CN114712372B - 巴戟天寡糖的新用途 - Google Patents
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Abstract
本发明公开了巴戟天寡糖的新用途。本发明提供了巴戟天寡糖在制备预防或治疗脑膜炎的药物中的应用。本发明还提供了巴戟天寡糖在制备调节免疫应答的药物中的应用。本发明公开的巴戟天寡糖的新用途扩大了巴戟天寡糖的应用范围。
Description
技术领域
本发明属于生物医药领域,具体涉及巴戟天寡糖的新用途。
背景技术
细菌性脑膜炎是中枢神经系统严重的感染性疾病,成人常见,儿童患者尤多。许多细菌均可引起本病,其中脑膜炎球菌所致者最多,最常见为流感杆菌、肺炎球菌、大肠杆菌等。
中枢神经系统是一种由血脑屏障保护的免疫特化组织。中枢神经系统实质被一系列重叠的膜所包围,它们被统称为脑膜。人类的硬脑膜是一种致密、坚硬的胶原膜,受高度神经支配,有血管化,并包含淋巴管。蛛网膜是一种将硬脑膜和中枢神经系统的其他部分分开的屏障。蛛网膜的细胞连接并调节血管运输,类似于血脑屏障。蛛网膜的下面是蛛网膜下腔,脑脊液流经的通道。这个空间包含由连接蛛网膜和软脑膜的成纤维细胞样细胞产生的骨小梁和胶原蛋白束。该空间内的脑脊液对大脑浮力很重要。
细菌性脑膜炎的致病机理主要是致病的细菌通过呼吸系统或者通过血流或者通过消化系统进入身体之后,不断的繁殖之后,经过血脑屏障层层对细菌分子的筛选之后进入大脑的蛛网膜下腔之后就会继续繁殖,之后就会引起脑膜和脊髓膜化脓性的炎症以及颅内压升高。可以出现发热,头痛,恶心,呕吐以及脑膜刺激征,同时会造成脑水肿,如果严重的脑水肿会引起导致迅速的死亡。
小胶质细胞是一种免疫细胞与免疫吞噬细胞来源相似,在个体生长早期小胶质细胞进入脑区内起保护作用,当脑内发生炎症、感染、创伤或其他神经系统疾病时,小胶质细胞会迅速被激活并获得吞噬功能。星形胶质细胞具有许多突起,伸展充填在神经细胞的胞体及其突起之间,起支持和分隔神经细胞的作用,并参与了血脑屏障的形成。在中枢神经系统实质内,表面相关的星形胶质细胞与脑膜并列,提供了另一种保护屏障,称为胶质边缘屏障。简单来说,当导致细菌性脑膜炎的细菌穿过星形胶质细胞的缝隙之后即突破了血脑屏障的阻隔,而大脑中充足的养料和适宜的生存环境无疑便成为细菌滋长的温床,当细菌在蛛网膜下腔大量繁殖,小胶质细胞的免疫吞噬功能已无招架之力,从而打破免疫平衡,大脑被细菌占据引发上文所述症状。
在感染性和非感染性条件下,脑膜和脑膜炎症通常先于神经功能障碍。常驻先天免疫哨兵被战略性地放置在整个脑膜上,以感知损伤,并在病原体到达实质之前对其作出反应和隔离。这些细胞可以有效地从血液中招募白细胞,有时还赋予它们进入实质的能力。一般来说,脑膜免疫反应可能是有益的或造成巨大的伤害,换言之,适度的免疫应答对细菌性脑膜炎的防治有利,过度的免疫应答往往造成自身免疫损伤。
导致细菌性脑膜炎的原因包括实验性自身免疫性脑脊髓炎、中风、偏头痛、无菌损伤、微生物进入脑膜并诱发炎症。现如今临床治疗方法主要包括一般治疗、药物治疗、手术治疗、中医治疗的方法。手术治疗为在并发脑积水、硬膜下积脓、脑脓肿时可能需要神经外科手术干预。中医治疗即该病的治疗以医药治疗为主,中药治疗为辅,中药治疗有助手缓解临床症状,增强患者自身免疫力,故必要时可在中医医师指导下进行辩证治疗。患者虽然能接受积极的抗生素治疗,但致死率和病残率仍然较高,成年人细菌性脑膜炎病死率高达30%。发达国家中,有30%的肺炎链球菌脑膜炎患者留有永久性神经系统后遗症,如听力丧失、局部神经功能缺损、神经心理障碍等。故细菌性脑膜炎的免疫干预更为重要。
