CN116920036A - 一种金匮肾气丸用于制备防治神经管畸形药物的用途 - Google Patents
一种金匮肾气丸用于制备防治神经管畸形药物的用途 Download PDFInfo
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Abstract
本发明属于药物用途及药理研究技术领域,具体涉及一种金匮肾气丸(Jingui shenqi pill,JSP)用于制备防治神经管畸形(Neural tube defects,NTDs)药物的新用途。本发明通过网络药理学的分析方法,开发并验证了JSP防治NTDs的新用途,并对JSP防控NTDs的有效成分、作用靶点及信号通路进行分析以及对JSP防控NTDs的关键靶点和途径进行了初步实验验证,对临床应用JSP防控NTDs提供一定的理论依据。
Description
技术领域
本发明属于药物用途及药理研究技术领域,具体涉及一种金匮肾气丸用于制备防治神经管畸形药物的新用途。
背景技术
神经管畸形(Neural tube defects,NTDs)是一种由遗传和环境因素影响的先天性神经系统缺陷所导致的畸形,由胚胎发育过程中神经管闭合不全所引起,是最常见的发生于中枢神经系统(Central nervous system,CNS)的出生缺陷,通常包括无脑畸形、脊柱裂、脑膨出等类型。据研究,神经管缺陷是神经管畸形发生的重要原因,神经轴不同位置的闭合不全表现出不同的临床症状。大多数有症状性疾病的患者一生都要坐在轮椅上,伴有大小便失禁和学习困难。目前,叶酸的应用可以在一定程度上降低NTDs的发病率,但发病机制尚不完全清楚,而且叶酸并不能防治所有NTDs的发生。已有研究表明,NTDs发生与多条信号通路密切相关:如经典Wnt/β-catenin信号通路、非经典Wnt/平面细胞极性(planar cellpolarity,PCP)信号通路、骨形态发生变化(bone morphogenetic protein,BMP)、维甲酸(retinoicacid,RA)[13],并且也与PI3K/Akt通路有关。
在传统中医方理论中,先天之精又称元精,除了布散于四肢百骸的先天之精,其他的先天之精聚藏于肾,这是“肾主蛰藏”以及“肾藏精”的功能体现。《素问·奇病论》所云:“肾藏精,精充骨而生髓,髓聚而为脑,髓满而脑髓充,精脱而脑髓消”。由此可见,肾为生髓之源,髓充则脑健。父母肾精亏虚,胎儿先天精气不足,影响胎儿生长发育,使神经管出现闭合障碍,这与NTDs发生的机制基本相符。
金匮肾气丸(Jingui shenqi pill,JSP)首见《金匮要略·血痹虚劳病篇》,又称八味肾气丸,全方共八味药物,其包括熟地黄、山茱萸、山药、泽泻、茯苓、丹皮具有滋补肾阴之功效,而桂枝、附子则具有补阳之功效,此方为“阴中求阳”之始,可发挥阴阳双补之效,是补肾助阳、助精化气的千古名方。JSP在骨质疏松、糖尿病、抗衰老等方面研究较多,但尚未见关于NTDs的实验报道。因此,本领域期待开发更多的药物新用途,对传统良方的发展具有积极的意义。
发明内容
为此,本发明所要解决的技术问题在于提供一种金匮肾气丸(JSP)用于制备防治神经管畸形药物的新用途;
本发明所要解决的第二个技术问题在于提供一种预防及治疗神经管畸形的药物制剂。
为解决上述技术问题,本发明公开了一种金匮肾气丸(JSP)用于制备防治神经管畸形(NTDs)药物的用途。
本发明还公开了一种金匮肾气丸(JSP)用于制备防治NTDs引起的神经管闭合不全病症药物的用途。
本发明还公开了一种金匮肾气丸(JSP)用于制备PI3K/Akt通路抑制剂的用途。
本发明还公开了一种药物组合物及其制剂用于制备防治神经管畸形(NTDs)药物的用途,所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
优选的,所述药物组合物的原料药组成包括:熟地黄24重量份、山茱萸6重量份、山药6重量份、泽泻6重量份、茯苓17.3重量份、丹皮6重量份、桂枝6重量份、附子1重量份;
