CN117651560A - 鼠李糖乳杆菌来源的囊泡及其用途 - Google Patents
鼠李糖乳杆菌来源的囊泡及其用途 Download PDFInfo
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Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及鼠李糖乳杆菌来源的囊泡及其用途,并且涉及包含鼠李糖乳杆菌来源的囊泡作为活性成分的用于预防、减轻或治疗免疫疾病或细胞衰老相关疾病的组合物。本发明人已经证实,鼠李糖乳杆菌来源的囊泡增加细胞稳态以抑制细胞衰老相关疾病的发生,并且通过抑制由病毒致病因素引起的免疫疾病模型中的免疫超敏反应来抑制免疫疾病的发生。因此,根据本发明的鼠李糖乳杆菌来源的囊泡可以有效地用于开发用于预防、减轻或治疗病毒感染性疾病、过敏性免疫疾病、自身免疫性疾病、炎性疾病、细胞衰老相关疾病等的药物或健康功能食品。
Description
技术领域
本发明涉及用于预防、减轻或治疗免疫疾病和细胞衰老相关疾病的组合物,其包含鼠李糖乳杆菌(Lactobacillus rhamnosus)来源的囊泡作为活性成分。
本申请要求分别于2021年6月3日和2021年12月6日向韩国知识产权局提交的韩国专利申请第10-2021-0072078号和第10-2021-0173139号的优先权和权益,并且两个申请说明书及附图中公开的全部内容均并入本申请。
背景技术
进入二十一世纪,过去被认为是传染病的急性感染性疾病的重要性有所下降。另一方面,疾病模式发生了变化,由于人体主要器官的免疫功能障碍和细胞衰老引起的慢性疾病已成为降低生活质量和决定人类寿命的重大疾病。这种疾病模式的改变与饮食模式的改变密切相关。过去营养不足时,营养不良引起的急性感染性疾病是主要死亡原因,但近年来,随着营养变得丰富,与营养过剩和细胞衰老引起的免疫功能障碍相关的慢性疾病正在成为主要问题。
由于营养过剩,脂肪不仅堆积在通常储存脂肪的脂肪组织中,而且堆积在血管、心脏、肝、肾和肌肉中,引起脂毒性,导致炎症和细胞衰老。换句话说,由于碳水化合物或脂质代谢紊乱,血液中的脂质和脂肪酸增加,并且随着细胞内脂肪酸的增加,会发生由脂肪酸引起的炎症反应,而炎症反应会导致细胞衰老和死亡,导致心血管系统和诸如肝、肾、肌肉、大脑等器官的功能障碍。由这些病因引起的疾病包括心血管疾病,例如心绞痛、血栓栓塞、心肌梗死、心肌病和中风,肾脏疾病,例如慢性肾病和肾功能衰竭,肌肉骨骼疾病,例如骨关节炎、痛风和骨质疏松,以及退行性脑部疾病,例如阿尔茨海默病和帕金森病。
免疫是针对生物、化学、物理和精神压力的细胞防御机制,通过先天性免疫和适应性免疫发生。特别地,当反复暴露于致病因素后出现不适当的免疫反应时,由于慢性炎症反应而发生疾病,代表性的例子包括因环境致病因素引起的免疫超敏反应引起的过敏性疾病和因内部产生的致病危险因素引起的超敏反应而发生的自身免疫性疾病。此外,最近研究发现,免疫功能与细胞的代谢功能密切相关。关于营养过剩引起的免疫功能障碍的病因学,胞质内代谢物如脂肪酸和尿酸充当危险信号,并被核苷酸结合寡聚化结构域(NLRP)识别,NLRP是存在于细胞质中的模式识别受体。已知NLRP通过形成炎症小体诱导细胞凋亡,同时分泌炎性介质诱导炎性细胞浸润。
同时,已知人体内共存的微生物数量达到100万亿个,比人类细胞多,并且微生物基因数量是人体的100倍。微生物群或微生物组是指存在于给定栖息地的微生物群落,包括细菌、古细菌和真核生物。
我们体内共存的细菌以及周围环境中存在的细菌会分泌纳米大小的囊泡,以与其它细胞交换信息,例如基因、低分子化合物和蛋白质。粘膜形成物理防御膜,尺寸为200纳米(nm)或更大的颗粒无法通过,因此粘膜中共存的细菌无法穿过粘膜,但细菌来源的囊泡的尺寸为200纳米或更小,从而相对自由地通过粘膜上皮细胞而被吸收到我们体内。如上所述,细菌源性囊泡虽然是由细菌分泌的,但在其成分、体内吸收率和副作用风险方面与细菌不同,因此,细菌来源的囊泡的使用与活细胞的使用完全不同或具有显著的效果。
局部分泌的细菌来源的囊泡通过粘膜上皮细胞吸收,以诱发局部炎症反应,并且通过上皮细胞的囊泡通过淋巴管被全身吸收并分布到各个器官,并调节囊泡所分布的器官中的代谢和免疫功能。例如,来源于致病性革兰氏阴性菌(如大肠杆菌(Escherichiacoli))的囊泡是引起局部结肠炎或食物中毒的致病性纳米颗粒,当被血管吸收时,会被吸收到血管内皮细胞中,通过诱导炎症反应来促进全身炎症反应和血液凝固,并且还被吸收到肌肉细胞中,胰岛素在肌肉细胞中起作用,导致胰岛素抵抗和代谢疾病,例如糖尿病等。相反,来源于有益细菌的囊泡可以通过调节由致病囊泡引起的免疫和代谢功能障碍来调节疾病。
乳杆菌属细菌被认为是分泌乳酸的代表性有益细菌。其中,鼠李糖乳杆菌是一种革兰氏阳性杆菌,其不仅在厌氧环境中也能在有氧环境中生长良好,是我们体内的共生菌,并且已知是发酵过程中的重要细菌。来源于革兰氏阳性菌例如鼠李糖乳杆菌的囊泡除了含有细菌来源的蛋白质、代谢物和核酸外,还含有细菌细胞壁成分肽聚糖和脂磷壁酸。
然而,尚无利用鼠李糖乳杆菌分泌的囊泡来预防或治疗与免疫功能障碍和细胞衰老相关疾病的案例。
发明内容
[技术问题]
作为解决上述传统问题的深入研究的结果,本发明人已经证实鼠李糖乳杆菌来源的囊泡对免疫疾病和细胞衰老相关疾病具有治疗作用,从而完成了本发明。
本发明旨在提供一种用于预防、减轻或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的药物组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
然而,本发明要解决的技术问题不限于前述问题,并且本领域技术人员可以从以下描述中清楚地理解未提及的其它问题。
[技术方案]
为了实现如上所述的本发明的目的,本发明人培养了鼠李糖乳杆菌细菌,从培养基中分离出囊泡,并将分离的囊泡经口施用于患有由高脂肪饮食引起的细胞衰老相关疾病的小鼠。结果,体重增加受到抑制,肾功能和肺功能得到改善,并且已证实该作用与抑制Th17和Th2超敏反应有关。此外,已证实本发明的囊泡增强AMP激活激酶(AMPK)的激活,AMPK是在ATP产生不能很好地进行的代谢应激情况(例如饥饿和运动)下通过自噬诱导细胞稳态的关键信号。此外,还证实了,当将囊泡经口施用于由病毒病原体poly(I:C)诱导的免疫疾病小鼠模型时,由干扰素-γ和IL-6介导的免疫超敏反应引起的全身炎症反应受到抑制,并且由TNF-α和IL-6介导的免疫超敏反应引起的局部肺部炎症也受到明显抑制。另外,证实了由上述病毒致病因素引起的免疫超敏反应受到抑制NF-κB信号及其下游信号诱导型NOS(iNOS)表达的囊泡的控制。
因此,本发明提供了用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的药物组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
在本发明的一个实施方案中,所述免疫疾病可以是选自由病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病组成的组中的一种或多种,但不限于此。