发明内容
本发明的一个目的在于提供一种用于预防或治疗脑膜炎的新药物。
本发明的另一目的在于提供一种可用于调节免疫细胞因子的药物。
本发明的另一目的在于提供一种提高免疫力的食品添加剂或营养制剂。
为实现这些目的,本发明采用了如下技术方案:
本发明提供了巴戟天寡糖在制备预防或治疗脑膜炎的药物中的应用。
在本发明的一个实施方案中,所述的脑膜炎包括细菌性脑膜炎、病毒性脑膜炎、结核性脑膜炎、隐球菌性脑膜炎,优选为细菌性脑膜炎。
在本发明的一个实施方案中,所述的药物还包括药学上可接受的载体、稀释剂、赋形剂。
术语“药学上可接受的”在本文中被限定为指在合理医学判断的范围内适合用于与受试者的组织相接触而无过度毒性、刺激过敏反应和其他问题并发症,并且与合理的益处/风险比相称的那些化合物、材料、组合物和/或剂型。
术语“受试者”是指任何动物(例如,哺乳动物),包括但不限于,人类、非人灵长类、犬、猫、啮齿动物等。
术语“药学上可接受的载体”是指活性成分与其组合以便于应用到个体且在生理学上可为受体所接受的载体物质。所述药学上可接受的载体可选自但不限于经皮载体、经粘膜载体、口服载体、肠胃外载体、储存制剂用载体和缓释制剂用载体。
用于制备药物的有用的药学上可接受的载体可以是固体,液体或气体;因此,所述药物可以采用片剂、丸剂、胶囊、栓剂、粉末剂、肠包衣的或其它保护的制剂(例如结合于离子交换树脂或包装在脂蛋白泡囊中)、缓释制剂、溶液、混悬剂、酏剂、气溶胶等的形式。所述载体可以选自不同油,包括石油、动物油、植物油或合成来源的油,例如,花生油,大豆油,矿物油,芝麻油等。水,盐水,含水葡萄糖,和乙二醇是优选的液体载体,特别是(当与血液等渗时)用于可注射溶液。例如,用于静脉施用的制剂包括活性成分的无菌水溶液,其通过将固体活性成分溶解于水来产生水溶液,并使得所述溶液无菌来制备。合适的药物赋形剂包括淀粉,纤维素,滑石,滑石,明胶,麦芽,大米,面粉,白垩,硅石,硬脂酸镁,硬脂酸钠,甘油单硬脂酸酯,氯化钠,无水脱脂乳,甘油,丙二醇,水,乙醇等。组合物可以加入常规药物添加剂比如防腐剂、稳定剂、湿润剂或乳化剂、用于调节渗透压的盐、缓冲剂等。合适的药物载体和它们的制剂在E.W.Martin的Remington′s Pharmaceutical Sciences中描述。在任何情况中,这种组合物将含有与合适的载体一起的有效量活性化合物,以制备适当剂型用于适当施用于接受者。
在本发明的一个实施方案中,所述药物的制剂包括液体制剂、固体制剂或半固体制剂,优选为液体制剂。
本发明的药物可通过包括肠道、粘膜、肠胃外和局部路径的本领域已知的任何路径施用到个体。所述肠道路径包括口服和包括自胃肠道吸收的任何路径。所述粘膜路径包括但不限于口腔、鼻、舌下、颊、经肺、经皮和经眼路径。所述肠胃外路径包括而不限于静脉内、皮内、肌肉内和皮下路径。
本发明所述的药物的剂量不受限制,只要获得期望的治疗效果即可,可以依据症状、性别、年龄等来恰当的确定,本发明的治疗药物或预防药物的剂量可以使用例如对疾病的治疗效果或者预防效果作为指标来确定。
