CN114917209B - 白皮杉醇在抗弓形虫感染的应用 - Google Patents
白皮杉醇在抗弓形虫感染的应用 Download PDFInfo
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Abstract
本发明提供了白皮杉醇在抗弓形虫感染的应用,属于寄生虫病防治技术领域,具体涉及白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用、一种预防或治疗弓形虫感染的组合物和一种组合物在制备预防或治疗弓形虫感染的药物中的应用。本发明人通过大量实验探究发现,白皮杉醇对于胞内寄生原虫弓形虫的多种虫株均有显著的抑制活性的效果,而且其毒副作用小、用量少,可为白皮杉醇的有效利用扩展新的途径。以感染弓形虫的Vero细胞为实验模型的细胞,通过测定EC50表明,白皮杉醇在6.9μg/mL时对弓形虫有一半的抑制效果,在24.4μg/mL时完全杀死弓形虫。因此,少量施用即可达到高效的抗弓形虫感染效果。有效解决现有抗弓形虫病药物副作用严重,治疗失败率高的缺陷。
Description
技术领域
本发明属于寄生虫病防治技术领域,涉及白皮杉醇在抗弓形虫感染的应用,具体涉及白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用、一种预防或治疗弓形虫感染的组合物和一种组合物在制备预防或治疗弓形虫感染的药物中的应用。
背景技术
弓形虫病是一种由刚地弓形虫引起的专性胞内寄生原虫病,弓形虫几乎感染所有的温血动物和人,甚至是一些冷血动物,并且能寄生于动物机体的所有有核细胞内。据统计,全球约有三分之一的人口感染弓形虫,弓形虫血清阳性率因地区而异,例如美洲、欧洲和亚洲地区的阳性率约30%,非洲地区的阳性率则60%以上。大部分人弓形虫感染呈隐性感染,但婴儿、免疫抑制患者(比如艾滋病患者、器官移植及恶性肿瘤)感染弓形虫会导致严重的或致命的疾病。弓形虫感染还是导致妊娠动物和孕妇发生流产、死胎及其他繁殖生殖障碍的重要原因,是我国孕检必查项目之一。多种动物(猪、牛、羊、马、犬、猫、鸡等)对弓形虫均有较高感染率,血清学调查表明,全世界高达30%的猪感染弓形虫。猪场发生急性弓形虫病时,发病率可达100%,死亡率高达60%以上。在美国和中国,猪被认为是众多食用动物中最重要的弓形虫传播者,存在巨大的公共卫生安全隐患。我国猪肉产量居世界第一,一旦爆发猪弓形虫病,将会给养殖业带来巨大的经济损失,同时也可能成为严重食品安全问题。
目前,临床治疗弓形虫感染仍依赖化学药物。由于弓形虫生命周期的复杂性、发病机制的多样性和生物学特性的差异性,现在尚无预防和特异性的药物治疗。尽管乙胺嘧啶和磺胺嘧啶的联合用药是目前临床上治疗弓形虫病的黄金标准,但该治疗方法往往伴随着严重的副作用,并且治疗不彻底,存在易复发的缺陷,治疗的失败率很高。因此,筛选出安全有效的抗弓形虫药物是目前亟需解决的问题,也具有较大的市场前景。
因此,研发出一种有效预防或治疗弓形虫感染的药物,是本领域技术人员亟待解决的问题。
发明内容
本发明的目的在于提供白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用。
白皮杉醇(Piceatannol,PIC)是一种天然多酚类化合物,主要存在于百香果,蓝莓、葡萄、甘蔗、白茶及大黄等植物中,具有抗氧化、抗增殖、提高免疫力、抗炎、抗血栓、防癌、抗癌、抗高血脂症、抗菌等多种的生物活性,广泛用于心脏病、白血病、癌症等疾病的治疗,但未有研究表明白皮杉醇对原虫有活性作用。白皮杉醇的分子式为C14H12O4,CAS号:10083-24-6,化学结构式为:
在一优选的实施方式中,所述预防或治疗弓形虫感染的药物为:预防或治疗弓形虫病的药物。
在一优选的实施方式中,所述预防或治疗弓形虫感染的药物为:抑制弓形虫增殖或抑制弓形虫裂解细胞能力的药物。
在一优选的实施方式中,所述预防或治疗弓形虫感染的药物为:消除人或非人动物体内弓形虫虫体的药物。其中,所述非人动物包括但不限于对弓形虫易感的猪、牛、羊、马、犬、猫、鸡等。
本发明的另一目的在于提供一种预防或治疗弓形虫感染的组合物,所述组合物的活性成分包括白皮杉醇。
