CN103860572B - 黄芩苷在制备治疗蓖麻毒素中毒药物中的应用 - Google Patents
黄芩苷在制备治疗蓖麻毒素中毒药物中的应用 Download PDFInfo
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Abstract
本发明公开了黄芩苷在制备治疗蓖麻毒素中毒药物中的应用,黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,在体内对小鼠蓖麻毒素中毒有明显的解救作用,研究表明黄芩苷能够应用在制备治疗蓖麻毒素中毒的药物中,本发明的有益效果:黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,对于蓖麻毒素中毒的解救具有重大意义,不管是吸入或食入或注射引起的蓖麻毒素中毒,上述含有黄芩苷的药物均有确切的疗效。
Description
技术领域
本发明涉及一种药物在制备治疗蓖麻毒素中毒药物中的应用,特别涉及黄芩苷在制备治疗蓖麻毒素中毒药物中的应用。
背景技术
蓖麻毒素是从蓖麻种子中提取出来的一种强毒性蛋白,属于II型核糖体失活蛋白家族,具有N-糖苷酶活性,能组织哺乳动物细胞蛋白合成而引起细胞凋亡和死亡。因此蓖麻毒素自从20世纪初期开始被用于生物战剂,由于其毒性高、容易提取和高稳定性,容易被恐怖组织利用,对人类的生命安全造成了极大的威胁。美国疾控中心将其列为生物恐怖级别B类,但目前临床中尚未有针对蓖麻毒素的有效解毒药。因此,研究能拮抗蓖麻毒素活性的小分子拮抗剂对于蓖麻毒素中毒的解救具有重大意义。
发明内容
本发明的目的在于目前临床中尚未有针对蓖麻毒素的有效解毒药的问题而提供的黄芩苷在制备治疗蓖麻毒素中毒药物中的应用。
本发明所述的黄芩苷在制备治疗蓖麻毒素中毒药物中的应用。
黄芩苷(Baicalin)是从中药黄芩、木蝴蝶等植物中提取分离出来的一种黄酮类化合物,具有明显的抗真菌活性,尤其对酵母菌具选择性作用,最低抑菌浓度(MIC)在70-100μg/ml之间,具体分子式如下:
黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,在体内对小鼠蓖麻毒素中毒有明显的解救作用,研究表明黄芩苷能够应用在制备治疗蓖麻毒素中毒的药物中。
上述的治疗蓖麻毒素中毒的药物为注射剂或胶囊或片剂。
不管是吸入或食入或注射引起的蓖麻毒素中毒,上述含有黄芩苷的的药物均有确切的疗效。
本发明的有益效果:
黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,对于蓖麻毒素中毒的解救具有重大意义,不管是吸入或食入或注射引起的蓖麻毒素中毒,上述含有黄芩苷的药物均有确切的疗效。
附图说明
图1是蓖麻毒素与黄芩苷晶体复合物的结构图。
图2是蓖麻毒素与黄芩苷的结合位点图。
图3是黄芩苷对小鼠蓖麻毒素中毒存活率的影响曲线图。
图4是蓖麻毒素中毒小鼠肾脏组织阳性对照图。
图5是蓖麻毒素中毒小鼠经黄芩苷治疗后的肾脏组织切片图。
图6是小鼠肾脏组织阴性对照图。
具体实施方式
本发明所述的黄芩苷在制备治疗蓖麻毒素中毒药物中的应用。
黄芩苷(Baicalin)是从中药黄芩、木蝴蝶等植物中提取分离出来的一种黄酮类化合物,具有明显的抗真菌活性,尤其对酵母菌具选择性作用,最低抑菌浓度(MIC)在70-100μg/ml之间,具体分子式如下:
黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,在体内对小鼠蓖麻毒素中毒有明显的解救作用,研究表明黄芩苷能够应用在制备治疗蓖麻毒素中毒的药物中。
上述的治疗蓖麻毒素中毒的药物为注射剂或胶囊或片剂或粉针剂。