在本发明的另一个实施方案中,所述病毒感染性疾病可以是选自由病毒性肺炎、病毒性肝炎、病毒性心脏炎、病毒性肠炎、病毒性肾炎、病毒性血栓栓塞、带状疱疹和梅尼埃病组成的组中的一种或多种,但不限于此。
在本发明的另一个实施方案中,所述自身免疫性疾病可以是选自由系统性红斑狼疮、类风湿性关节炎、干燥综合征、白塞病、强直性脊柱炎和多发性硬化症组成的组中的一种或多种,但不限于此。
在本发明的另一个实施方案中,所述过敏性免疫疾病可以是选自由特应性皮炎、银屑病、过敏性结膜炎、过敏性鼻炎、过敏性哮喘、超敏性肺炎、食物过敏、乳糜泻、肠易激综合征和过敏反应组成的组中的一种或多种,但不限于此。
在本发明的另一个实施方案中,所述细胞衰老相关疾病可以是选自由以下组成的组中的一种或多种:选自由心绞痛、心肌梗死、心肌病、血栓栓塞和中风组成的组中的一种或多种心血管疾病;选自由酒精性脂肪性肝炎、肝硬化、慢性胆管炎、慢性胆囊炎和慢性胰腺炎组成的组中的一种或多种肝胆胰疾病;选自由痛风、骨关节炎和骨质疏松症组成的组中的一种或多种肌肉骨骼疾病;和选自由阿尔茨海默病、帕金森病和黄斑变性组成的组中的一种或多种神经性疾病,但不限于此。
作为本发明的另一个示例性实施方案,囊泡可以具有10至1000nm的平均直径,但不限于此。
在本发明的另一个实施方案中,囊泡可以从鼠李糖乳杆菌的培养基中分离,但不限于此。
在本发明的又一个实施方案中,囊泡可以从通过添加鼠李糖乳杆菌制备的食品中分离,但不限于此。
作为本发明的另一个示例性实施方案,囊泡可以是由鼠李糖乳杆菌天然分泌的或人工产生的,但本发明不限于此。
另外,本发明提供了一种用于预防或减轻选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的食品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或治疗衰老的药物组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或减轻衰老的食品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或减轻衰老的化妆品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的方法,所述方法包括向有此需要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
另外,本发明提供了包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的用途。
另外,本发明提供了来源于鼠李糖乳杆菌的囊泡在制备用于治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的治疗剂中的用途。
另外,本发明提供了一种用于预防或治疗衰老的方法,所述方法包括向有此需要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
另外,本发明提供了包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗衰老的用途。
此外,本发明提供了来源于鼠李糖乳杆菌的囊泡在制备用于治疗衰老的治疗剂中的用途。
[有益效果]
已证实,当将根据本发明的来源于鼠李糖乳杆菌细菌的囊泡经口施用于与高脂肪饮食引起的细胞衰老相关疾病的小鼠模型时,体重增加受到抑制,并且肾功能和肺功能得到改善。此外,还证实了囊泡会激活AMPK,AMPK是在ATP产生不能很好地进行的能量代谢应激情况下通过自噬诱导细胞稳态的关键信号。
此外,当将囊泡经口施用于与病毒致病因素poly(I:C)诱导的免疫功能障碍相关疾病的小鼠模型时,由免疫超敏反应引起的全身炎症反应被抑制,并且由于病毒致病因素引起的免疫超敏反应引起的局部肺部炎症也受到明显抑制。另外,确认了由上述病毒致病因素引起的免疫超敏反应受到抑制NF-κB信号及其下游信号诱导型NOS(iNOS)表达的囊泡的控制。
因此,根据本发明的鼠李糖乳杆菌来源的囊泡预期有效地用于开发用于预防、减轻或治疗包括病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病在内的免疫疾病和细胞衰老相关疾病的药物或健康功能食品。
附图说明
图1示出了通过向由高脂肪饮食诱导的细胞衰老相关疾病的小鼠模型口服施用鼠李糖乳杆菌来源的囊泡来评估对细胞衰老相关疾病的治疗效果的实验方案。
图2示出了通过向由高脂肪饮食诱导的细胞衰老相关疾病的小鼠模型口服施用鼠李糖乳杆菌来源的囊泡来评估体重减轻效果的结果。
图3a和图3b示出了通过向由高脂肪饮食诱导的细胞衰老相关疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡来确认血清中的肾功能测试(BUN、肌酐)水平的结果。
图4示出了通过向由高脂肪饮食诱导的细胞衰老相关疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡来观察肺功能变化的结果。
图5a和图5b示出了通过向由高脂肪饮食诱导的细胞衰老相关疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡来确认气道灌洗液中的Th17和Th2相关细胞因子水平的结果。
图6示出了评估鼠李糖乳杆菌来源的囊泡通过肌肉细胞中的AMPK激活维持细胞稳态的效果的结果。
图7示出了通过向由鼻内施用poly(I:C)诱导的免疫功能障碍相关疾病的小鼠经口施用鼠李糖乳杆菌来源的囊泡来评估对免疫疾病的治疗效果的实验方案,poly(I:C)是模拟病毒感染引起的免疫疾病的致病因素。
图8a和图8b示出了通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡来观察气道灌洗液中的(a)炎性细胞的数量和(b)巨噬细胞和淋巴细胞的数量的变化的结果。
图9a和图9b示出了通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡,通过H&E染色观察到的肺部组织学变化的图像(图9a)和浸润到呼吸道周围的免疫细胞的数量(图9b)。
图10示出了通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡,确认作为血液炎症指标的hs-CRP水平的结果。
图11a和图11b示出了通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡,确认气道灌洗液中的炎性细胞因子(IFN-γ、IL-6)水平的结果。
图12a和图12b示出了确认通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡获得的脾T细胞中用抗CD3和抗CD28抗体刺激T细胞后T细胞分泌的炎性细胞因子(IFN-γ、IL-6)水平的结果。
图13示出了确认通过向由鼻内施用poly(I:C)诱导的免疫疾病的小鼠模型经口施用鼠李糖乳杆菌来源的囊泡后获得的肺组织中的NF-κB和iNOS表达的结果。
图14是从分子生物学水平总结鼠李糖乳杆菌对免疫疾病和代谢疾病的作用机制的图。
具体实施方式
本发明涉及鼠李糖乳杆菌来源的囊泡及其用途。
