CN116712441A - 一种天然产物在制备治疗自身免疫性疾病的药物中的应用 - Google Patents
一种天然产物在制备治疗自身免疫性疾病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种天然产物在制备治疗自身免疫性疾病的药物中的应用，属于生物医药领域。本发明所述的天然产物Ruscogenin是中药麦冬中的主要皂苷元和有效成分之一，具有良好的抗炎功效。本发明实验结果表明Ruscogenin能够显著抑制Th17细胞分化，抑制IL‑17A、GM‑CSF等Th17细胞相关炎症因子的表达，降低Il17a、Il17f、Il21、Il23r、Irf4、Rorc等基因转录水平，并能够显著缓解溃疡性结肠炎小鼠模型的发病症状，因此具有治疗自身免疫性疾病的功能。本发明提供了天然产物Ruscogenin在制备治疗自身免疫性疾病的药物中的新用途，拓宽了Ruscogenin的医药应用，具有重要的临床意义。
Description
技术领域
本发明属于生物医药领域，具体涉及一种天然产物在制备治疗自身免疫性疾病的药物中的应用。
背景技术
自身免疫性疾病是由于机体免疫系统区分外源病原体入侵和宿主自身抗原的能力受到限制，进而攻击自身组织引起的慢性炎症反应，主要包括炎症性肠病（inflammatorybowel disease，IBD）、系统性红斑狼疮（systemic lupus erythematosus，SLE）、多发性硬化症（multiple sclerosis，MS）等。溃疡性结肠炎（ulcerative colitis，UC）是IBD的一类，是一种常见的复发性肠道自身免疫性疾病，病因主要包括遗传、免疫、环境等，免疫失衡是其主要的发病机制之一，Th17细胞在其中发挥重要功能，Th17细胞是Th家族发现的第三类辅助性T细胞，其区别于Th1、Th2细胞，是一类强促炎性的CD4+T细胞，IL-17A、IL-17F、IL-22及GM-CSF是Th17细胞产生的主要效应物，在疾病诱发的炎症微环境下，炎症因子持续地刺激肠道，导致维持肠道稳态及肠黏膜修复的非致病性Th17细胞向致病性Th17细胞转变，分泌如IL-17A、IL-17F及GM-CSF等多种促炎因子，这些促炎因子协同作用，最终导致自身免疫性疾病溃疡性结肠炎的发生。
溃疡性结肠炎患者多表现为体重降低、腹泻、便血等症状，且疾病周期长，且较难治愈，已成为一个迫切解决的社会健康难题。目前现代医学对溃疡性结肠炎的治疗存在多种方法，5-氨基水杨酸类、糖皮质激素、单抗抑制剂、生物制剂等是临床上比较常见的药物，但仍存在不良预后，包括毒副作用、缺乏安全性等风险，因此研究新型、高效、具有良好安全性的治疗方法仍是目前的研究目标。近年有研究证明，中药在治疗溃疡性结肠炎中具有显著疗效，其中针对于中药的活性成分研究取得了很大的进展，最具代表性的如皂苷类、萜类、多糖类、黄酮类等活性成分。
Ruscogenin，CAS：472-11-7，分子式为C27H42O4，分子量为430.62g/mol。Ruscogenin是中药麦冬中的一种主要甾体皂苷元，首次从假叶树中分离出来，用于治疗急慢性炎症和心血管疾病。药理学研究表明，Ruscogenin具有多种药理学活性，例如其通过调节TLR4保护LPS诱导的肺损伤和内皮细胞凋亡，具有显著的抗炎和抗凋亡作用。同时，Ruscogenin还能通过抑制MAPK信号通路缓解脑缺血损伤诱导的血脑屏障（BBB）功能障碍，对神经系统具有保护作用。目前尚未有针对Ruscogenin在调节Th17细胞参与的自身免疫性疾病中的功能研究。本发明通过对Ruscogenin治疗自身免疫性疾病具体功能的研究，发现了Ruscogenin能够用于制备治疗自身免疫性疾病的药物。
发明内容
本发明的目的是提供Ruscogenin在制备治疗自身免疫性疾病的药物中的应用。经实验表明，所述化合物Ruscogenin在体外能够显著抑制Th17细胞分化，在体内具有抑制Th17细胞的分化和促炎因子IL-17A、GM-CSF产生的作用，并可以减轻溃疡性结肠炎的诸多临床症状，具有良好的应用前景，Ruscogenin为自身免疫性疾病的治疗提供了新策略。