本发明所述的药物一般必须无菌且在生产储存条件下稳定。可以将该药物配制成溶液、微乳液、分散液、脂质体或其它适合于高药物浓度的有序结构。通过将所需量的该巴戟天寡糖与所需上述成分的一种或组合一起加入适当的溶剂中并接着进行除菌过滤制备无菌注射液。一般而言,通过将该巴戟天寡糖加入含有基本分散介质和所需的上述其它成分的无菌溶媒中制备分散液。在用于制备无菌注射液的无菌粉剂的情况下,推荐的制备方法是真空干燥和冷冻干燥剂。例如,通过诸如卵磷脂的包衣、在分散液的情况下通过保持所需颗粒大小和通过使用表面活性剂,可以保持溶液的适当流动性。通过在该药物中包括延迟吸收的药剂(例如单硬脂酸盐或明胶)可以达到注射药物的延长吸收。
本发明还提供了巴戟天寡糖在制备提高免疫力的食品添加剂或营养制剂中的应用。
本发明所述营养制剂优选为例如可经肠施用的粉剂、片剂、胶囊、液体浓缩物、固体产品或即饮饮料。
本发明还提供了巴戟天寡糖在制备预防或治疗免疫相关疾病的药物中的应用。
本说明书中,“免疫相关疾病”是指症状的显现与免疫系统的功能有关的疾病。作为免疫相关疾病,例如可以举出肿瘤、免疫缺陷病、感染症、自身免疫性疾病、器官移植所伴随的排异反应、过敏性疾病、炎症性疾病等,但本发明并不仅限于上述例示。
作为肿瘤,例如可以举出舌癌、牙龈癌、恶性淋巴瘤、黑色素瘤、上颚癌、鼻癌、鼻腔癌、喉癌、咽癌、神经胶质细胞瘤、神经母细胞瘤、甲状腺乳头状癌、甲状腺滤泡癌、甲状腺髄样癌、原发性肺癌、鳞状细胞癌、腺癌、肺泡细胞癌、大细胞未分化癌、小细胞未分化癌、类癌、睾丸肿瘤、前列腺癌、乳腺癌、乳腺派杰氏病、乳房肉瘤、骨肿瘤、甲状腺癌、肝癌、急性髓细胞白血病、急性早幼粒细胞性白血病、急性粒单核细胞白血病、急性单核细胞白血病、急性淋巴细胞白血病、急性未分化型白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、成人T细胞白血病、恶性淋巴瘤、多发性骨髓瘤、原发性巨球蛋白血症、儿童白血病、食道癌、胃癌、胃/大肠平滑肌肉瘤、胃/肠恶性淋巴瘤、胰腺/胆囊癌、十二指肠癌、大肠癌、原发性肝癌、肝肉芽肿、子宫上皮内癌、子宫颈鳞状细胞癌、子宫腺癌、子宫腺鳞癌、子宫体腺样癌、子宫肉瘤、子宫癌肉瘤、子宫侵蚀性葡萄胎、子宫恶性绒毛膜上皮癌、子宫恶性黑色素瘤、卵巢癌、中胚叶混合瘤、肾癌、肾细胞癌、肾盂移行细胞癌、输尿管移行细胞癌、膀胱乳头状癌、膀胱移行细胞癌、尿道鳞状细胞癌、尿道腺癌、维尔姆斯瘤、横纹肌肉瘤、纤维肉瘤、骨肉瘤、软骨肉瘤、滑膜肉瘤、粘液肉瘤、脂肪肉瘤、尤文氏肉瘤、皮肤鳞状细胞癌、皮肤基底细胞癌、皮肤鲍恩氏病、皮肤派杰氏病、皮肤恶性黑色素瘤、恶性间皮癌、转移性腺癌、转移性鳞状细胞癌、转移性肉瘤、间皮瘤等,但本发明并不仅限于上述例示。
作为免疫缺陷病,例如可以举出获得性免疫缺陷综合征(AIDS)、重症疾病(例如癌症、再生障碍性贫血、白血病、骨髓纤维化、肾衰竭、糖尿病、肝疾病、脾疾病等)所伴随的严重联合免疫缺陷病(SCID)、普通变异型免疫缺陷病、原发性免疫缺陷综合征等,但本发明并不仅限于上述例示。