以下,对本发明进行详细说明。
本发明人已经证实,当培养鼠李糖乳杆菌细菌并从培养基中分离出囊泡并将其经口施用于已经由高脂肪饮食诱导了细胞衰老的慢性疾病小鼠时,体重增加受到抑制,肾功能和肺功能得到改善,并且还证实了该作用与抑制由Th17和Th2细胞引起的超敏反应有关(参见实施例2和3)。
另外,已证实本发明的囊泡激活AMPK,AMPK是在ATP产生不能很好地进行的能量代谢应激情况下通过自噬诱导细胞稳态的关键信号(参见实施例4)。
另外,已证实当将囊泡经口施用于由病毒致病因素poly(I:C)诱导的免疫疾病小鼠模型时,全身炎症反应受到抑制,并且由病毒致病因素引起的局部肺部炎症也受到显著抑制(参见实施例5和实施例6)。
另外,已证实由上述病毒致病因素引起的免疫超敏反应受到抑制NF-κB信号及其下游信号诱导型NOS(iNOS)表达的囊泡的控制(参见实施例7)。因此,已证实根据本发明的鼠李糖乳杆菌来源的囊泡可以有效地用作用于预防或治疗免疫疾病和细胞衰老相关的神经性疾病的组合物。
因此,本发明提供了用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的药物组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
如本文所用,术语“细胞外囊泡”或“囊泡”是指由多种细菌分泌的纳米尺寸的膜形成的结构,并且在本发明中,囊泡统指由鼠李糖乳杆菌天然分泌或人工产生的膜构成的所有结构。
可以通过在鼠李糖乳杆菌培养过程中热处理或高压灭菌,或者使用选自由以下组成的组中的一种或多种方法来分离囊泡:细胞培养物的离心、超速离心、高压灭菌、挤出、超声处理、细胞裂解、匀浆、冻融、电穿孔、机械降解、化学处理、用过滤器过滤、凝胶过滤色谱、预流电泳和毛细管电泳。另外,为了分离,可以进一步进行用于除去杂质的洗涤以及所获得的囊泡的浓缩。
本发明的从鼠李糖乳杆菌的培养基或发酵食品中分离囊泡的方法没有特别限制,只要其提供囊泡即可。例如,可以使用诸如离心、超高速离心、通过过滤器过滤、凝胶过滤色谱法、自由流动电泳或毛细管电泳及其组合的方法来分离囊泡,并且还可以包括诸如用于除去杂质的洗涤和所得囊泡的浓缩的过程。
本发明的囊泡可以从鼠李糖乳杆菌的培养基中分离,或者从通过添加鼠李糖乳杆菌制备的食品中分离,并且可以从鼠李糖乳杆菌天然分泌或人工产生,但不限于此。
在本发明中,通过上述方法分离的囊泡的平均直径可以为10~1000nm、10~900nm、10~800nm、10~700nm、10~600nm、10~500nm、10~400nm、10~300nm、10~220nm、10~200nm、10~100nm、10~90nm、10~80nm、10~70nm、10~60nm、10~50nm、10~40nm、或20至40nm,但不限于此。
本发明中使用的术语“免疫疾病”统指由生物体内的免疫功能障碍引起的疾病。通常,在免疫疾病中,炎症是由致病因素引起的,结果包括炎性介质诱导细胞凋亡和炎性细胞浸润。另外,本发明的“免疫功能障碍相关疾病”或“免疫疾病”统指以外部因素或内部因素引起的免疫超敏反应为特征的免疫功能障碍所引起的疾病。一般来说,病毒感染性疾病和过敏性免疫疾病是由于以对外部因素如病毒和过敏原的超敏反应为特征的免疫功能障碍而发生的,自身免疫性疾病是由于对内部致病因素如自身抗原的免疫功能障碍而发生的。免疫功能障碍相关疾病或免疫疾病包括病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病。
本发明中,病毒感染性疾病可以是选自由以下组成的组中的一种或多种:病毒性肺炎、肺结核、结核、普通感冒、流行性感冒、呼吸道感染、鼻炎、鼻咽炎、中耳炎、支气管炎、淋巴结炎、腮腺炎、淋巴结炎、唇炎、口腔炎、关节炎、肌炎、皮炎、血管炎、牙龈炎、牙周炎、角膜炎、结膜炎、伤口感染、腹膜炎、肝炎、骨髓炎、蜂窝组织炎、脑膜炎、脑炎、脑脓肿、脑脊髓炎、脑膜炎、骨髓炎、肾炎、心脏炎、心内膜炎、肠炎、胃炎、食道炎、十二指肠炎、结肠炎、尿道炎、膀胱炎、阴道炎、宫颈炎、输卵管炎、传染性红斑、细菌性痢疾、脓肿和溃疡、菌血症、腹泻、痢疾、胃肠炎、泌尿生殖道脓肿、开放性伤口或伤口感染、化脓性炎症、脓肿、疖肿、脓皮病、脓疱病、毛囊炎、蜂窝组织炎、术后伤口感染、皮肤裂伤综合征、皮肤烧伤综合征、血栓性血小板减少症、溶血性尿毒症综合征、肾功能衰竭、肾盂肾炎、肾小球肾炎、神经系统脓肿、鼓室炎、鼻窦炎、咽炎、扁桃体炎、乳突炎、蜂窝组织炎、牙源性感染、泪囊炎、胸膜炎、腹腔脓肿、肝脓肿、胆囊炎、脾脓肿、心包炎、心肌炎、胎盘炎、羊膜炎、乳腺炎、感染性休克、全身炎症反应综合征(SIRS)、多器官功能障碍综合征(MODS)、血栓栓塞、带状疱疹和梅尼埃病,但不限于此。
本发明中,自身免疫性疾病可以是选自由以下组成的组中的一种或多种:败血症、动脉硬化、菌血症、全身炎症反应综合征、多器官功能障碍、骨质疏松、牙周炎、系统性红斑狼疮、类风湿性关节炎、骨关节炎、幼年慢性关节炎、脊椎关节炎、多发性硬化症、系统性硬化症、特发性炎症性肌肉疾病、干燥综合征、系统性血管炎、结节病、自身免疫性溶血性贫血、自身免疫性血小板减少症、甲状腺炎、糖尿病、免疫介导的肾病、中枢神经系统或周围神经系统脱髓鞘疾病、特发性脱髓鞘性多发性神经炎、吉兰-巴利综合征、慢性炎症性脱髓鞘性多发性神经炎、肝胆疾病、感染性或自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、硬化性胆管炎、炎症性肠病(IBD)、溃疡性结肠炎、克罗恩病、肠易激综合征、麸质敏感肠病、惠普尔病、自身免疫性或免疫介导的皮肤病、起泡性皮肤病、多形性红斑、接触性皮炎、银屑病、过敏性免疫疾病、哮喘、过敏性鼻炎、特应性皮炎、食物不耐受、痤疮、荨麻疹、肺部免疫疾病、嗜酸性粒细胞性肺炎、特发性肺纤维化和超敏性肺炎,但不限于此。
在本发明中,过敏性免疫疾病可以是选自由以下组成的组中的一种或多种:特应性皮炎、过敏性结膜炎、过敏性鼻炎、过敏性哮喘、超敏性肺炎、食物过敏、乳糜泻、肠易激综合征和过敏反应,但不限于此。
本发明中使用的术语“细胞衰老相关疾病”统指由于营养过剩导致的生物体内的能量代谢应激而加速细胞衰老时发生的疾病。细胞衰老相关疾病包括:选自由高血压、动脉硬化、心绞痛、高脂血症、心力衰竭、心肌梗死、心肌病、血栓栓塞和中风组成的组中的一种或多种心血管疾病;
选自由非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎、肝硬化、胆管炎、胆囊炎和胰腺炎组成的组中的一种或多种肝胆胰疾病;
选自由肾小球肾炎和慢性肾病组成的组中的一种或多种肾脏疾病;
选自由张力缺乏、肌肉萎缩、肌肉营养不良、肌无力、恶病质、痛风、肌肉减少症、骨质疏松症、佩吉特病、类风湿性关节炎和骨关节炎组成的组中的一种或多种肌肉骨骼疾病;和
选自由以下组成的组中的一种或多种神经性疾病:轻度认知障碍、痴呆、阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症(ALS)、巴顿病、卡恩斯-赛尔综合征(KSS)、慢性进行性外眼肌麻痹(CPEO)、线粒体脑肌病伴乳酸性酸中毒和中风样发作(MELAS)综合征、肌阵挛性癫痫伴锯齿状红纤维(MERRF)综合征、神经源性无力伴共济失调和色素性视网膜炎(NARP)综合征、Leigh综合征(LS)、线粒体隐性共济失调综合征(MIRAS)、路易体痴呆(DLB)、多发梗死性痴呆(MID)、额颞叶变性(FTLD)、皮克病、皮质基底节变性(CBD)、进行性核上性麻痹(PSP)、衰老相关性黄斑变性(AMD)、嗅觉障碍、耳聋和糖尿病视网膜病变。