本发明所述的Ruscogenin，分子式为C27H42O4，分子量为430.62g/mol，结构式如式1所示：
为了实现上述目的，本发明提供了以下技术方案：
本发明提供了Ruscogenin在制备治疗自身免疫性疾病的药物中的新用途。
进一步地，所述Ruscogenin包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体及其他衍生物。
进一步地，所述自身免疫性疾病以致病性细胞亚群包含Th17细胞为特征。
进一步地，所述的Ruscogenin具有抑制Th17细胞分化的作用。
进一步地，所述药物为以Ruscogenin为活性成分，并进一步包含药学上可接受的药用辅料。
本发明的创新性及优势：
本发明首次揭示提取自中草药物麦冬中的皂苷Ruscogenin在体外具有显著抑制Th17细胞分化的作用，降低Il17a、Il17f、Il21、Il23r、Irf4、Rorc等相关转录因子和炎症因子的基因水平，在体内溃疡性结肠炎模型也能够显著抑制Th17细胞分化及促炎因子IL-17A、GM-CSF的产生，并能够有效缓解溃疡性结肠炎相关临床症状，因此，Ruscogenin能够广泛应用于自身免疫性疾病，具有潜在的医药价值。同时，与传统治疗（糖皮质激素、免疫抑制剂等）手段相比，Ruscogenin作为传统的中药成分，抑制炎症显著，且未见报道其对人体的副作用，预期能得到较好的预防和治疗效果。
附图说明
图1显示Ruscogenin处理野生型小鼠Th17细胞体外分化实验。
图2显示qRT-PCR检测Ruscogenin对野生型小鼠Th17细胞相关转录因子和炎症因子基因的转录表达调控。
图3显示Ruscogenin对患溃疡性结肠炎小鼠疾病活动指数的影响。
图4显示Ruscogenin对患溃疡性结肠炎小鼠体重的影响。
图5显示Ruscogenin对患溃疡性结肠炎小鼠结肠长度，肠系膜淋巴结、淋巴结和脾脏大小的影响。
图6显示Ruscogenin对患溃疡性结肠炎小鼠结肠病理变化的影响。
图7显示Ruscogenin对患溃疡性结肠炎小鼠Th17细胞分化的影响。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，以下结合具体实施例，并参照附图，对本发明做进一步的详细说明。
下述实施例中的实验方法，如无特殊说明，均为常规方法，均按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例采用GraphPad8.0.2统计软件对数据进行处理，实验结果以平均值±标准偏差表示，两两比较采用配对样本T检验，P<0.05（*）表示具有显著性差异，P<0.01（**）表示具有极显著性差异，P<0.001（***）表示具有极显著性差异，P<0.0001（****）表示具有极显著性差异，NS表示无显著性差异。
下面实施例中，所涉及的野生型小鼠品系为C57BL/6，购自北京维通利华实验动物技术有限公司。实验所用小鼠年龄均为6-8周。
实施例1 Ruscogenin对野生型小鼠Th17细胞体外分化的抑制
1. 原代T细胞的体外培养
提取小鼠脾脏和淋巴结浸润至MACS溶液中，通过0.44μm的滤膜研磨成细胞悬液，4°C，1800rpm，4min，弃上清，MACS溶液重悬，加入CD4+磁珠，混合均匀，4°C避光孵育20分钟，通过免疫磁珠法富集CD4+ T细胞，随后将细胞加入至Th17分化培养基中（IL-6、TGF-β、抗小鼠IFN-γ、抗小鼠IL-4），并加入化合物干预，干预组为Ruscogenin，浓度分别为0.1μM、1μM、10μM，未干预组为DMSO，最后将细胞接种于抗CD3和CD28包被的细胞培养板中，37°C二氧化碳培养箱中培养3天，诱导Th17细胞分化。
2. 流式细胞术分析检测Th17细胞分化
利用淋巴细胞分离液分离淋巴细胞，用含胞内刺激试剂的完全培养基对细胞进行刺激，随后膜标记抗体CD4-PE染色，最后进行胞内染色，包括IL-17A-AF700，并通过流式细胞术检测。
3. 实验结果