优选的,所述药物组合物还包括牛膝6重量份和/或车前子6重量份。
本发明还公开了一种药物组合物及其制剂用于制备防治NTDs引起的神经管闭合不全病症药物的用途,所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
优选的,所述药物组合物的原料药组成包括:熟地黄24重量份、山茱萸6重量份、山药6重量份、泽泻6重量份、茯苓17.3重量份、丹皮6重量份、桂枝6重量份、附子1重量份;
优选的,所述药物组合物还包括牛膝6重量份和/或车前子6重量份。
本发明还公开了一种药物组合物及其制剂用于制备PI3K/Akt通路抑制剂的用途,所述药物组合物的原料药组成包括:所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
优选的,熟地黄24重量份、山茱萸6重量份、山药6重量份、泽泻6重量份、茯苓17.3重量份、丹皮6重量份、桂枝6重量份、附子1重量份;
优选的,所述药物组合物还包括牛膝6重量份和/或车前子6重量份。
本发明还公开了一种组合物用于制备防治神经管畸形(NTDs)药物的用途,所述组合物的关键活性成分包括槲皮素(Quercetin)、汉黄芩素(Wogonin)、谷甾醇(Beta-Sitosterol)、山奈酚(Kaempferol)和豆甾醇。
本发明还公开了一种组合物用于制备防治NTDs引起的神经管闭合不全药物的用途,所述组合物的关键活性成分包括槲皮素(Quercetin)、汉黄芩素(Wogonin)、谷甾醇(Beta-Sitosterol)、山奈酚(Kaempferol)和豆甾醇。
本发明还公开了一种组合物用于制备PI3K/Akt通路抑制剂的用途,所述组合物的关键活性成分包括槲皮素(Quercetin)、汉黄芩素(Wogonin)、谷甾醇(Beta-Sitosterol)、山奈酚(Kaempferol)和豆甾醇。
本发明通过网络药理学的分析方法,开发并验证了金匮肾气丸(JSP)防治NTDs的新用途,并对JSP防控NTDs的有效成分、作用靶点及信号通路进行分析以及对JSP防控NTDs的关键靶点和途径进行了初步实验验证,对临床应用JSP防控NTDs提供一定的理论依据。
本发明通过网络药理学对JSP防控NTDs的靶点和活性成分进行分析,获得了以槲皮素(Quercetin)、汉黄芩素(Wogonin)、谷甾醇(Beta-Sitosterol)、山奈酚(Kaempferol)、豆甾醇(Stigmasterol)为主的26个关键活性成分以及以IL-10、IL-6、Bcl-2等为主的64个核心靶点,并通过KEGG通路分析表明JSP可能通过调控PI3K/Akt通路、音猬因子(Sonichedgehog,shh)等信号通路发挥作用,并且分子对接结果显示,JSP可以很好的与PI3K/Akt通路相关蛋白很好的结合。这与现有研究提出的NTDs发生与PI3K/Akt通路有关的网络药理学结果相符合,再次验证了JSP防控NTDs的作用和效果。
本发明通过动物实验进一步证明JSP可以促进PI3K/Akt通路的激活,其机制可能与下游所调控的细胞增殖与凋亡、炎症及活性氧代谢等生物过程有关。Akt作为PI3K/Akt通路核心蛋白,当Akt磷酸化后会作用于Bcl-2蛋白家族,其中Bcl-2可以起到抑制细胞凋亡的作用。Bax蛋白也是Bcl-2蛋白家族之一,当细胞凋亡时,Bax可以促进细胞色素C的释放,使凋亡加速,并且Bcl-2/Bax的值越高,凋亡发生的程度越低。PI3K/Akt通路与凋亡的密切关系与NTDs发生发展中神经管上皮细胞的凋亡的机制符合。本发明动物实验结果结合文献进一步表明,JSP中关键活性成分槲皮素、汉黄芩素、谷甾醇、山奈酚、豆甾醇具有潜在抑制凋亡发生的作用,进一步证实了PI3K/Akt通路在JSP防控NTDs过程中的重要作用。