本发明的组合物中囊泡的量可以根据疾病的症状、症状的进展程度、患者的状态等适当调整,并且相对于组合物的总重量,范围可以为例如0.0001wt%至99.9wt%或0.001wt%至50wt%,但本发明不限于此。量比率是基于除去溶剂的干燥产物的量的值。
根据本发明的药物组合物可以还包含通常用于制备药物组合物的合适的载体、辅料和稀释剂。辅料可以是例如选自由以下组成的组中的一种或多种:稀释剂、粘合剂、崩解剂、润滑剂、吸附剂、保湿剂、薄膜包衣材料和控释添加剂。
根据本发明的药物组合物可以通过根据常用的方法配制成以下形式来使用,例如粉剂、颗粒剂、缓释型颗粒剂、肠溶颗粒剂、液体剂、滴眼剂、酏剂、乳剂、混悬剂、醑剂、锭剂、芳香水、柠檬水、片剂、缓释型片剂、肠溶片剂、舌下含片剂、硬胶囊剂、软胶囊剂、缓释型胶囊剂、肠溶胶囊剂、丸剂、酊剂、软浸膏剂、干浸膏剂、流浸膏剂、注射剂、胶囊剂、灌注剂或外用制剂,例如硬膏剂、洗剂、糊剂、喷雾剂、吸入剂、贴剂、无菌注射液剂或气雾剂。外用制剂可以具有诸如霜剂、凝胶剂、贴剂、喷雾剂、软膏剂、硬膏剂、洗剂、搽剂、糊剂或巴布剂的制剂。
作为可包含在根据本发明的药物组合物中的载体、辅料和稀释剂,可以使用乳糖、右旋糖、蔗糖、低聚糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。
对于制剂,使用常用的稀释剂或辅料,例如填充剂、增稠剂、粘合剂、润湿剂、崩解剂和表面活性剂。
作为根据本发明的片剂、粉剂、颗粒剂、胶囊剂、丸剂和锭剂的添加剂,可以使用辅料,例如玉米淀粉、马铃薯淀粉、小麦淀粉、乳糖、白砂糖、葡萄糖、果糖、D-甘露糖醇、沉淀碳酸钙、合成硅酸铝、磷酸氢钙、硫酸钙、氯化钠、碳酸氢钠、纯羊毛脂、微晶纤维素、糊精、海藻酸钠、甲基纤维素、羧甲基纤维素钠、高岭土、尿素、胶体硅胶、羟丙基淀粉、羟丙基甲基纤维素(HPMC)、HPMC 1928、HPMC 2208、HPMC 2906、HPMC 2910、丙二醇、酪蛋白、乳酸钙和和粘合剂,例如明胶、阿拉伯胶、乙醇、琼脂粉、乙酸邻苯二甲酸纤维素、羧甲基纤维素、羧甲基纤维素钙、葡萄糖、纯净水、酪蛋白酸钠、甘油、硬脂酸、羧甲基纤维素钠、甲基纤维素钠、甲基纤维素、微晶纤维素、糊精、羟基纤维素、羟丙基淀粉、羟甲基纤维素、纯化虫胶、淀粉、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇和聚乙烯吡咯烷酮,并且可以使用崩解剂,例如羟丙基甲基纤维素、玉米淀粉、琼脂粉、甲基纤维素、膨润土、羟丙基淀粉、羧甲基纤维素钠、海藻酸钠、羧甲基纤维素钙、柠檬酸钙、十二烷基硫酸钠、硅酸酐、1-羟丙基纤维素、葡聚糖、离子交换树脂、聚乙酸乙烯酯、甲醛处理的酪蛋白和明胶、海藻酸、直链淀粉、瓜尔胶、碳酸氢钠、聚乙烯吡咯烷酮、磷酸钙、凝胶化淀粉、阿拉伯胶、支链淀粉、果胶、聚磷酸钠、乙基纤维素、白砂糖、硅酸镁铝、二山梨糖醇溶液和轻质无水硅酸;和润滑剂,例如硬脂酸钙、硬脂酸镁、硬脂酸、氢化植物油、滑石、石松粉、高岭土、凡士林、硬脂酸钠、可可脂、水杨酸钠、水杨酸镁、聚乙二醇(PEG)4000、PEG 6000、液体石蜡、氢化大豆油(Lubri蜡)、硬脂酸铝、硬脂酸锌、十二烷基硫酸钠、氧化镁、Macrogol、合成硅酸铝、硅酸酐、高级脂肪酸、高级醇、硅油、石蜡油、聚乙二醇脂肪酸醚、淀粉、氯化钠、乙酸钠、油酸钠、dl-亮氨酸和轻质无水硅酸。
作为根据本发明的液体剂的添加剂,可以使用水、稀盐酸、稀硫酸、柠檬酸钠、单硬脂酸蔗糖、聚氧乙烯山梨糖醇脂肪酸酯(双酯)、聚氧乙烯单烷基醚、羊毛脂醚、羊毛脂酯、乙酸、盐酸、氨水、碳酸铵、氢氧化钾、氢氧化钠、谷醇溶蛋白、聚乙烯吡咯烷酮、乙基纤维素和羧甲基纤维素钠。
在根据本发明的糖浆剂中,可以使用白砂糖溶液、其它糖类或甜味剂等,并且根据需要,可以使用香料、着色剂、防腐剂、稳定剂、助悬剂、乳化剂、粘稠剂等。
在根据本发明的乳剂中,可以使用纯净水,并且根据需要,可以使用乳化剂、防腐剂、稳定剂、香料等。
在根据本发明的混悬剂中,可以使用助悬剂,例如阿拉伯胶、黄芪胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、微晶纤维素、海藻酸钠、羟丙基甲基纤维素(HPMC)、HPMC1828、HPMC 2906、HPMC 2910等,并且根据需要,可以使用表面活性剂、防腐剂、稳定剂、着色剂和香料。
根据本发明的注射剂可以包含:溶剂,例如注射用蒸馏水、0.9%氯化钠溶液、林格氏溶液、葡萄糖溶液、右旋葡萄糖+氯化钠溶液、PEG、乳酸林格氏溶液、乙醇、丙二醇、非挥发油——芝麻油、棉籽油、花生油、大豆油、玉米油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苯酯;助溶剂,例如苯甲酸钠、水杨酸钠、乙酸钠、尿素、氨基甲酸酯、单乙基乙酰胺、苯基丁氮酮、丙二醇、Tween系列、烟酸酰胺、乌洛托品和二甲基乙酰胺;缓冲剂,例如弱酸及其盐(乙酸和乙酸钠)、弱碱及其盐(氨水和乙酸铵)、有机化合物、蛋白质、白蛋白、蛋白胨和树胶;等渗剂,例如氯化钠;稳定剂,例如亚硫酸氢钠(NaHSO3)二氧化碳气、焦亚硫酸钠(Na2S2O5)、亚硫酸钠(Na2SO3)、氮气(N2)和乙二胺四乙酸;硫酸化剂,例如0.1%硫氢化钠、甲醛次硫酸氢钠、硫脲、乙二胺四乙酸二钠和丙酮亚硫酸氢钠;镇痛剂,例如苯甲醇、氯丁醇、盐酸普鲁卡因、葡萄糖和葡萄糖酸钙;和助悬剂,例如CMC钠、海藻酸钠、Tween 80和单硬脂酸铝。
在根据本发明的栓剂中,可以使用基质,例如可可脂、羊毛脂、Witepsol、聚乙二醇、甘油明胶、甲基纤维素、羧甲基纤维素、硬脂酸和油酸的混合物、Subanal、棉籽油、花生油、棕榈油、可可脂+胆固醇、卵磷脂、lanette蜡、单硬脂酸甘油酯、Tween或span、imhausen、monolan(丙二醇单硬脂酸酯)、甘油、Adeps solidus、buytyrum Tego-G、cebes Pharma 16、hexalide base 95、cotomar、Hydrokote SP、S-70-XXA、S-70-XX75(S-70-XX95)、Hydrokote25、Hydrokote711、idropostal、massa estrarium(A、AS、B、C、D、E、I、T)、masa-MF、masupol、masupol-15、neosuppostal-N、paramount-B、supposiro(OSI、OSIX、A、B、C、D、H、L)、栓剂基质IV型(AB、B、A、BC、BBG、E、BGF、C、D、299)、suppostal(N、Es)、Wecoby(W、R、S、M、Fs)和teg酯甘油三酯物质(TG-95、MA、57)。
用于经口施用的固体制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊剂等,此类固体制剂是通过将组合物与至少一种辅料例如淀粉、碳酸钙、蔗糖、乳糖、明胶等混合而配制的。除了简单的辅料外,还使用润滑剂,例如硬脂酸镁和滑石。