由图1所示，在野生型小鼠Th17细胞分化实验中，Ruscogenin处理后，显著抑制Th17细胞分化，抑制IL-17A的表达，且Ruscogenin对Th17细胞分化的抑制作用呈浓度依赖性。
4. 结果讨论
我们体外进行了Ruscogenin处理野生型小鼠Th17细胞分化实验，发现了Ruscogenin具有抑制Th17细胞分化的功能。接下来，我们想进一步探究Ruscogenin对Th17细胞相关转录因子和炎症因子基因的转录调控作用。
实施例2 qRT-PCR检测Ruscogenin对野生型小鼠Th17细胞相关转录因子和炎症因子基因的转录表达调控
1. 细胞RNA抽提
收取3h、12h、24h经Ruscogenin和DMSO处理后的Th17细胞，加入Trizol裂解，室温静置5分钟，加入氯仿，立即涡旋混匀，4°C ，12000g离心15min，将上层RNA溶液转移至异丙醇溶液中，4°C放置10分钟沉淀RNA，再次离心，弃掉异丙醇，并加入75%无水乙醇，重复两次，最终获得呈片状的RNA沉淀，干燥15min，加入DEPC水溶解RNA。
2. 反转录和荧光定量PCR
向离心管中加入RNA样品，gDNA wiper Mix以及无RNA酶水，吹打混匀，PCR仪中42°C孵育2分钟，进行DNA的消化，结束后加入Hifair Ⅲ SuperMix plus预混液，进行反转录反应，随后将cDNA样品、引物及qPCR SYBR Green Mix混合，进行荧光定量PCR。
3. 实验结果
收取3h、12h、24h经Ruscogenin和DMSO处理后的Th17细胞，检测不同时间点Ruscogenin干预后Th17细胞相关转录因子和炎症因子的基因转录水平。由图2所示，Ruscogenin干预显著抑制Th17细胞相关炎症因子Il17a、II17f、II21、II23r，转录因子Irf4、Rorc的转录表达。
4. 结果讨论
通过实施例1至2，我们发现天然产物Ruscogenin在体外具有抑制Th17细胞分化，抑制Th17细胞相关转录因子和炎症因子的基因转录表达等多方面功能。但Ruscogenin是否在体内具有抑制Th17细胞分化的作用我们仍不清楚，因此，我们接下来进行了Ruscogenin对患溃疡性结肠炎小鼠干预实验。
实施例3 Ruscogenin对患溃疡性结肠炎小鼠疾病活动指数的影响
1. 溃疡性结肠炎造模流程
DSS诱导的小鼠结肠炎动物模型是医药领域认可的经典的急性溃疡性结肠炎造模方法，本发明配置成3% DSS水溶液进行造模。
实验小鼠分为3组，第一组，给与自来水，第二组，3% DSS水溶液，连续7天腹腔注射PBS溶液，第三组，3% DSS水溶液，连续7天腹腔注射Ruscogenin（5mg/kg），诱导小鼠溃疡性结肠炎，实验周期为7天，每天固定时间记录各组小鼠体重和粪便数据。
疾病活动指数（Disease activity score，DAI）用以评价溃疡性结肠炎的发病程度，其评分规则为分别对小鼠的体重下降百分比、粪便性状和粪便潜血情况进行评分，总评分取三个指标得分之和，具体细则按照下表1进行评估。
表1 疾病活动指数评分细则：
| 得分 | 体重下降比例（%） | 粪便性状 | 粪便潜血 |
| 0 | <1 | 正常 | 无 |
| 1 | 1-5 | 软便且干 | 较弱隐血 |
| 2 | 6-10 | 软便且未成形 | 较强隐血 |
| 3 | 11-20 | 湿便且未成形 | 肉眼可见的血便 |
| 4 | >20 | 腹泻 | 直肠出血 |
2. 实验结果
如图3所示，喂用自来水的小鼠活动正常，疾病活动指数得分为0，DSS造模小鼠出现腹泻、血便等症状，Ruscogenin能够显著缓解结肠炎小鼠的疾病活动指数，改善其粪便性状及潜血评分。
实施例4 Ruscogenin对患溃疡性结肠炎小鼠体重的影响
1. 体重变化统计方法
小鼠模型构建、受试药物剂量以及给药方式同实施例3。体重以第0天的为100%，造模期间的小鼠体重变化以第0天体重指数为基础通过百分制计算。
2. 实验结果