作为感染症,例如可以举出病毒感染症、病原性原生动物感染症、细菌感染症、真菌感染症等,但本发明并不仅限于上述例示。作为引起病毒感染症的病毒,例如可以举出甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒等人肝炎病毒;HIV1、HIV2等人免疫缺陷病毒;HTLV1、HTLV2等人T细胞白血病病毒;I型单纯疱疹病毒、II型单纯疱疹病毒等疱疹病毒;Epstein-Barr(EB)病毒;巨细胞病毒;水痘-带状疱疹病毒;人疱疹病毒6型等人疱疹病毒;脊髓灰质炎病毒;麻疹病毒;风疹病毒;流行性乙型脑炎病毒;流行性腮腺炎病毒;流行性感冒病毒;腺病毒、肠道病毒、鼻病毒等感冒综合征的致病病毒;冠状病毒等严重急性呼吸系统综合征(SARS)的致病病毒;埃博拉病毒;西尼罗河病毒等,但本发明并不仅限于上述例示。作为引起病原性原生动物感染症的病原性原生动物,例如可以举出锥虫、疟原虫、弓形虫等,但本发明并不仅限于上述例示。作为引起细菌感染症的细菌,例如可以举出分枝杆菌、沙门氏菌、李斯特菌等,但本发明并不仅限于上述例示。作为引起真菌感染症的真菌,例如可以举出假丝酵母等,但本发明并不仅限于上述例示。
作为自身免疫性疾病,例如可以举出关节炎、自身免疫性肝炎、自身免疫性肾小球肾炎、自身免疫性胰腺炎、自身免疫性睾丸炎、自身免疫性卵巢炎、溃疡性结肠炎、干燥综合征、克罗恩氏病、白塞氏病、韦格纳肉芽肿、过敏性血管炎、结节性动脉周围炎、桥本病、粘液水肿、Basedow病、爱迪生氏病、自身免疫性溶血性贫血、特发性血小板减少性紫癜、恶性贫血、重症肌无力、脱髓鞘疾病、大动脉炎综合征、牛皮癣、天疱疮、类天疱疮、胶原病(例如系统性红斑狼疮、慢性类风湿性关节炎、弥漫性硬皮病、进行性系统性硬皮病、皮肌炎、结节性多动脉炎、风湿热等)、格林巴利综合征、多内分泌腺自身免疫综合征II型、原发性胆汁性肝硬化、白癜风、I型糖尿病、自身免疫性血栓症(例如自身免疫性的动脉血栓症、自身免疫性的静脉血栓症等)、习惯性流产、血小板减少症、抗磷脂抗体综合征等,但本发明并不仅限于上述例示。
作为器官移植所伴随的排异反应,例如可以举出肾移植、肝移植、心脏移值、肺移植等伴随的排异反应;骨髓移植中的排异反应;移植物抗宿主病等,但本发明并不仅限于上述例示。
作为过敏性疾病,例如可以举出哮喘、支气管哮喘、特应性皮炎、荨麻疹、过敏性鼻炎、过敏性结膜炎、过敏性胃肠炎、过敏性休克、食物过敏等,但本发明并不仅限于上述例示。
作为炎症性疾病,例如可以举出湿疹、面疱、接触性皮炎等皮炎;大肠炎;大动脉炎、巨细胞动脉炎(颞动脉炎)、结节性多动脉炎、韦格纳肉芽肿、Churg-Strauss综合征(变应性肉芽肿性血管炎)、过敏性皮肤血管炎、过敏性紫癜、过敏性血管炎、血管炎综合征、血栓闭塞性脉管炎(伯格氏病)、结节性血管炎等血管炎;风湿性关节炎、慢性类风湿性关节炎、变形性关节炎、结核性关节炎、化脓性关节炎、牛皮癣性关节炎、膝关节内紊乱、特发性骨坏死、骨关节炎等关节炎;病毒性肝炎、自身免疫性肝炎等肝炎;急性肾小球肾炎、慢性肾炎、急进性肾小球肾炎综合征、急性链球菌感染后肾小球肾炎、膜增生性肾小球肾炎、Goodpasture综合征、系膜增生性肾小球肾炎(IgA肾病)、间质性肾炎等肾炎;急性感染性胃炎、慢性胃炎等胃炎;胰腺炎、肠炎、喉炎、神经炎等,但本发明并不仅限于上述例示。
本发明还提供了巴戟天寡糖在制备调节免疫应答的药物中的应用。
作为一个实施方案,所述的调节免疫应答包括调节免疫细胞水平、调节细胞因子水平。
作为一种优选的实施方案,所述的免疫细胞包括CD11b+单核巨噬细胞、CD4+T细胞。
作为一种优选的实施方案,所述的细胞因子包括IL-10。
作为一种更为优选的实施方案,所述的巴戟天寡糖能够下调CD11b+单核巨噬细胞水平。