本发明基于网络药理学结合体内实验探讨探究JSP防控NTDs的作用机制。通过网络药理学初步探究了JSP治疗NTDs可能的作用靶点及作用途径,并结合动物实验验证,证明JSP可以降低胎鼠NTDs的发生率,减少神经管上皮的细胞凋亡并且可以提高PI3K/Akt信号通路相关蛋白的表达。综上JSP发挥防控NTDs的作用很有可能是通过激活PI3K/Akt通路减少细胞凋亡的发生来实现的,为更深层次的应用JSP提供了理论依据,填补了现有技术中尚未有JSP在NTDs方面研究及应用的空白。
附图说明
为了使本发明的内容更容易被清楚的理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,其中,
图1为药物-活性成分-疾病-靶点的网络示意图;其中,方形节点表示作用靶点,椭圆形节点表示活性成分,圆形节点是药物名称;每条边表示靶点与活性成分之间的互相作用关系;
图2为JSP-NTDs靶点的韦恩图示意图;
图3为JSP-NTDs的共同靶点PPI网络及核心靶点筛选示意图;其中,节点的大小和颜色变化表示degree值的大小,节点越大,颜色越深说明对应的degree值越大,与之相连接的边就越多,就越重要;
图4为“活性成分-靶点-疾病”网络示意图;
图5为WYP防控NTDs核心靶点的GO功能富集分析结果;
图6为WYP防控NTDs核心靶点的KEGG通路分析(前20);纵坐标从上往下表示富集程度排名靠前的通路,横坐标表示基因列表富集到目的通路基因数占基因列表包含总基因的比例,点越大表示富集到通路上的靶点越多;
图7为关键活性成分与核心靶点的对接结合能图;颜色越深,结合能越低,越浅则越高,结合能小于0说明分子之间具有结合活性,小于-5.0kc al·mol-1说明分子之间具有较强的结合活性,且能量越低结合能力越强;
图8为关键活性成分与核心靶点的对接模式图;其中,(A)为槲皮素-Akt1,(B)为汉黄芩素-IL6,(C)为β-谷甾醇-PIK3CG,(D)为山奈酚-Akt2,(E)为豆甾醇-IL10,中央深色分子为药物,浅色为核心蛋白,虚线短棒及相邻的小分子深色部分为氢键和药物与核心蛋白连接的氨基酸残基;
图9为正常及NTDs胎鼠的体视显微镜下图及HE染色图;其中,(A)为体视显微镜下正常组胚胎形态(8x),(B)为正常组颈部横切面HE染色(5x);(C)为正常组颈部横切面HE染色(10x);(D)为体视显微镜下NTDs胚胎(8x);(E)为模型组颈部横切面HE染色(5x);(F)为模型组颈部横切面HE染色(10x);
图10为不同浓度的JSP对各组胎鼠NTDs发生率的影响;△表示与正常组比较:△P<0.05、△△P<0.01;*表示与模型组比较:*P<0.05、**P<0.01;#表示与叶酸组比较:#P<0.05;
图11为各组PI3K/Akt通路蛋白的表达结果;△表示与正常组比较:△P<0.05、△△P<0.01;*表示与模型组比较:*P<0.05、**P<0.01;#表示与叶酸组比较:#P<0.05;
图12为各组凋亡相关蛋白的表达结果;*P<0.05、**P<0.01。
具体实施方式
本发明如下实施例中,利用网络药理学方法验证JSP的作用及药理研究。
实施例1药物活性成分的获取
本实施例应用中药系统药理学分析平台(Traditional chinese medicinesystems pharmacology database and analysis platform,TCMSP)检索JSP全方中泽泻、山茱萸、山药、牛膝、牡丹皮、桂枝、附子、茯苓、地黄、车前子的所有活性成分。以口服生物利用度(OB)≥30%,类药性(DL)≥0.18为限制条件进行筛选,得到WYP的生物活性成分。
本实施例中,通过TCMSP数据库,以OB≥30%和DL≥0.18为筛选条件对JSP中10味中药已报道活性成分进行检索,获得泽泻27、山茱萸132、山药44、牛膝67、牡丹皮33、桂枝187、附子19、茯苓20、地黄41、车前子37。去掉重复分子和无对应靶点者,共得到125个活性成分,具体成分见下表1。
表1JSP中活性成分
实施例2WYP活性成分潜在作用靶点的筛选及预测