用于经口施用的液体制剂的实例包括混悬剂、内服液体剂、乳剂、糖浆剂等,这些液体制剂除了简单常用的稀释剂如水和液体石蜡外,还可以包含各种类型的辅料,例如润湿剂、甜味剂、香料、防腐剂等。用于肠胃外施用的制剂包括无菌水溶液、非水性溶剂、混悬剂、乳剂、冻干制剂和栓剂。非水性溶剂和混悬剂的非限制性实例包括丙二醇、聚乙二醇、植物油如橄榄油和可注射酯如油酸乙酯。
根据本发明的药物组合物以药学有效量施用。在本发明中,“药学有效量”是指足以在适用于医学治疗的合理收益/风险比下治疗疾病的量,并且有效剂量水平可根据包括患者的疾病类型、疾病的严重程度、药物的活性、对药物的敏感性、施用时间、施用途径、排泄率、治疗周期、同时使用的药物的因素和其它医学领域众所周知的因素来确定。
根据本发明的组合物可以作为单独的治疗剂或与其它治疗剂组合施用,可以与相关领域的治疗剂顺序或同时施用,并且可以以单剂量或多剂量施用。考虑到所有上述因素,重要的是以可以获得最大效果而没有任何副作用的最小量施用组合物,并且这可以由本领域普通技术人员容易地确定。
本发明的药物组合物可以通过多种途径施用于受试者。所有的施用方法都是可以预见的,药物组合物可以通过例如经口施用、皮下注射、腹膜内注射、静脉内注射、肌肉内注射、鞘内(脊髓周围间隙)注射、舌下施用、经颊粘膜施用、直肠内插入、阴道内插入、眼部施用、耳内施用、鼻内施用、吸入、经口或鼻喷洒、透皮施用、经皮施用等来施用。
本发明的药物组合物根据作为活性成分的药物的种类,以及诸如待治疗的疾病、施用途径、患者的年龄、性别和体重以及疾病的严重程度等各种相关因素来决定。具体地,根据本发明的组合物的有效量可以根据患者的年龄、性别和体重而变化,并且通常,每1kg体重可以每天或每隔一天施用0.001至150mg组合物,优选地,0.01至100mg组合物,或者可以一天施用一次至三次。然而,由于有效量可能根据施用途径、肥胖的严重程度、性别、体重、年龄等而增加或减少,因此该剂量不旨在以任何方式限制本发明的范围。
另外,本发明提供了用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的方法,所述方法包括向有需此要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
另外,本发明提供了包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的用途。
另外,本发明提供了来源于鼠李糖乳杆菌的囊泡在制备用于治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的治疗剂中的用途。
如本文所用,“受试者”是指需要治疗疾病的受试者,更具体地,是指哺乳动物如人或非人灵长类动物、小鼠、大鼠、狗、猫、马和牛,但本发明不限于此。
如本文所用,“施用”是指通过使用任意适当的方法向受试者提供预定的本发明的组合物。
本文所用的术语“预防”是指抑制或延缓目标疾病发作的所有行为。本文所用的术语“治疗”是指通过施用根据本发明的药物组合物减轻或有益地改变目标疾病和由此引起的异常代谢症状的所有行为。本文所用的术语“减轻”是指通过施用根据本发明的组合物降低与目标疾病(例如症状)相关参数的程度的所有行为。
另外,本发明提供了一种用于预防或减轻选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的食品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
食品组合物可以是健康功能食品组合物,但不限于此。
根据本发明的囊泡可以通过将囊泡直接添加到食品中使用或者可以与其它食品或食品成分一起使用,但是可以根据典型的方法适当地使用。活性成分的混合量可根据其使用目的(用于预防或减轻)适当确定。通常,当制备食品或饮料时,本发明组合物的添加量基于原料为15wt%或更少,优选为10wt%或更少。然而,以健康和卫生为目的或以健康管理为目的长期摄取时,该量可以小于上述范围,并且囊泡在稳定性方面没有问题,因此可以以大于上述范围的量使用活性成分。
食品的种类没有特别限制。可以添加该材料的食品的实例包括肉、香肠、面包、巧克力、糖果、点心、甜食、披萨、方便面、其它面条、口香糖、乳制品(包括冰淇淋)、各种汤、饮料、茶、饮品、酒精饮料、维生素复合物等,包括典型意义上的所有健康功能食品。
根据本发明的健康饮料组合物可以如典型饮料那样包含各种香精或天然碳水化合物等作为附加成分。上述天然碳水化合物可以是单糖如葡萄糖和果糖,二糖如麦芽糖和蔗糖,多糖如糊精和环糊精,以及糖醇如木糖醇、山梨糖醇和赤藓糖醇。作为甜味剂,可以使用天然甜味剂如奇异果甜蛋白和甜叶菊提取物,合成甜味剂如糖精和阿斯巴甜,等等。天然碳水化合物的比例通常为每100ml本发明的组合物约0.01至0.20g,或约0.04至0.10g。
除上述成分外,本发明的组合物还可以含有各种营养素、维生素、电解质、香料、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳酸化剂等。此外,本发明的组合物可以包含果肉以制备天然果汁、果汁饮料和植物饮料。这些成分可以单独使用或组合使用。这些添加剂的比例并不重要,但通常选择在每100重量份本发明组合物中0.01至0.20重量份的范围内。
另外,本发明提供了一种用于预防或治疗衰老或衰老相关疾病的药物组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或减轻衰老或衰老相关疾病的食品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或减轻衰老的化妆品组合物,其包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
另外,本发明提供了一种用于预防或治疗衰老的方法,所述方法包括向有此需要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
另外,本发明提供了包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗衰老的用途。
另外,本发明提供了来源于鼠李糖乳杆菌的囊泡在制备用于治疗衰老的治疗剂中的用途。
在本发明中,“衰老”统指体内随时间发生的所有生理变化,并且指由于多种因素而根据个体以极其不同的方式发生的生命现象。当具体考虑衰老现象时,各组成器官和组织的功能都会发生变化,并且个体的衰老最终是由构成个体的细胞的衰老引起的。在本发明中,衰老可以是由于脑、肝、肺、肾、肌肉、皮肤或这些器官的细胞衰老,但不限于此。
在本发明中,“衰老相关疾病”可以是由存在于器官例如脑、肝、肺、肾、心脏、肌肉和皮肤中的细胞的衰老引起的疾病,但不限于此。
根据本发明的化妆品组合物的制剂可以包括润肤乳、皮肤软化剂、爽肤水、化妆水、洗剂、乳液、保湿乳液、滋养乳液、按摩霜、滋养霜、喷雾、保湿霜、护手霜、洗手液、粉底、精华液、滋养精华液、面膜、香皂、洁面泡沫、洁面乳、洁面霜、卸妆油、卸妆膏、润肤露或沐浴露。