不管是吸入或食入或注射引起的蓖麻毒素中毒,上述含有黄芩苷的的药物均有确切的疗效。
具体实验如下所述:
1、黄芩苷对Hela细胞的保护作用:
将培养的Hela细胞以每孔15000个细胞铺到96孔细胞培养板中,培养24小时完全贴壁后每孔加入纯化的蓖麻毒100pg,并加入不同梯度的黄芩苷溶液,置于CO2培养箱中培养72小时后离心去细胞培养液上清检测其乳酸脱氢酶释放量,通过乳酸脱氢酶释放评价其对细胞的保护作用。结果显示黄芩苷能显著抑制蓖麻毒素导致的Hela细胞毒性作用,并呈现剂量依赖性。加入不同浓度的黄芩苷后Hela细胞的存活率如下表1:
表1.黄芩苷对蓖麻毒素导致的Hela细胞毒性的抑制作用
黄芩苷(μg/ml) | 存活率(%) |
0 | 21.39 |
4 | 27.56 |
8 | 42.18 |
16 | 56.89 |
32 | 77.42 |
2、黄芩苷抗蓖麻毒素机制分析及靶点确证:
为了明确黄芩苷抗蓖麻毒素活性的机制,本研究以悬滴法得到黄芩苷与蓖麻毒素的蛋白晶体,晶体数据经过软件计算后得到了黄芩苷与蓖麻毒素的复合物晶体结构,见附图1。通过分析发现黄芩苷与蓖麻毒素作用后促进蓖麻毒素形成了多聚体,多聚后其活性位点被阻挡而失去大部分活性,黄芩苷与蓖麻毒素的结合位点(见附图2)为Arg189,Thr190,Arg193,Tyr194,Arg235,Arg258。经过进一步试验验证发现黄芩苷作用于蓖麻毒素的主要作用位点为Arg189,Thr190,Arg193,Tyr194,Arg235。
小鼠蓖麻毒素中毒的实验治疗学研究
3.1小鼠蓖麻毒素中毒模型
BALB/C小鼠(雄性,18-22g)经乙醚麻醉后,经腹腔给予纯化的蓖麻毒素蛋白,小鼠平躺直至苏醒,建立小鼠蓖麻毒素中毒模型。存活率试验、病理学试验给予100ng纯化的蓖麻毒素蛋白。
3.2保护率试验
小鼠注射蓖麻毒素蛋白6h后皮下注射200mg/kg的黄芩苷,每6h给药一次。不给药对照组给与100μl的灭菌PBS,每组20只小鼠,统计其死亡率。结果表明,经黄芩苷处理后,显著提高小鼠蓖麻毒素中毒后的存活率,见附图3.
3.3病理组织学实验
小鼠注射蓖麻毒素蛋白6h后皮下注射200mg/kg的黄芩苷,每6h给药一次。不给药对照组给与100μl的灭菌PBS,每组10只小鼠,感染72小时后将小鼠麻醉致死取肾脏做病理切片观察其病理变化。结果发现,阳性对照组小鼠肾脏有出血,肾小管上皮细胞有大量细胞脱落和管型,肾小球肿胀;而给药组肾组织仅有少量出血,与正常组小鼠比较无明显差异,见附图4、附图5和附图6所示。
通过以上得出黄芩苷能在细胞水平抑制蓖麻毒素引起的细胞死亡,在体内对小鼠蓖麻毒素中毒有明显的解救作用,表明黄芩苷能够应用在制备治疗蓖麻毒素中毒的药物中。
Claims (2)
1.黄芩苷在制备治疗蓖麻毒素中毒药物中的应用。
2.根据权利要求1所述的黄芩苷在制备治疗蓖麻毒素中毒药物中的应用,其特征在于:所述的治疗蓖麻毒素中毒的药物为注射剂或胶囊或片剂。
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PCT/CN2014/076439 WO2015127714A1 (zh) | 2014-02-26 | 2014-04-29 | 黄芩苷在制备治疗蓖麻毒素中毒药物中的应用 |
US15/116,793 US20160361334A1 (en) | 2014-02-26 | 2014-04-29 | Application of baicalin in preparation of drug for treating ricin poisoning |
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