作为一种更为优选的实施方案,所述的巴戟天寡糖能够上调CD4+T细胞水平。
作为一种更为优选的实施方案,所述的巴戟天寡糖能够上调细胞因子IL-10水平。
相对于现有技术,本发明具有以下有益效果:
本发明首次公开了巴戟天寡糖的新用途:巴戟天寡糖在治疗脑膜炎、或进行免疫干预中的应用。巴戟天寡糖可用于制备治疗脑膜炎的药物,还可以用于制备提高免疫力的食品添加剂或营养制剂,具有很好的应用前景。
附图说明
图1是经巴戟天寡糖预给药的肺炎链球菌脑膜炎小鼠的临床评分分析图;
图2是经巴戟天寡糖预给药的肺炎链球菌脑膜炎小鼠的体重分析图;
图3是经巴戟天寡糖预给药的肺炎链球菌脑膜炎小鼠的生存率分析图;
图4是流式分析巴戟天寡糖预给药对健康小鼠CD11b+单核巨噬细胞水平的影响结果图,其中,图A是健康对照组,图B是25mg/kg巴戟天寡糖溶液给药组,图C是50mg/kg巴戟天寡糖溶液给药组,图D是统计图;
图5是流式分析巴戟天寡糖预给药对健康小鼠IL-10水平的影响结果图,其中,图A是健康对照组,图B是25mg/kg巴戟天寡糖溶液给药组,图C是50mg/kg巴戟天寡糖溶液给药组,图D是统计图;
图6是流式分析巴戟天寡糖预给药对健康小鼠CD4+T细胞水平的影响结果图,其中,图A是健康对照组,图B是25mg/kg巴戟天寡糖溶液给药组,图C是50mg/kg巴戟天寡糖溶液给药组,图D是统计图。
具体实施方式
下面结合具体实施例,进一步阐述本发明,仅用于解释本发明,而不能理解为对本发明的限制。本领域的普通技术人员可以理解:在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照厂商所建议的条件实施检测。
本研究所采用巴戟天寡糖粉末(有效部位)是从巴戟天中提取的、以菊淀粉型低聚寡糖为主要成分(其中质量控制标准为:3-9聚寡糖含量53-70%;其中5聚糖含量不低于6%),由北京同仁堂股份有限公司生产。巴戟天寡糖粉末中其他成分也是糖类成分。目前还没有该药预防治疗细菌性脑膜炎这一急重疾病作用的任何报道。
实施例1巴戟天寡糖预给药对肺炎链球菌脑膜炎小鼠的治疗作用
一、实验目的
研究预先灌胃给予巴戟天寡糖溶液(提前给药6d)对肺炎链球菌脑膜炎小鼠的生存率、体重和临床评分的影响。
二、实验材料
C57BL/6小鼠30只,雄性,8周龄,体质量21±1g(购自斯贝福生物技术有限公司,动物合格证号:SCXK(京)2019-0010),饲养于温度(18-24℃)和湿度(55±2%)相对恒定的动物饲养室,自由摄食饮水;巴戟天寡糖(北京同仁堂股份有限公司生产);生理盐水(华润双鹤制药)。
四、实验设备
微量注射器(上海安亭),恒温摇床(太仓实验设备)
五、实验方法
1.C57BL/6小鼠灌胃给予巴戟天寡糖溶液
①配制巴戟天寡糖溶液。称取巴戟天寡糖粉末40mg,溶于8mL生理盐水,配制成浓度为5mg/mL的巴戟天寡糖溶液;取上述母液2mL,加生理盐水2mL,稀释成浓度为2.5mg/mL的巴戟天寡糖溶液;上述溶液均用0.22μm滤膜过滤后备用。
②每日上午8-10时,对小鼠灌胃给予溶液200μL/20g(a组(n=10):生理盐水,b组(n=10):25mg/kg巴戟天寡糖溶液,c组(n=10):50mg/kg巴戟天寡糖溶液),连续给药6d,第7d通过颅内注射肺炎链球菌菌液的方法建立小鼠脑膜炎模型。