本发明的化妆品组合物可以还包含选自由水溶性维生素、油溶性维生素、聚合物肽、聚合物多糖和鞘脂组成的组中的组合物。
水溶性维生素可以是可与化妆品混合的任何物质,但其实例包括维生素B1、维生素B2、维生素B6、吡哆醇、盐酸吡哆醇、维生素B12、泛酸、烟酸、烟酰胺、叶酸、维生素C、维生素H等及其盐(盐酸硫胺素、抗坏血酸钠等)或其衍生物(2-磷酸抗坏血酸钠、2-磷酸抗坏血酸镁等)也可包括在本发明中使用的水溶性维生素中。这些水溶性维生素可以通过常规方法例如微生物转化、从微生物培养物中纯化、酶法或化学合成法获得。
油溶性维生素可以是可与化妆品混合的任何物质,但其实例包括维生素A、胡萝卜素、维生素D2、维生素D3、维生素E(d1-α-生育酚、d-α-生育酚)等及其衍生物(例如,抗坏血酸棕榈酸酯、抗坏血酸硬脂酸酯、抗坏血酸二棕榈酸酯、d1-α-生育酚乙酸酯、d1-α-生育酚烟酸酯、维生素E、DL-泛醇、D-泛醇、泛醇乙基醚)也可包括在本发明中使用的油溶性维生素中。这些油溶性维生素可以通过常规方法例如微生物转化、从微生物培养物中纯化、或者酶法或化学合成获得。
聚合物肽可以是可与化妆品混合的任何物质,但其实例可包括胶原、水解胶原、明胶、弹性蛋白、水解弹性蛋白和角蛋白。聚合物肽可以通过任何常规方法纯化和获得,例如从微生物培养物纯化、酶法或化学合成法,或者通常可以通过从天然物质例如猪、牛等的真皮和蚕的丝纤维纯化来使用。
聚合物多糖可以是可与化妆品混合的任何物质,但其实例可包括羟乙基纤维素、黄原胶、透明质酸钠和硫酸软骨素或其盐(钠盐)等。例如,硫酸软骨素或其盐通常可以从哺乳动物或鱼类中纯化并使用。
鞘脂可以是可与化妆品混合的任何物质,但其实例可包括神经酰胺、植物鞘氨醇和鞘糖脂。鞘脂可以通过常规方法从哺乳动物、鱼类、贝类、酵母或植物中纯化,或者可以通过化学合成方法获得。
本发明的化妆品组合物可以根据需要包含与上述必需成分一起混合在常规化妆品中的其它成分。
待混合的附加成分的实例可以包括脂质成分、保湿剂、润肤剂、表面活性剂、有机和无机颜料、有机粉末、UV吸收剂、防腐剂、消毒剂、抗氧化剂、植物提取物、pH调节剂、酒精、颜料、香料、血液循环促进剂、清凉剂、止汗剂和纯净水。
脂质成分可以包括例如酯脂质、烃脂质、有机硅脂质、氟脂质、动物脂肪、植物油等。
酯脂质可包括例如三2-乙基己酸甘油酯、2-乙基己酸鲸蜡酯、肉豆蔻酸异丙酯、肉豆蔻酸丁酯、棕榈酸异丙酯、硬脂酸乙酯、棕榈酸辛酯、异硬脂酸异鲸蜡酯、硬脂酸丁酯、亚油酸乙酯、亚油酸异丙酯、油酸乙酯、肉豆蔻酸异鲸蜡酯、肉豆蔻酸异硬脂酯、棕榈酸异硬脂酯、肉豆蔻酸辛基十二烷基酯、异硬脂酸异鲸蜡酯、癸二酸二乙酯、己二酸二异丙酯、新戊酸异烷基酯、三(辛酸、癸酸)甘油酯、三羟甲基丙烷三2-乙基己酸酯、三羟甲基丙烷三异硬脂酸酯、季戊四醇四2-乙基己酸酯、辛酸鲸蜡酯、月桂酸癸酯、月桂酸己酯、肉豆蔻酸癸酯、肉豆蔻酸肉豆蔻酯、肉豆蔻酸鲸蜡酯、硬脂酸硬脂酯、油酸癸酯、蓖麻油酸鲸蜡酯、月桂酸异硬脂酯、肉豆蔻酸异十三烷基酯、棕榈酸异鲸蜡酯、硬脂酸辛酯、硬脂酸异鲸蜡酯、油酸异癸酯、油酸辛基十二烷基酯、亚油酸辛基十二烷基酯、异硬脂酸异丙酯、2-乙基己酸鲸蜡硬脂酯、2-乙基己酸硬脂酯、异硬脂酸己酯、二辛酸乙二醇酯、二油酸乙二醇酯、二癸酸丙二醇酯、二(辛酸、癸酸)丙二醇酯、二辛酸丙二醇酯、二癸酸新戊二醇酯、二辛酸新戊二醇酯、三辛酸甘油酯、三十一酸甘油酯、三异棕榈酸甘油酯、三异硬脂酸甘油酯、新戊酸辛基十二烷基酯、辛酸异硬脂酯、异壬酸辛酯、新癸酸己基癸酯、新癸酸辛基十二烷基酯、异硬脂酸异鲸蜡酯、异硬脂酸异硬脂酯、异硬脂酸辛基癸酯、油酸聚甘油酯、异硬脂酸聚甘油酯、柠檬酸三异鲸蜡酯、柠檬酸三异烷基酯、柠檬酸三异辛酯、乳酸月桂酯、乳酸肉豆蔻酯、乳酸鲸蜡酯、乳酸辛基癸酯、柠檬酸三乙酯、柠檬酸乙酰基三乙酯、柠檬酸乙酰基三丁酯、柠檬酸三辛酯、苹果酸二异硬脂酯、羟基硬脂酸2-乙基己酯、琥珀酸二2-乙基己酯、己二酸二异丁酯、癸二酸二异丙酯、癸二酸二辛酯、胆固醇硬脂酸酯、胆固醇异硬脂酸酯、胆固醇羟基硬脂酸酯、胆固醇油酸酯、二氢胆固醇油酸酯、植物甾醇异硬脂酸酯、植物甾醇油酸酯、12-硬脂酰羟基硬脂酸异鲸蜡酯、12-硬脂酰羟基硬脂酸硬脂酰酯、12-硬脂酰羟基硬脂酸异硬脂酯等。
烃脂质可以包括例如角鲨烯、液体石蜡、α-烯烃低聚物、异链烷烃、纯地蜡、石蜡、液体异链烷烃、聚丁烯、微晶蜡、凡士林等。
有机硅脂质可以包括例如聚甲基硅、甲基苯基硅、甲基环聚硅氧烷、八甲基聚硅氧烷、十甲基聚硅氧烷、十二甲基环硅氧烷、二甲基硅氧烷/甲基鲸蜡氧基硅氧烷共聚物、二甲基硅氧烷/甲基硬脂氧基硅氧烷共聚物、烷基改性硅油、氨基改性硅油等。
氟脂质可以包括全氟聚醚等。
动物或植物油可以包括鳄梨油、杏仁油、橄榄油、芝麻油、米糠油、红花油、大豆油、玉米油、油菜花油、杏桃仁油、棕榈仁油、棕榈油、蓖麻油、葵花油、葡萄籽油、棉籽油、椰子油、牛油坚果油、小麦胚芽油、大米胚芽油、乳木果油、月见草油、澳洲坚果油、白芒花籽油、蛋黄油、牛油、大麻籽油、貂油、大西洋胄胸鲷油、荷荷巴油、小烛树蜡、巴西棕榈蜡、液体羊毛脂、脱水蓖麻油等。
保湿剂可以包括水溶性低分子保湿剂、油溶性分子保湿剂、水溶性聚合物、油溶性聚合物等。
水溶性低分子保湿剂可以包括丝氨酸、谷氨酰胺、山梨糖醇、甘露醇、吡咯烷酮-羧酸钠、甘油、丙二醇、1,3-丁二醇、乙二醇、聚乙二醇B(聚合度:n=2或更高)、聚丙二醇(聚合度:n=2或更高)、聚甘油B(聚合度:n=2或更高)、乳酸、乳酸盐等。
油溶性低分子保湿剂可以包括胆固醇、胆固醇酯等。
水溶性聚合物可包括羧乙烯基聚合物、聚天冬酰胺酸盐、黄芪胶、黄原胶、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、水溶性甲壳质、壳聚糖、糊精等。
油溶性聚合物可以包括例如聚乙烯吡咯烷酮/二十碳烯共聚物、聚乙烯吡咯烷酮/十六碳烯共聚物、硝基纤维素、糊精脂肪酸酯、有机硅聚合物等。
润肤剂可以包括例如长链胆固醇酯酰基谷氨酸酯、胆固醇羟基硬脂酸酯、12-羟基硬脂酸、硬脂酸、松香酸、羊毛脂脂肪酸胆固醇酯等。
表面活性剂可以包括例如非离子表面活性剂、阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂等。
非离子表面活性剂可以包括自乳液型单硬脂酸甘油酯、丙二醇脂肪酸酯、甘油脂肪酸酯、聚甘油脂肪酸酯、脱水山梨糖醇脂肪酸酯、聚氧乙烯(POE)脱水山梨糖醇脂肪酸酯、POE山梨糖醇脂肪酸酯、POE甘油脂肪酸酯、POE烷基醚、POE脂肪酸酯、POE脱水蓖麻油、POE蓖麻油、聚氧乙烯/聚氧丙烯(POE/POP)共聚物、POE/POP烷基醚、聚醚改性有机硅、烷醇酰胺月桂酸酯、烷基氧化胺、水合大豆磷脂等。
阴离子表面活性剂可以包括脂肪酸皂、α-酰基磺酸盐、烷基磺酸盐、烷基烯丙基磺酸盐、烷基萘磺酸盐、烷基硫酸盐、POE烷基醚硫酸盐、烷基酰胺硫酸盐、烷基磷酸盐、POE烷基磷酸盐、烷基酰胺磷酸盐、烷酰基烷基牛磺酸盐、N-酰基氨基酸盐、POE烷基醚羧酸盐、烷基磺基琥珀酸盐、烷基磺基乙酸钠、酰化水解胶原肽盐、全氟烷基酯磷酸盐等。
阳离子表面活性剂可以包括,例如,烷基三甲基氯化铵、硬脂基三甲基氯化铵、硬脂基三甲基溴化铵、鲸蜡硬脂基三甲基氯化铵、二硬脂基二甲基氯化铵、硬脂基芳基二甲基苄基氯化铵、二十二烷基三甲基溴化铵、苯扎氯铵、二乙基氨基乙基酰胺硬脂酸酯、二甲基氨基丙基酰胺硬脂酸酯、羊毛脂衍生物的季铵盐等。