本发明的另一目的在于提供一种组合物在制备预防或治疗弓形虫感染的药物中的应用,所述组合物包括白皮杉醇和一种或多种药学上可接受的载体。
在一优选的实施方式中,所述预防或治疗弓形虫感染的药物包括:预防或治疗弓形虫病的药物、抑制弓形虫增殖或抑制弓形虫裂解细胞能力的药物、消除人或非人动物体内弓形虫虫体的药物。其中,所述非人动物包括但不限于对弓形虫易感的猪、牛、羊、马、犬、猫、鸡等。
在本发明中,所述载体包括药学上可接受的稀释剂、润湿剂、黏合剂、闪崩剂、润滑剂、色香味调节剂、溶剂、增溶剂、助溶剂、乳化剂、抗氧剂、金属络合剂、防腐剂、pH调节剂、表面活性剂、赋形剂、填充剂和增效剂。更优选的,稀释剂包括如淀粉、蔗糖、纤维素类、无机盐类等;润湿剂包括如水、乙醇等;黏合剂包括如淀粉浆、糊精、糖、纤维素衍生物、明胶、聚维酮、聚乙二醇等;崩解剂包括如淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、联羧甲基纤维素钠、表面活性剂等;润滑剂包括如滑石粉、硬脂酸钙、硬脂酸镁、十二烷基硫酸镁、聚乙二醇等;色香味调味剂包括如色素、甜味剂、香料、胶浆剂等;溶剂包括如水、甘油、乙醇等;增溶剂包括如吐温类、卖泽类、硫酸化物、磺酸化物等;助溶剂包括如有机酸(如枸橼酸)及其盐类、无机盐、聚乙二醇等;乳化剂包括如司盘类、甘油脂肪酸酯、阿拉伯胶、明胶、琼脂、海藻酸钠等;抗氧剂包括如亚硫酸盐、抗坏血酸、没食子酸及其盐类等;金属络合剂包括如乙二胺四乙酸二钠、多羧酸化合物等;防腐剂,包括如尼泊金类、季铵类化合物、醋酸氯己定等;pH调节剂包括如盐酸、酒石酸、醋酸、氢氧化钠、碳酸氢钠、乙二胺、葡甲胺、磷酸盐、枸橼酸盐等。
在本发明中,所述组合物剂型包括但不限于粉剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂、喷雾剂等的口服剂、外用剂、栓剂及无菌注射溶液形式的剂型。可以理解的是,本发明所述的白皮杉醇,基于不同的辅料、不同的剂型,相应的,其给药的方式也可以是多样的。
与现有技术相比,本发明的技术方案具有如下优点:
1、本发明人在研究过程中发现,白皮杉醇对于胞内寄生原虫弓形虫有显著的抑制活性的效果,而且其毒副作用小、对多种弓形虫虫株均有显著的抑制效果,可为白皮杉醇的有效利用扩展新的途径。
2、本发明人经过大量的实验证明白皮杉醇具有显著的预防或治疗弓形虫感染虫效果,具体地:以感染弓形虫的Vero细胞为实验模型的细胞,通过测定EC50表明,白皮杉醇在6.9μg/mL时对弓形虫有一半的抑制效果,在 24.4μg/mL时完全杀死弓形虫。因此,少量施用即可达到高效的抗弓形虫感染效果。
3、另经试验证实,白皮杉醇作为抗弓形虫药物还具有低毒的优点,具体地:通过CCK8方法检测了白皮杉醇对绿猴肾细胞(Vero)的细胞毒性,结果表明在最大使用到122.1μg/mL剂量时,白皮杉醇对Vero细胞仍没有细胞毒性。且一定浓度白皮杉醇对绿猴肾细胞有促进生长的作用。因此,相对于现有治疗弓形虫感染药物副作用大的问题,本发明方案中所采用的白皮杉醇其有效抑制浓度远小于其细胞毒性,具有高效、低毒、安全的特点。
4、本发明经大量实验探索发现,白皮杉醇的抗弓形虫作用主要是通过抑制其胞内增殖。使用24.42μg/mL白皮杉醇作用细胞内的弓形虫24h后,弓形虫的存活率仅为1.1%,并且白皮杉醇对弓形虫的作用呈剂量依赖性,说明浓度越高抗虫效果越佳。而且,对弓形虫虫株具有普适性的效果。具体地:经实验验证白皮杉醇不仅对Ⅰ型强毒株RH有显著的抑制作用,还对Ⅱ型弱毒株Pru有显著的抑制作用,提示白皮杉醇不仅对急性弓形虫病有效,而且对于弓形虫的慢性感染也有效。
附图说明
从下面结合附图对本发明实施例的详细描述中,本发明的这些和/或其它方面和优点将变得更加清楚并更容易理解,其中:
图1为本发明实施例1中白皮杉醇和对照组对Vero细胞的毒性试验结果图;
图2为本发明实施例2中白皮杉醇对弓形虫的抑制作用曲线图;
图3为本发明实施例3中白皮杉醇和对照组的噬斑实验图;
图4为本发明实施例4中白皮杉醇和对照组对细胞外弓形虫的抗入侵作用结果图;
图5为本发明实施例4中白皮杉醇和对照组对细胞内RH的抗增殖作用统计图;
图6为本发明实施例5中白皮杉醇和对照组对细胞内Pru的抗增殖作用的统计图。
具体实施方式