将实施例1中得到的JSP生物活性成分,通过TCMSP平台寻找其相关的潜在靶点,然后利用UniPort数据库中UniProKBt的检索功能获取各活性成分靶标蛋白对应的人类基因,限定物种为人,将所有靶基因名称校正为官方名称official gene symbol。而在TCMSP数据库中无靶点者,查其CAS/InChI号,再结合Pubchem(https://pubchem.ncbi.nlm.nih.gov/)数据库和SwissTargetPrediction(http://www.swisstargetprediction.ch/)分析平台加以补充。
本实施例经上述操作并去除重复靶点后共计获得172个作用靶点,详细列于下表2。
表2JSP中各活性成分蛋白对应的人类基因
实施例3NTDs疾病靶点的获取
通过Gencards(http://www.genecards.org/)数据库,以“Neural Tube Defects”为关键词进行检索,以大于“Relevancescore”的2倍中位数为筛选条件,收集相关靶点。再结合OMIM(https://omim.org/)数据库,TTD(http://db.idrblab.net/ttd/)数据库进行补充。
本实施例中,结合TTD数据库补充的290个靶点,共计筛选获得1585个靶点,下表3中列举其中的180个靶点。
表3 NTDs的疾病靶点
实施例4“药物-活性成分-靶点”的网络构建
本实施例利用上述筛选得到的活性成分,将获得的疾病基因依次导入cytoscape软件中,构建“药物-活性成分-疾病-靶点”图,如附图1所示。可见,该网络中共有237个节点,527条边,更加直观地展示多成分、多靶点的相互关系。
实施例5药物与疾病共同靶点筛选及蛋白互作网络构建
本实施例首先通过在线Venn(http://www.bioinformatics.com.cn)对JSP和NTDs靶点求交集,获得JSP-NTDs的共同靶点64个,并绘制韦恩图,见附图2所示。
然后将上述JSP-NTDs的共同作用靶点导入STRING(https://string-db.org)数据库中,进行蛋白质-蛋白质相互作用(Protein-protein interaction,PPI),并将得到的结果导入Cytoscape软件中进行可视化分析,构建PPI网络以筛选核心靶点。由附图3所示结果可见,可得到64个节点、897条边的网络图。
通过上述“药物-活性成分-疾病-靶点”网络将Venn图得到的药物与疾病靶点取交集基因,通过Cytoscape软件制作“活性成分-靶点-疾病”网络,见附图4,并根据交集基因提取核心成分,通过Network Analyzer插件计算度值,分析筛选主要药效成分,为分子对接小分子配体。可见,共得到26个核心成分,和64个交集基因,计算度值对JSP活性成分进行排序,排名前5的活性成分:槲皮素(Quercetin)、汉黄芩素(Wogonin)、谷甾醇(Beta-Sitosterol)、山奈酚(Kaempferol)、豆甾醇(Stigmasterol)将其作为JSP治疗NTDs的关键活性成分,用于分子对接。
实施例6GO功能和KEGG通路富集分析
本实施例采用Metascape平台,通过将核心靶点导入Metascape数据库进行GO和KEGG分析。选择“Homosapiens”对JSP防控NTDs的核心靶点进行基因本体(Gene ontology,GO)功能和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析。
本实施例通过对GO分析结果整理汇总,生物过程(biologicalprocess,BP)1117个、细胞组分(cellularcomponent,CC)45个、分子功能(molecularfunction,MF)95个,详见附图5。而GO功能富集以BP条目最具代表性,主要涉及对细胞因子的作用、氧化应激的调控、凋亡过程的调控等生物过程;CC主要涉及RNA聚合酶II转录调控复合物、细胞溶质、细胞质等;MF主要涉及RNA聚合酶II转录因子结合、转录共调节因子结合、三磷酸腺苷集合、类固醇结合等。体现了JSP对NTDs的治疗可能是多重作用的结果。