两性表面活性剂可以包括羧基甜菜碱、酰胺甜菜碱、磺基甜菜碱、羟基磺基甜菜碱、酰胺磺基甜菜碱、磷酸甜菜碱、氨基羧酸盐、咪唑啉衍生物、基于酰胺胺的两性表面活性剂等。
有机和无机颜料可以包括:无机颜料,例如硅酸、无水硅酸、硅酸镁、滑石、绢云母、云母、高岭土、三氧化二铁、粘土、膨润土、二氧化钛涂覆的云母、氯氧化铋、氧化锆、氧化镁、氧化锌、氧化钛、氧化铝、硫酸钙、硫酸钡、硫酸镁、碳酸钙、碳酸镁、氧化铁、群青、氧化铬、氢氧化铬、炉甘石及它们的组合;有机颜料,例如聚酰胺、聚酯、聚丙烯、聚苯乙烯、聚氨酯、乙烯基树脂、脲醛树脂、酚树脂、氟树脂、硅树脂、丙烯酸树脂、三聚氰胺树脂、环氧树脂、聚碳酸酯树脂、二乙烯基苯/苯乙烯共聚物、丝粉、纤维素、CI颜料黄和CI颜料橙;以及无机和有机颜料的复合颜料。
有机粉末可以包括:金属皂,例如硬脂酸钙;烷基磷酸的金属盐,例如鲸蜡酸锌钠、月桂酸锌和月桂酸钙;酰基氨基酸的多金属盐,例如N-月桂酰-β-丙氨酸钙、N-月桂酰-β-丙氨酸锌和N-月桂酰甘氨酸钙;酰胺磺酸的多金属盐,例如N-月桂酰牛磺酸钙和N-棕榈酰牛磺酸钙;N-酰基碱性氨基酸,例如N-ε-月桂酰-L-赖氨酸、N-ε-棕榈酰赖氨酸、N-α-棕榈酰鸟氨酸、N-α-月桂酰精氨酸、N-α-脱水牛脂脂肪酸酰基精氨酸;N-酰基多肽,例如N-月桂酰甘氨酰甘氨酸;α-氨基脂肪酸,例如α-氨基辛酸和α-氨基月桂酸;聚乙烯;聚丙烯;尼龙;聚甲基丙烯酸甲酯;聚苯乙烯;二乙烯基苯/苯乙烯共聚物;四氟化乙烯;等。
UV吸收剂可以包括对氨基苯甲酸、对氨基苯甲酸乙酯、对氨基苯甲酸戊酯、对氨基苯甲酸辛酯、水杨酸乙二醇酯、水杨酸苯酯、水杨酸辛酯、水杨酸苄酯、水杨酸丁基苯酯、水杨酸高孟酯、肉桂酸苄酯、对甲氧基肉桂酸-2-乙氧基乙基酯、对甲氧基肉桂酸辛酯、二对甲氧基肉桂酸单-2-乙基己烷甘油酯、对甲氧基肉桂酸异丙酯、二异丙基/二异丙基肉桂酸酯混合物、尿刊酸、尿刊酸乙酯、羟基甲氧基二苯甲酮、羟基甲氧基二苯甲酮磺酸及其盐、二羟基甲氧基二苯甲酮、二羟基甲氧基二苯甲酮二磺酸钠、二羟基二苯甲酮、四羟基二苯甲酮、4-叔丁基-4'-甲氧基二苯甲酰甲烷、2,4,6-三苯胺基-p-(碳-2'-乙基己基-1'-氧基)-1,3,5-三嗪、2-(2-羟基-5-甲基苯基)苯并三唑等。
消毒剂可以包括扁柏酚、三氯酸、三氯羟基二苯醚、葡萄糖酸氯己定、苯氧乙醇、间苯二酚、异丙基甲基苯酚、甘菊环、水杨酸、吡啶硫酮锌、苯扎氯铵、光敏元件No.301、单硝基愈创木酚钠、十一碳烯酸等。
抗氧化剂可以包括丁基羟基茴香醚、没食子酸丙酯、异抗坏血酸等。
pH调节剂可以包括柠檬酸、柠檬酸钠、苹果酸、苹果酸钠、富马酸、富马酸钠、琥珀酸、琥珀酸钠、氢氧化钠、磷酸氢二钠等。
醇可以包括高级醇,例如鲸蜡醇。
另外,要混合的附加成分不限于上述实例,并且上述成分中的任何一种可以在不会不利地影响本发明的目的和效果的范围内混合,但相对于组合物的总重量,其范围可以为0.01wt%至5wt%或0.01wt%至3wt%。
对于本发明的洗剂、糊剂、霜剂或凝胶制剂,作为载体成分,可以使用动物纤维、植物纤维、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅、膨润土、二氧化硅、滑石、氧化锌等。
对于本发明的粉剂或喷雾制剂,可以使用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末作为载体成分。特别地,在喷雾制剂的情况下,组合物可以还包含喷射剂,例如氯氟烃、丙烷/丁烷或二甲醚。
对于本发明的溶液剂或乳剂制剂,可以使用溶剂、增溶剂或乳化剂作为载体成分,并且载体成分可以是例如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、甘油脂肪族酯、聚乙二醇或脱水山梨糖醇脂肪酸酯。
对于本发明的混悬剂制剂,作为载体成分,可以使用液体稀释剂如水、乙醇或丙二醇,助悬剂如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇酯或聚氧乙烯脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、黄芪胶等。
对于本发明的含有表面活性剂的清洁制剂,作为载体成分,可以使用脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉鎓衍生物、甲基牛磺酸盐、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物、乙氧基化甘油脂肪酸酯等。
[发明方式]
下面,将提出有助于理解本发明的优选实施例。然而,提供以下实施例只是为了更容易理解本发明,并且本发明的内容不限于以下实施例。
[实施例]
实施例1.鼠李糖乳杆菌来源的囊泡的分离
为了分离鼠李糖乳杆菌来源的细胞外囊泡(EV),将鼠李糖乳杆菌菌株接种到自行开发的培养基中并在厌氧环境中培养。在37℃进行静置培养直至吸光度(OD600nm)达到1.0至1.5后,再次接种到培养基中进行培养。然后,回收含有细菌细胞的培养基,并且在4℃以13,000g离心15分钟,得到除去了细菌细胞的上清液。使用0.22μm过滤器再次过滤获得的上清液,并使用100kDa Pellicon 2Cassette滤膜(Merck Millipore)和MasterFlex泵系统(Cole-Parmer)将过滤后的上清液浓缩至50mL或更小体积。将浓缩的上清液再次通过0.22μm过滤器过滤以分离鼠李糖乳杆菌来源的囊泡(MDH-003)。在下述实施例中,使用分离的囊泡进行实验。
实施例2.鼠李糖乳杆菌来源的囊泡在患有营养过剩诱导的细胞衰老相关疾病的
小鼠中的治疗效果
肥胖是由于营养过剩而发生的,并且在肥胖(一种低水平的全身慢性炎症状态)中,因营养过剩而在体内产生异常代谢物,分泌炎性介质,从而引起慢性炎症。此外,由于在能量代谢应激情况下维持细胞稳态的AMPK信号传导因营养过剩而受到抑制,从而促进细胞衰老,可能会发生细胞衰老相关疾病。特别是,许多研究结果表明,肥胖是涉及哮喘发生和肺功能下降的危险因素。因此,按照以下方式进行实验以评估鼠李糖乳杆菌来源的囊泡(MDH-003)在高脂肪饮食诱导营养过剩的小鼠中的治疗效果。
具体而言,在通过向BALB/c 6周龄雌性小鼠饲喂高脂饮食(Harlan,调整的热量饮食)22周诱导肥胖后,第23周至第26周连续饲喂高脂肪饮食4周,同时以50μg的剂量每周4次经口施用鼠李糖乳杆菌来源的囊泡,以进行鼠李糖乳杆菌来源的囊泡的功效评估(参见图1)。
2-1.体重减轻效果的确认
在第24周至第27周测量高脂肪饮食小鼠的体重。
结果,如图2所示,从第26周开始,与肥胖组(Obese)相比,在鼠李糖乳杆菌来源的囊泡施用组(MDH-003)观察到体重减轻效果。
2-2.肾功能改善效果的确认
通过检测血清中的血尿素氮(BUN)和肌酐(Cr)水平来评估肾功能,这是肾脏损伤的标志。
使用目前市售的测定试剂盒(Pointe Scientific,Lincoln Park,MI)测量血清中的肌酐和BUN。
如图3a和3b所示,在饲喂高脂肪饮食27周的小鼠中BUN和Cr水平增加,并且在施用鼠李糖乳杆菌来源的囊泡的组中,恢复了由高脂肪饮食诱导的肾功能障碍,即肾损伤。
2-3.肺功能改善效果的确认
