例较健康C57BL/6小鼠显著降低,而抗体分泌型B细胞包括浆母细胞(plasmablast)、浆细胞(plasma cell)细胞比例显著升高。蟛蜞菊内酯处理组小鼠脾脏中/>B细胞比例升高,浆母细胞和浆细胞呈下降趋势。这说明蟛蜞菊内酯能够逆转狼疮小鼠中失衡的B细胞亚群,具有调节免疫功能的作用。
2.6小鼠生存情况
到19周龄时,对照组有10只小鼠存活,存活率为83.3%,蟛蜞菊内酯处理组有12只小鼠存活,存活率为100%。
实施例2:蟛蜞菊内酯在体外实验中对B细胞分化的影响
1.实验方法
取C57BL/6小鼠脾脏,研磨并过滤成单细胞悬液后裂红,使用小鼠Pan B细胞磁珠分选试剂盒将脾脏中Pan B细胞分选出来后接种到24孔细胞培养板中,分别给予不同处理:细胞随机分为两组,对照组和蟛蜞菊内酯处理组,对照组给予R848和小鼠IL-4刺激活化,蟛蜞菊内酯处理组除给予R848和小鼠IL-4外,还添加蟛蜞菊内酯5ug/ml,B细胞培养2天后进行流式细胞术检测各B细胞亚群。
2.实验结果
浆细胞(Plasma cell)是分化成熟的效应B细胞,主要功能是分泌抗体。在MRL/lpr小鼠病理过程中,增殖的B细胞分化为浆细胞并产生大量自身抗体,对多种脏器及系统造成损害。图6是蟛蜞菊内酯对小鼠脾脏B细胞分化的影响,蟛蜞菊内酯显著降低了浆细胞亚群和浆母细胞亚群的比例,提高了记忆B细胞的比例,表明其具有抑制抗体分泌型B细胞分化的作用。
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本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 (1)
1.蟛蜞菊内酯作为唯一活性成分在制备治疗系统性红斑狼疮药物中的应用。
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