本实施例通过KEGG通路分析富集于158条通路(P<0.05),排名前10的结果见附图6,主要有:癌症通路(Pathwaysincancer)、乙型肝炎(Hepatitis B)、磷脂酰肌醇3-激酶/蛋白激B(phosphatidylinositol-3-kinase/pr oteinkinaseB,PI3K/Akt)信号通路、丙型肝炎(Hepatitis C)等信号通路。其中最相关的通路是PI3K/Akt通路,且与多种生物过程相关,因此将其作为后续动物实验的验证通路。
实施例7分子对接验证
本实施例通过获取活性成分-疾病-靶点网络的交集,根据交集基因提取核心成分,核心靶点通过蛋白互作网络分析获取,并结合其通路分析以及文献研究最终确定。通过Autodock软件,选择核心活性成分作为对接配体与核心靶点及关键通路蛋白对接,结合能表示活性物质与蛋白质的亲和力和构象的稳定性,见附图7。
本实施例中,蛋白质结构需要选择PDB(https://www.rcsb.org)数据库中发布时间较新的、分辨率较高的、结构较完整的,通过PyMOL软件去水及小分子,再通过autodock软件加氢,导出为pdbqt文件,设置为配体;药物活性成分的文件从TCMSP下载得到,部分成分需要从Pubchem(https://pubchem.ncbi.nlm.nih.gov/)下载得到sdf文件并使用openbabel软件转换为mol2文件,在Autodock软件中加氢、检测扭转键、选择扭转键、设置为配体、导出为pdbqt文件。设置对接Box、导出为gpf文件、运行Autogrid,设置对接参数(对接次数50次)及运算方法、导出为dpf文件、运行Autodock。查看结果;导出结合能最高的结果为pdbqt文件,采用PyMOL软件进行可视化处理。
本实施例使用PyMoL软件对部分结果进行结构匹配分析,成分与靶点之间通过形成氢键等相互作用使结构趋于稳定,详见附图8。
实施例8动物实验验证
动物:健康成年C57BL/6小鼠,雌雄比例为2:1,体质量(23±2)g,由北京维通利华实验动物技术有限公司提供,动物合格证号SCXK(京)2021-0006。饲养环境通风良好,自由摄取水食,按昼夜节律自然照明、室温(22±2)℃、湿度45%-55%。
药物和试剂:
JSP(由泽泻、山茱萸、山药、牛膝、牡丹皮、桂枝、附子、茯苓、地黄、车前子组成)由北京同仁堂股份有限公司同仁堂制药厂生产(批号2035248),通过查阅大量文献确定出JSP给予小鼠灌胃的高、中、低剂量分别是0.7、1.4、2.8g/kg(剂量按体表面积折算,分别相当于成人临床推荐日用量的0.5倍、1倍、2倍);
全反式维甲酸(All-trans-retinoicacid,atRA)购于美国Sigma公司;
HE染色试剂盒(批号20201016)、BSA(批号9048-46-8)、1×TBST(批号T1086)购于Solarbio;
一步法PAGE凝胶快速制备试剂盒(10%)购于雅酶生物医药科技有限公司(批号PG212);
1×电泳转移缓冲液购于Solarbio公司(批号D1061);
1×Tris-甘氨酸电泳缓冲液电泳液购于Solarbio公司(批号T1072);
特超敏ECL化学发光即用型底物(批号AR1197)、BCA蛋浓度测定试试剂盒(批号AR0197)购于Boster Biological Technology公司;
PVDF膜购于Millipore公司(批号IPVH00010);
山羊抗兔(批号ZJ2020-R)、β-actin抗体(批号AP0060)购于Bioword公司;
Akt(批号4685S)、p-Akt(批号4060S)、PI3K(批号4249S)、p-PI3K(批号4228S)、Bcl-2(#3498)、Bax(#14796)、cleaved caspase-3(#9664)购于Cell Signaling公司。