2.构建小鼠肺炎链球菌脑膜炎模型。
①肺炎链球菌的活化与测定。从-80℃冰箱取出一支冻存菌液(v=200μL),加入800μL含羊血的THY培养基,220rpm,37℃摇菌16h(培养基为9.5mL THY+0.5mL羊血+10μL庆大霉素)。16h后将1mL菌液从EP管中转移至螺旋管中,加入4ml上述培养基,220rpm,37℃摇菌16h,摇菌结束后涂板,检测OD600值。
②涂板实验。取7支1.5mL EP管,分别标记为0-6号,1-6号加入900μL生理盐水;从螺旋管中吸取1mL菌液加入0号EP管中,10000rpm,2min离心,吸弃上清,加1mL生理盐水重悬;从0号EP管中取100μL菌液,加入1号EP管中,弃枪头;取新枪头,混匀1号EP管中液体,取100μL加入到2号EP管;依次稀释到6号EP管,即菌液稀释为10-6倍;从6号管中取100μl菌液涂板。稀释倍数为10-2的2号管菌液用于建模。
③建立小鼠模型。小鼠称重,按10μL/g剂量腹腔注射水合氯醛麻醉;小鼠麻醉后,用75%乙醇溶液消毒小鼠额顶部皮肤,用剪刀在两耳连线中间竖直剪一小口,清理多余毛发,用棉签沾取酒精擦拭小鼠暴露皮肤;将小鼠放于自制固定板上,小鼠头部搭在10mL注射器上以固定小鼠头部,使小鼠头部与躯干呈约120°,暴露枕骨大孔;手持微量进样器,沿枕骨大孔进针,感受到轻微落空感后注射10μL菌液;注射完毕后停针2min,防止菌液漏出,之后拔出针头。
④将小鼠放回笼内,保持温度,等待小鼠苏醒。
⑤每日观察小鼠状态,记录生存情况、体重和临床评分,连续观察记录12d,脑膜炎临床评分方法参考Koopmans等学者的相关研究(Koopmans MM,Engelen-Lee J,BrouwerMC,et al.Characterization of a Listeria monocytogenes meningitis mouse model[J].J Neuroinflamm,2018,15(1):257)。数据以±s表示,使用GraphPad Prism8.0软件进行统计分析和作图,生存率统计采用Kaplan-Meier法,组间比较采用two-way anova检验,其余统计结果采用t检验,以P<0.05为差异有统计学意义。
六、实验结果
如图1-3所示,3组小鼠生存率、临床评分和体重变化均有显著性差异,证明巴戟天寡糖预给药对肺炎链球菌脑膜炎小鼠有治疗作用。
实施例2巴戟天寡糖预给药对健康小鼠免疫功能的影响
一、实验目的
健康C57BL/6小鼠灌胃给予巴戟天寡糖溶液,考察小鼠血液、脾脏中CD4+ T淋巴细胞、巨噬细胞和相关细胞因子的变化情况。
二、实验材料
C57BL/6小鼠20只,雄性,8周龄,体质量21±1g(购自斯贝福生物技术有限公司,动物合格证号:SCXK(京)2019-0010),饲养于温度(18-24℃)和湿度(55±2%)相对恒定的动物饲养室,自由摄食饮水;巴戟天寡糖(北京同仁堂股份有限公司生产);生理盐水(华润双鹤制药);胎牛血清(康源生物);小鼠外周血淋巴细胞分离液(Ficoll,灏洋生物);流式抗体(,CD4-FITC,IL-10-PE,CD11b-percp,均购自美国Sigma公司);胞内染色刺激剂(500×,美国Thermo公司);胞内染色固定/透化液(Fixation/Permeabilization Concentrate andPerm Diluent,美国Thermo公司);胞内染色洗液(Intracellular Staining Perm WashBuffer(10×),北京安诺论);反转录试剂盒(全式金),TRIzon试剂(北京康为试剂),多聚甲醛,三氯甲烷(国药集团),异丙醇(国药集团),无水乙醇(国药集团),灭菌注射用水(华润双鹤制药)。