为了使本领域技术人员更好地理解本发明,下面结合附图和具体实施方式对本发明作进一步详细说明,但应当理解本发明的保护范围并不受具体实施方式的限制。
若未特别指明,本发明中所用技术手段为本领域技术人员所熟知的常规手段,本发明中所用的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。其中,白皮杉醇购买于阿拉丁试剂(上海)有限公司,vero细胞与HFF细胞均购买于ATCC细胞库。
实施例1
白皮杉醇对Vero细胞的毒性研究
1、实验过程
细胞毒性实验:在96孔细胞培养板中每孔铺Vero细胞5000个。于37℃, 5%CO2和95%的空气混合物下培养四小时待细胞贴壁后加入白皮杉醇,加入白皮杉醇浓度分别为0.0μg/mL(DMSO组),4.9μg/mL,12.2μg/mL, 19.5μg/mL,24.4μg/mL,48.8μg/mL,73.2μg/mL,122.1μg/mL各100μ L。每组三个重复,37℃,5%CO2和95%的空气混合物下培养24h,轻柔吸出培养板中原DMEM细胞培养基,每孔加入100μL DMEM细胞培养基和10μL CCK-8试剂,继续培养1h后用酶标仪测定450nm处的吸光度。
细胞存活率(%)=(OD白皮杉醇组-OD空白组)/(ODDMSO组-OD空白组)×100%
2、实验结果
统计加入不同浓度白皮杉醇培养的细胞在450nm处吸光度,结果如图1 所示,加入白皮杉醇组和加DMSO组的Vero细胞在450nm处吸光度无明显差异且一定浓度白皮杉醇对细胞增殖有促进作用,表明白皮杉醇对细胞具有低毒,安全等特点。
实施例2
白皮杉醇对弓形虫的抑制作用
1、实验过程
将Vero细胞铺满96孔细胞培养板,收集Luciferase虫株速殖子,将1 ×105个速殖子接种到Vero细胞,分为9组,每组三个孔,分别加入不同浓度白皮杉醇为0.0μg/mL(DMSO组),3.7μg/mL,8.5μg/mL, 13.4μg/mL,18.3μg/mL,22.0μg/m L,26.9μg/mL,31.8μg/mL,36.6μg/mL各100μL。37℃,5%CO2和95%的空气混合物条件下培养24h,轻柔吸出孔中原DMEM细胞培养基,每孔加入100μL细胞裂解液。裂解5min 后吸出裂解液,置于1mLEP管中,12000r/min离心5分钟吸100μL上清加入96孔酶标板,在避光条件下每孔加入100μL荧光素酶,混匀后测每孔荧光值。
抑制率(%)=(荧光值DMSO组-荧光值白皮杉醇组)/荧光值DMSO组×100%。
2、实验结果
统计每孔荧光值大小,结果如图2所示,加入白皮杉醇组与加入DMSO 组的荧光值大小有显著差异(p<0.001),随着加入白皮杉醇浓度的升高,测得荧光值大小逐渐降低,表明白皮杉醇对弓形虫有良好的抑制效果。
实施例3
白皮杉醇抑制细胞内弓形虫形成噬斑的作用
1、实验过程
将HFF细胞铺满12孔细胞培养板,收集RH虫株的速殖子,然后将150 个速殖子接种到HFF细胞(接入弓形虫数量宿主细胞数比值为1:200),分为两组,每组6个孔,A组为每毫升DMEM加入1μL 24.42mg/mL白皮杉醇组,B组为不加白皮杉醇,加等量DMSO作为对照,即DMSO组。37℃,5%CO2和95%的空气混合物培养7天,4%多聚甲醛室温固定30min,PBS洗涤,利用结晶紫进行染色,观察噬斑面积大小。
2、实验结果
统计噬斑面积大小,结果如图3所示,加入白皮杉醇组和加DMSO组的 HFF细胞中形成的噬斑的面积有显著差异(p<0.001),加入白皮杉醇形成的噬斑面积明显少于加DMSO组,表明白皮杉醇显著抑制弓形虫的生长。
实施例4
白皮杉醇对细胞内弓形虫I型虫株(RH)的抗增殖作用
1、实验过程
增殖实验:收集RH虫株的速殖子,将1×105个速殖子接种到HFF细胞 (接入弓形虫数量宿主细胞数比值为1:200),37℃,5%CO2和95%的空气混合物培养三小时待虫入侵后,分为两组,每组6个孔,A组为每毫升DMEM 加入1μL 24.42mg/mL白皮杉醇组,即PIC组,B组为不加白皮杉醇,加等量DMSO作为对照,即DMSO组。37℃,5%CO2和95%的空气混合物培养24h,然后进行IFA免疫荧光法检测。在荧光显微镜下计算100个纳虫空泡中,含有2、4、8、16个速殖子的纳虫空泡比例,计算三次取平均值。