仪器:
BS224S型万分之一电子天平(德国赛多利斯集团);
凝胶成像分析仪(美国Azure Biosystems公司);
SMZ-168体视显微镜(麦克奥迪实业集团有限公司);
垂直电泳槽(美国Bio-Rad公司);
转膜仪(美国Bio-Rad公司)。
建立神经管畸形胎鼠模型:
C57BL/6雄鼠和雌鼠1:2比例于晚上8时合笼,次日早上8时分笼并检查阴栓,有阴栓者为孕鼠。将发现阴栓的当天上午8时定为胚胎(Embryo,E)0.5d。用橄榄油溶解atRA粉末,按50mg/kg剂量腹腔注射干预E7.5d孕鼠。课题组前期研究发现,用ATRA对E7.5d孕鼠进行干预,胎鼠于E9.5d开始出现神经管畸形,且神经管畸形发生进程一直到E11.5d(神经管发育完成)结束,所以本实验选取E11.5d胎鼠进行研究。解剖E11.5d孕鼠取出胎鼠,参照正常组,光镜下观察胎鼠神经管的形态,鉴定神经管畸形的发生。
分组:
大鼠适应性喂养一周后,将发现阴栓的小鼠分为正常组、模型组、JSP低剂量(0.7g/kg)和atRA同时干预组、JSP中剂量(1.4g/kg)和atRA同时干预组、JSP高剂量(2.8g/kg)和atRA同时干预组、叶酸和atRA同时干预组(见下表4)。每组5只孕鼠,以其胎鼠为研究对象。
表4动物实验分组
分组 | JSP低剂量 | JSP中计量 | JSP高剂量 | FA组 |
Dose | 0.7g/kg | 1.4g/kg | 2.8g/kg | 37μg/kg |
给药:
将发现阴道栓塞孕鼠当天上午8时记为妊娠(Embryo,E)0.5天(E0.5d),进行随机分组并标记。在E7.5d,除正常对照组外,实验组孕鼠腹腔注射atRA(7.5mg/kg/d),正常对照组则给予等体积橄榄油腹腔注射。E0.5d-E11.5d,JSP和FA组持续进行药物灌胃干预,每天一次,正常组和atRA组则给与同体积的生理盐水。E11.5d麻醉脱颈位处死孕鼠,实行剖宫产手术分离胚胎。
样品制备及指标检测:
E11.5d时颈椎脱臼法处死各组孕鼠,仰卧固定四肢于手术台上。于腹中线剪开皮肤和肌肉,暴露腹腔,可见子宫,剪断子宫系膜,将子宫取出,用PBS清洗后,移入盛有PBS的玻璃培养皿中,解剖显微镜下小心剥离胎盘和胎膜组织,取出胚胎,光镜下鉴定神经管畸形的发生情况,用神经管畸形发生率(每只孕鼠神经管畸形胎鼠数/每只孕鼠总胎鼠数×100%)表示。
苏木素-伊红(HE)染色:
取前述制备的冰冻切片,室温置于苏木精试剂中染色3min,沥干染液,小水流水洗5min快速反蓝,0.5%盐酸酒精分化15s,流水冲洗2min,伊红染液10min,小水流快速水洗3min除去染液,置于梯度酒精脱水(70%酒精30s;70%酒精30s;80%酒精30s;95%酒精30s;100%酒精1min;100%酒精2min),置于二甲苯溶液中进行组织透明(酒精:二甲苯1min;100%二甲苯2min;100%二甲苯5min),待切片自然晾干后用中性树胶封片。
免疫蛋白质印迹(Western Blot)实验:
将胎鼠组织从-80℃冰箱取出并称重,将胎鼠组织置于置于研磨器中,加入组织裂解液(每1mg组织样品中加入10μL裂解液,含1μL磷酸酶抑制剂和1mM的蛋白酶抑制剂PMSF 1μL)于冰上进行充分研磨至无明显组织块后充分裂解30min。将得到的组织混悬液移至提前预冷的EP管中,放入4℃离心机中12000转离心20min,取上清液并分装保存于-80℃冰箱,得到的上清液即为胎鼠组织蛋白,利用Western Blot技术检测各组胎鼠组织中PI3K/Akt信号通路中核心蛋白(Akt、p-Akt、PI3K、p-PI3K)及通路下游凋亡相关蛋白(Bcl-2、Bax、cleavedcaspase-3)的表达情况。
统计学方法:
采用SPSS17.0统计软件分析数据,应用单因素方差分析(one-wayAN O-VA)比较各组间均数。P<0.05表示差异有统计学意义
实施例9动物实验验证结果