四、实验设备
流式细胞分析仪(美国BD公司),PCR仪(美国Bio-Rad公司),实时荧光定量PCR仪(美国罗氏公司),CO2孵育箱(美国Thermo公司),高速离心机(德国Eppendorf公司)
五、实验方法
1.健康C57BL/6小鼠灌胃给予巴戟天寡糖溶液
①配制巴戟天寡糖溶液。称取巴戟天寡糖粉末40mg,溶于8mL生理盐水,配制成浓度为5mg/mL的巴戟天寡糖溶液;取上述母液2mL,加生理盐水2mL,稀释成浓度为2.5mg/mL的巴戟天寡糖溶液;上述溶液均用0.22μm滤膜过滤后备用。
②每日上午8-10时,对小鼠灌胃给予溶液200μL/20g(a组(n=6):生理盐水;b组(n=6):25mg/kg巴戟天寡糖溶液;c组(n=8):50mg/kg巴戟天寡糖溶液),连续给药6d,第7d取小鼠器官并进行后续实验。
2.取小鼠脾脏并进行流式细胞分析
①配制2%FACS洗液。
配制2%FACS洗液:吸取10mL胎牛血清加入500mL生理盐水中混匀(在超净台中操作)。
②取小鼠脾脏置于12孔板中,加生理盐水1mL,研磨,用带棉芯的小移液管过滤(棉芯预先用生理盐水润湿,使滤液体积为3-5mL)。
③梯度密度离心分离脾脏免疫细胞。在玻璃试管中准备3mL Ficoll,将脾脏滤液沿管壁缓慢加入到Ficoll液面上,2000rpm,25℃,升0降0,20min离心。
④在玻璃试管中准备5mL FACS洗液,将梯度密度离心后的中间白膜层转入FACS洗液中;1500rpm,4℃,8min离心,吸弃上清。
⑤进行胞内染色刺激。
进行胞内染色须预先对细胞进行刺激,本实验中IL-10细胞因子为胞内染色。细胞转移到1.5mL EP管中,每管加入200μL FACS洗液+0.5μL刺激剂(即将500×刺激剂稀释成1×使用),37℃刺激5h(中间每2h弹匀一次);刺激结束后,每管中加入1mL FACS洗液,7500rpm,1min离心,吸弃上清,准备染色。
⑥胞外染色。每管中加入100μL FACS洗液和1μL流式抗体,弹匀,4℃避光染色30min(中间弹匀一次);染色结束后每管加1mL FACS洗液,7500rpm,1min离心,吸弃上清,然后用胞内染色固定/透化液(稀释液:浓缩液=3:1,200μL/管)固定过夜。
⑦胞内染色。次日每管先加入1mL胞内染色洗液(10×稀释成1×使用),7500rpm,1min离心,吸弃上清,然后用PB洗液稀释荧光进行胞内染色(比例、时间、操作同胞内染色),染色完毕后用200μL PB洗液悬浮,上机检测。
⑧流式染色方案:
A.CD4-FITC
B.IL-10-PE
C.CD11b-percp
3.PCR检测小鼠外周血和脾脏免疫细胞细胞因子水平
①制备小鼠外周血PCR样品。
小鼠摘眼球取血7-8滴至EP管中,管中预先加入30μL肝素;取120-150μL抗凝血至新EP管,每管加破红液1mL,37℃孵育5min,7500rpm,1min离心,吸弃上清,每管加1mLTRIzon试剂,-20℃冻存备用。