入侵实验:收集RH虫株的速殖子,将1×105个速殖子接种到HFF细胞 (接入弓形虫数量宿主细胞数比值为1:100),同时分为两组,每组6个孔,A组为每毫升DMEM加入1μL24.42mg/mL白皮杉醇组,即PIC组,B组为不加白皮杉醇,加DMSO作为对照,即DMSO组,培养30min,吸出DMEM,使用PBS轻柔洗涤三次,洗去未入侵的速殖子后继续于37℃,5%CO2和95%的空气混合物条件下培养24小时,然后进行IFA在荧光显微镜下随机扫描50个视野,分别统计每个视野中纳虫空泡的个数和细胞核的个数,以纳虫空泡数/细胞核的比例表示虫体入侵能力的强弱。
2、实验结果
统计结果如图4显示,加白皮杉醇组的入侵率约14.0%,加DMSO组的入侵率约为15.5%。实验组与对照组无显著差异。弓形虫侵入宿主细胞后会形成纳虫空泡,速殖子在其中以内二分裂的方式进行增殖,因此在侵入细胞后相同时间内,纳虫空泡中速殖子的个数可以反映出虫体的增殖能力。增殖实验统计结果如图5所示,与对照组相比(加入DMSO组),加白皮杉醇组的虫体增殖能力显著下降响。表明白皮杉醇显著抑制RH弓形虫的增殖,但不影响入侵。
实施例5
白皮杉醇对细胞内弓形虫II型虫株(Pru)的抗增殖作用
1、实验过程
增殖实验:收集Pru虫株的速殖子,将1×105个速殖子接种到HFF细胞 (接入弓形虫数量宿主细胞数比值为1:200),37℃,5%CO2和95%的空气混合物培养三小时待虫入侵后,分为两组,每组6个孔,A组为每毫升DMEM 加入1μL 24.42mg/mL白皮杉醇组,即PIC组,B组为不加白皮杉醇,加等量DMSO作为对照,即DMSO组。37℃,5%CO2和95%的空气混合物培养24 h,然后进行IFA免疫荧光法检测。在荧光显微镜下计算100个纳虫空泡中,含有2、4、8、16个速殖子的纳虫空泡比例,计算三次取平均值。
2、实验结果
统计结果如图6显示,与对照组相比(加入DMSO组),加白皮杉醇组的虫体增殖能力显著下降响。表明白皮杉醇显著抑制弓形虫Pru虫株的增殖。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式,并且很显然,根据上述教导,可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
Claims (4)
1.白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用,其特征在于,所述弓形虫为弓形虫II型虫株Pru。
2.如权利要求1所述的白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用,其特征在于,所述预防或治疗弓形虫感染的药物为:预防或治疗弓形虫病的药物。
3.如权利要求1所述的白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用,其特征在于,所述预防或治疗弓形虫感染的药物为:抑制弓形虫增殖或抑制弓形虫裂解细胞能力的药物。
4.如权利要求1所述的白皮杉醇在制备预防或治疗弓形虫感染的药物中的应用,其特征在于,所述预防或治疗弓形虫感染的药物为:消除人或非人动物体内弓形虫虫体的药物。
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CN105078934A (zh) * | 2015-08-31 | 2015-11-25 | 昆药集团股份有限公司 | 白皮杉醇的新用途 |
CN113398118A (zh) * | 2021-06-25 | 2021-09-17 | 中国农业科学院兰州畜牧与兽药研究所 | 海恩酮在制备治疗弓形虫感染疾病药物中的应用 |
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CN113398118A (zh) * | 2021-06-25 | 2021-09-17 | 中国农业科学院兰州畜牧与兽药研究所 | 海恩酮在制备治疗弓形虫感染疾病药物中的应用 |
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