atRA诱导的NTDs胎鼠形态学观察和神经管闭合情况的病理学观察
脊柱裂和无脑畸形是NTDs最典型的畸形类型。如图9所示结果,体视显微镜下观察胎鼠外观发育情况,正常胎鼠中脑、后脑、末脑、间脑、端脑、四脑室等各结构发育良好,外观光滑,发育状态良好;NTDs胎鼠见中脑、间脑、端脑,后脑、末脑被破坏,神经组织外露。HE染色观察正常及NTDs胎鼠冠状切片病理变化。HE染色结果显示正常胎鼠神经管管腔规则,闭合良好,各结构清晰,细胞排列整齐;而NTDs胎鼠神经管呈现出未闭合状态。
JSP对各组胎鼠NTDs发生率的影响
本实施例通过体视显微镜观察,统计分析了各组胎鼠NTDs发病率,见附图10所示。可见,与正常组相比,atRA组胎鼠NTDs发病率显著升高(P<0.01);与atRA组相比JSP低、中、高剂量组与FA组均可降低胎鼠畸形率(P<0.01),且atRA+2.8g/kg/d组较atRA+FA组效果更好(P<0.05)。
JSP可以促进PI3K/Akt通路的表达
本实施例通过Western Blot技术检测了JSP对PI3K/Akt通路Akt、p-Akt、PI3K、p-PI3K通路蛋白表达水平,结果见附图11所示。可见,与正常组相比,atRA组p-PI3K和p-Akt表达水平均显著降低(P<0.01);与atRA组相比,JSP和FA治疗组p-PI3K表达提高(P<0.01),JSP的p-Akt表达明显升高(P<0.01),FA的p-Akt表达水平升高(P<0.05);与FA组比较,JSP组p-PI3K和p-Akt的表达均升高(P<0.05)。
JSP可以减少凋亡蛋白的表达
通过Western Blot技术检测了JSP对Bcl-2、Bax、cleaved caspase-3蛋白表达水平,结果见附图12所示。atRA组Bcl-2表达水平显著降低(P<0.01),且Bax、cleaved-caspase3表达水平均显著增加(P<0.01),Bcl-2/Bax比值减小(P<0.01)。与atRA组相比,JSP组Bcl-2表达提高(P<0.01),Bax、cleaved-caspase3均明显降低(P<0.01),Bcl-2/Bax比值升高(P<0.01)。与FA组比较,JSP组Bcl-2的表达升高(P<0.05),Bax、cleaved-caspase3的表达均降低(P<0.05),Bcl-2/Bax比值升高(P<0.05)。
综上,本发明基于网络药理学结合体内实验探讨探究JSP防控小鼠神经管畸形(Neural tube defects,NTDs)的作用机制,通过数据库收集JSP中的活性成分及其治疗NTDs的靶点,构建蛋白质-蛋白质相互作用(Prote in-protein interaction,PPI)网络,并进行基因本体(Gene ontology,GO)功能和京都基因与基因组百科全书(Kyotoencyclopedia of genes and gen omes,KEGG)通路富集分析;通过AutoDock软件对关键作用靶点与主要活性成分进行分子对接验证。筛选出JSP的125种活性成分,得到JSP治疗NTDs的靶点172个,核心靶点64个;KEGG通路富集分析表明磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase,PI3K)/Akt信号通路是JSP抗NTDs的关键机制之一;分子对接显示,JSP中关键活性成分与核心作用靶点中的Akt1、Akt2、PIK3CG和PI3GCA等具有较为稳定的结合活性。