②提取细胞中总RNA。
由于空气中到处存在RNA酶,所以全程必需带口罩操作,以避免RNA降解;尽量全程控制低温,使用冰盒放置样品。
1)打开4℃离心机预冷,用RNAase-free枪尖加200μl氯仿(三氯甲烷),剧烈振荡(涡旋振荡)混匀至整体呈现均匀的粉色。
2)12 000rpm,4℃离心15min,取新的1.5mL进口EP管(无RNA酶),加500μL异丙醇,放4℃冰箱预冷。离心后液体分为三层,RNA在最上层水相中,中间白膜层主要为DNA,下层有机相主要为蛋白质。用200μL移液枪小心分次取上层水相(尽量取尽,但是不可吸取到白膜层和粉色层),加入到预冷的500μL异丙醇中,上下颠倒混匀。
3)12 000rpm,4℃离心10min,在这过程中配制75%乙醇(每个样品用1mL),4℃冰箱预冷;弃上清,每个EP管加入75%乙醇1mL,上下颠倒混匀3-5次。
4)12 000rpm,4℃离心5min,弃上清,倒扣于卫生纸上,待乙醇挥发(约5-10min,这个过程不能太久,期间可用移液枪将EP管壁上的乙醇液滴引流出来),同时准备反转录试剂。
③将RNA反转录为cDNA。
1)反转录体系为20μL/样(体系组成视所使用的试剂盒而定,本实验使用全式金公司试剂盒):
a.AllMIX 4μL
b.gDNA remover 1μL
c.RNase-free Water 15μL
用移液枪吸取20μL上述体系,轻轻吹打EP管底部小白点,吹打过程中保持枪尖在液面以下,避免出现气泡,然后转移至PCR反应管中;过程中如果出现气泡可采用离心的方式除去。
2)上机进行反转录,反转录条件为:
a.50℃ 5min(孵育,使引物与mRNA结合)
b.85℃ 5s(灭活反转录酶)
c.4℃ forever
所得cDNA较为稳定,加80μL灭菌水稀释,可以放置在4℃或-20℃冰箱保存。
④进行实时荧光定量PCR检测。
1)计算本次实验所需八连排孔数=样品数×3(每个样品3个复孔)×n(n=所检测的基因数)。
2)20μL体系
a.2*Ultra SYBR mixture 10μL
b.灭菌水 7.2μL
c.引物 0.8μL(上游引物:下游引物:无菌水=1:1:8)
3)摆好八连排管,逐孔加入上述体系,然后逐孔加入cDNA样品2μL,注意每孔更换枪头;加样后盖好盖子,盖盖子时注意戴好PE手套,尽量避免触碰盖顶小窗,影响结果;盖盖后上下颠倒混匀,顺离后上机检测。
六、实验结果
如图4-6所示,巴戟天寡糖预给药影响健康小鼠的免疫功能。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (5)
1.巴戟天寡糖在制备预防细菌性脑膜炎的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述的药物还包括药学上可接受的载体、稀释剂、赋形剂。
3.根据权利要求2所述的应用,其特征在于,所述的载体包括经皮载体、经粘膜载体、口服载体、肠胃外载体、储存制剂用载体、缓释制剂用载体。
4.根据权利要求1所述的应用,其特征在于,所述药物的制剂包括液体制剂、固体制剂或半固体制剂。
5.根据权利要求4所述的应用,其特征在于,所述的药物的制剂为液体制剂。
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