如图4所示，喂用自来水的小鼠体重未出现下降，呈现轻微地上升，DSS造模小鼠体重自第2天起持续性地下降，Ruscogenin能够显著减弱结肠炎小鼠体重下降的程度，在第7天时Ruscogenin干预组与未干预组体重差异显著。
实施例5 Ruscogenin对患溃疡性结肠炎小鼠结肠长度，肠系膜淋巴结、淋巴结和脾脏大小的影响
1. 结肠、肠系膜淋巴结、淋巴结和脾脏的测量
小鼠模型构建、受试药物剂量以及给药方式同实施例3。造模7天后，分离小鼠结肠，测量长度并拍照，同时也对小鼠的肠系膜淋巴结、淋巴结及脾脏进行拍照测量。
2. 实验结果
如图5所示，相较于喂用自来水的小鼠结肠形态、长度及外周淋巴器官大小，DSS造模小鼠结肠出现充血，结肠长度缩短，且脾脏和淋巴结均有明显肿胀，Ruscogenin能够明显缓解结肠炎小鼠结肠的缩短和充血，抑制脾脏和淋巴结的肿胀。
实施例6 Ruscogenin对患溃疡性结肠炎小鼠结肠病理变化的影响
1. 结肠病理切片染色
小鼠模型构建、受试药物剂量以及给药方式同实施例3。造模7天后，分离小鼠结肠，剪取1cm长度的肠段，HE染色观察肠壁结构、肠隐窝及肠黏膜形态变化。
2. 实验结果
如图6所示，相较于喂用自来水的小鼠结肠组织结构，DSS造模小鼠结肠出现肠隐窝缺失、杯状细胞排列紊乱及缺失、炎症细胞浸润增加、粘膜侵蚀显著等病理变化，Ruscogenin能在不同程度上减轻上述结肠变化，缓解结肠损伤。
实施例7 Ruscogenin对患溃疡性结肠炎小鼠Th17细胞分化的影响
1. 肠道固有层淋巴细胞的提取
分离小鼠结肠，剪成1cm小段，用含EDTA和DTT的PBS溶液进行预消化处理，37°C，200rpm，摇床上摇晃35min，弃去液体，再用不含EDTA和DTT的RPMI 1640进行洗涤，最后利用胶原酶Ⅳ对肠段进行消化，37°C，200rpm，摇床上摇晃60min，再通过0.44μm滤器研磨过滤，密度梯度离心法分离肠道固有层淋巴细胞。
2. 流式细胞术分析检测细胞比例
通过肠道固有层淋巴细胞分离技术，我们提取了肠道固有层淋巴细胞，用含胞内刺激试剂的完全培养基对细胞进行刺激，随后膜标记抗体CD4-PE染色，最后进行胞内染色，包括IL-17A-AF700，GM-CSF-APC，并通过流式细胞术检测。
3. 实验结果
如图7所示，结肠炎小鼠肠道炎症性Th17细胞的比例显著上升，并伴随着促炎性因子IL-17A、GM-CSF的表达升高。当额外用Ruscogenin干预后，肠道炎症性Th17细胞的比例显著降低，同时促炎性因子IL-17A、GM-CSF的表达明显下降。
4. 结果讨论
根据实施例3至7的实验结果，我们发现在DSS诱导的小鼠溃疡性结肠炎模型中，肠道浸润的炎症性Th17细胞比例增加是诱发小鼠患病的重要因素，加剧了小鼠体重的降低、结肠缩短和充血，Ruscogenin干预能够抑制Th17细胞的分化，显著下调炎症部位促炎性因子IL-17A、GM-CSF的表达，减轻肠炎导致的以上症状，维护肠道稳态。
以上所述的具体实施例，对本发明的发明内容，研究目的、技术方案以及潜在药理功效进行了进一步详细说明。应注意的是，以上仅是本发明的优选实施例，并非用来限制本发明的实施范围，凡属于本发明研究思路下的技术路线均属于本发明的保护范围。特别指出，在不脱离本发明的精神范围下做出的修改、删减以及同等替换，均应属于本发明的保护范围。
Claims (4)
1.一种式1所示的天然产物Ruscogenin在制备治疗自身免疫性疾病的药物中的应用，其特征在于，所述Ruscogenin包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体及其他衍生物：
2.根据权利要求1所述的应用，其特征在于，所述自身免疫性疾病以致病性细胞亚群包含Th17细胞为特征。
3.根据权利要求1所述的应用，其特征在于，所述的Ruscogenin具有抑制Th17细胞分化的作用。
4.根据权利要求1-3中任一项所述Ruscogenin的用途，其特征在于，所述药物为以Ruscogenin为活性成分，并进一步包含药学上可接受的药用辅料。
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