综上,本发明通过动物实验进行验证,用全反式维甲酸(All-trans-retinoicacid,atRA)给孕鼠腹腔注射建立神经管畸形胎鼠模型,给予JSP低、中、高剂量(0.7、1.4、2.8g/kg)和叶酸(37μg/kg)进行防控,于E11.5d解剖孕鼠取出胎鼠。经统计胎鼠畸形数量分析各组畸形率以及采用苏木素-伊红(Hematoxylin-eosin,HE)染色法考察脑组织病理变化;采用Western Blot检测胎鼠全胚胎蛋白激酶B(protein kinase B,Akt)、磷酸化Akt(phosphorylated Akt,p-Akt)、磷酸肌醇3-激酶蛋白(phosphatidylinosito l 3-kiases,PI3K)、磷酸化磷酸肌醇3-激酶(phosphorylated phosphatidyli nositol-3-kiases,p-PI3K)蛋白表达。动物实验结果显示:与正常组相比,atRA组胎鼠NTDs发病率显著升高(P<0.01);与atRA组相比,JSP低、中、高剂量组与FA组均可降低胎鼠畸形率(P<0.01),且atRA+2.8mg/kg JSP组较atRA+FA组效果更好(P<0.05);HE染色结果显示正常胎鼠神经管管腔规则,闭合良好,各结构清晰,细胞排列整齐;而NTDs神经管呈现出未闭合状态;Western Blot检测结果显示与正常组相比,atRA组p-PI3K和p-Akt表达水平均显著降低(P<0.01);与atRA组相比,JSP和FA治疗组p-PI3K表达提高(P<0.01),JSP的p-Akt表达明显升高(P<0.01),FA的p-Akt表达水平升高(P<0.05);与FA组比较,JSP组p-PI3K和p-Akt的表达均升高(P<0.05)。atRA组Bcl-2表达水平显著降低(P<0.01),且Bax、cleaved-caspase3表达水平均显著增加(P<0.01),Bcl-2/Bax比值减小(P<0.01)。与atRA组相比,JSP组Bcl-2表达提高(P<0.01),Bax、cleaved-caspase3均明显降低(P<0.01),Bcl-2/Bax比值升高(P<0.01)。与FA组比较,JSP组Bcl-2的表达升高(P<0.05),Bax、cleaved-caspase3的表达均降低(P<0.05),Bcl-2/Bax比值升高(P<0.05)。
综上,本发明上述实施例不仅验证了JSP用于防治神经管畸形的药物新用途和效果,且验证了其可能通过作用激活PI3K/Akt信号通路抑制细胞凋亡来防控神经管畸形的机理,为JSP的进一步开发及应用提供了理论支持。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (9)
1.一种金匮肾气丸用于制备防治神经管畸形药物的用途。
2.一种金匮肾气丸用于制备防治NTDs引起的神经管闭合不全病症药物的用途。
3.一种金匮肾气丸用于制备PI3K/Akt通路抑制剂的用途。
4.一种药物组合物及其制剂用于制备防治神经管畸形药物的用途,其特征在于,所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
5.一种药物组合物及其制剂用于制备防治NTDs引起的神经管闭合不全病症药物的用途,其特征在于,所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
6.一种药物组合物及其制剂用于制备PI3K/Akt通路抑制剂的用途,其特征在于,所述药物组合物的原料药组成包括:熟地黄20-28g重量份、山茱萸4-8重量份、山药4-8重量份、泽泻4-8重量份、茯苓15-2017.3重量份、丹皮4-8重量份、桂枝4-8重量份、附子0.5-1.5重量份;
优选的,所述药物组合物还包括牛膝4-8重量份和/或车前子4-8重量份。
7.一种组合物用于制备防治神经管畸形药物的用途,其特征在于,所述组合物的关键活性成分包括槲皮素、汉黄芩素、谷甾醇、山奈酚和豆甾醇。
8.一种组合物用于制备防治NTDs引起的神经管闭合不全病症药物的用途,其特征在于,所述组合物的关键活性成分包括槲皮素、汉黄芩素、谷甾醇、山奈酚和豆甾醇。
9.一种组合物用于制备PI3K/Akt通路抑制剂的用途,其特征在于,所述组合物的关键活性成分包括槲皮素、汉黄芩素、谷甾醇、山奈酚和豆甾醇。
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