评估了高脂肪饮食引起的肺功能变化。具体来说,使用flexiVent(SCIREQ,Canada)测量气道高反应性(AHR)。这是一种侵入性方法,其中在小鼠处于麻醉状态时,根据乙酰甲胆碱浓度(0、5、10、25、50mg/ml)的变化来测量气道阻力(Rrs)值。通过在小鼠吸入乙酰甲胆碱之前喷洒0.9%盐水溶液10秒来测量小鼠的基础对照气道高反应性,并且为了确定对乙酰甲胆碱的气道反应的差异,通过使用超声波雾化器增加每只小鼠的乙酰甲胆碱浓度来进行测量。施用不同浓度乙酰甲胆碱后,对Rrs值测量3分钟,并且使用平均值。气道功能的变化程度表示为基于吸入0.9%盐水溶液后获得的基线Rrs值的差异的百分比。
如图4所示,与阴性对照组相比,肥胖组中的气道高反应性增加,并且确认了该增加的气道高反应性在施用鼠李糖乳杆菌来源的囊泡的组中得到了改善。
从上述结果可以看出,鼠李糖乳杆菌来源的囊泡可以有效治疗因营养过剩导致的细胞衰老加速而引起的肾功能障碍和肺功能障碍。
实施例3.鼠李糖乳杆菌来源的囊泡对患有营养过剩诱导的细胞衰老相关疾病的
小鼠的免疫功能调节作用
免疫可分为先天性免疫和适应性免疫,当响应于外部或内部因素而疫功能异常时,就会发生疾病。特别地,在获得性免疫反应中很重要T细胞通过分泌细胞因子诱导免疫疾病。特别地,Th17细胞主要分泌IL-17、IL-6等,从而诱导以中性粒细胞性炎症为特征的炎症性疾病,而Th2细胞分泌IL-4、IL-5等,从而诱导以嗜酸性粒细胞性炎症为特征的炎症性疾病。
因此,评估了鼠李糖乳杆菌来源的囊泡对由Th17和Th2细胞引起的过敏反应的治疗效果。具体地,如实施例2的方法,将鼠李糖乳杆菌来源的囊泡经口施用给通过高脂肪饮食诱导营养过剩的小鼠,并且通过使用酶联免疫吸附测定(ELISA,R&D Systems)方法测量气道灌洗液中Th17和Th2相关细胞因子(IL-17、IL-4和IL-5)的水平。对于ELISA分析,将捕获抗体在PBS中稀释,并将所得溶液根据工作浓度以各50μl的体积分配至96孔聚苯乙烯板,并在4℃反应过夜。用100μl PBST(含有0.05% Tween-20的PBS)溶液洗涤2次后,分配100μlRD(含有1% BSA的PBST)溶液,以在室温封闭1小时。再次用100μl PBST洗涤两次后,根据浓度分别分配样品和标准品各50μl,并在室温反应2小时。再次用100μl PBST洗涤两次后,将检测抗体在RD中稀释,根据工作浓度分配各50μl,并在室温反应2小时。再次用100μl PBST洗涤两次后,将链霉亲和素-HRP在RD中稀释1/200,以各50μl的体积分配,并在室温反应30分钟。最后,用100μl PBST洗涤3次后,分配50μl的TMB底物与0.04%过氧化氢的1:1混合物,然后经过足够的时间进行显色。当显色进行5至20分钟时,分配50μl 1M硫酸溶液以终止反应,并使用SynergyTMHT多重检测酶标仪(BioTek,USA)在450nm处测量吸光度。
结果,如图5a和5b所示,与正常营养状态的小鼠相比,肥胖组的气道灌洗液中的IL-17(Th17细胞因子)以及IL-4和IL-5(Th2细胞因子)显著增加。另一方面,在施用鼠李糖乳杆菌来源的囊泡的组中,气道灌洗液中的Th17和Th2细胞因子的水平降低至正常水平。
通过上述结果可以看出,鼠李糖乳杆菌来源的囊泡有效地抑制和改善了由营养过剩诱导的免疫功能障碍。
实施例4.鼠李糖乳杆菌来源的囊泡对维持细胞稳态以抵抗能量代谢应激的治疗
效果
细胞衰老被定义为由于重复的物理、化学、生物和精神应激而导致细胞分裂能力丧失,以及由于重复应激而导致的细胞衰老,随着细胞再生能力的降低而发生细胞衰老和衰老相关疾病。特别是,在ATP产生较少的代谢应激情况下,细胞激活AMPK蛋白作为细胞内信号传导通路,从而诱导细胞代谢稳态并抑制细胞衰老和凋亡。
因此,以如下方式进行实验以评估鼠李糖乳杆菌来源的囊泡(MDH-003)通过细胞内的AMPK激活对细胞衰老的影响。即,为了根据肌肉细胞中鼠李糖乳杆菌来源的囊泡的浓度来评估AMPK活性,用鼠李糖乳杆菌来源的囊泡以0、0.1、1和10μg/ml的浓度处理细胞1小时。作为对照组,以10μg/ml的浓度使用抑制衰老的二甲双胍。用药物处理细胞后,通过蛋白质印迹法测量pAMPK量的差异,pAMPK是AMPK信号传导的重要指标。
结果,如图6所示,在鼠李糖乳杆菌来源的囊泡处理的情况下,与二甲双胍类似地增强AMPK的磷酸化(pAMPK),并且该效果根据本发明的囊泡的浓度而增强。
通过上述结果可以看出,鼠李糖乳杆菌来源的囊泡通过激活AMPK信号传导来增强细胞稳态以抵抗代谢应激,从而增强细胞活力并预防衰老。
实施例5.鼠李糖乳杆菌来源的囊泡在由病毒致病因素poly(I:C)诱导的免疫疾病
的小鼠模型中的炎症抑制作用
Poly(I:C)是一种人工合成的双结构核糖核苷酸聚合物,其在结构上与某些病毒中存在的dsRNA相似,激活多种炎症信号传导途径,从而引起病毒感染性疾病。
因此,以如下方式进行实验以评估鼠李糖乳杆菌来源的囊泡在由病毒致病因素诱导的免疫疾病模型中的治疗效果。即,如图7所示,通过每隔一天给C57BL/6 6周龄雄性小鼠鼻内施用病毒致病因素poly(I:C)持续2周来产生免疫疾病小鼠模型。从施用poly(I:C)前6天开始,每隔一天经口施用鼠李糖乳杆菌来源的囊泡,持续2周。作为对照药物,以2mg/kg的剂量腹膜内施用地塞米松。
5-1.炎性细胞增加减少效果的确认
施用后,获得来自小鼠的气道灌洗液,并评估炎性细胞的数量。
结果,如图8a和8b所示,观察到气道灌洗液中炎性细胞数量的变化。结果,在施用poly(I:C)的情况下,气道灌洗液中的炎性细胞的数量增加,特别是巨噬细胞和淋巴细胞的数量增加。同时,与地塞米松(Dex)治疗类似,鼠李糖乳杆菌来源的囊泡显著抑制了由poly(I:C)增加的气道灌洗液中炎性细胞的数量。
5-2.肺组织损伤减轻效果的确认
通过苏木精和伊红(H&E)染色评估肺组织的变化。
如图9a所示,在正常组的肺组织中观察到均匀的小尺寸肺泡,而在poly(I:C)施用组中,观察到许多细胞聚集在肺泡周围。另外,在用地塞米松治疗的组和施用鼠李糖乳杆菌来源的囊泡的组中,肺泡的形状保持相对均匀。
另外,如图9b所示,证实了气道周围的免疫细胞的浸润减少。
5-3.全身炎症性反应抑制效果的确认
通过血液高敏C反应蛋白(hsCRP)水平评估病毒致病因素引起的全身炎症性反应。CRP是一种急性期反应蛋白,已被用作全身炎症性反应的标志物,而hsCRP并不是心血管疾病的简单标志物,而是独立的危险因素。与标准CRP测试相比,hsCRP测试可以更准确地检测较低浓度的蛋白质。人们普遍认为,hsCRP通过加速血管内皮细胞功能障碍和促进血栓形成等作用,在动脉硬化及其引起的并发症的发生中发挥重要作用。在本实施例中,使用免疫比浊测定法测量hsCRP浓度。
如图10所示,鼠李糖乳杆菌来源的囊泡降低了hsCRP水平。
通过上述结果可以看出,由poly(I:C)诱导的全身炎症性反应和肺部疾病可以被鼠李糖乳杆菌来源的囊泡有效治疗。
实施例6.鼠李糖乳杆菌来源的囊泡在由病毒致病因素poly(I:C)诱导的免疫疾病
的小鼠模型中的免疫调节作用
6-1.气道灌洗液中炎性细胞因子分泌的确认
炎性细胞分泌的TNF-α和IL-6是代表性的炎性介质,诱发致病因素引起的炎症性疾病。在本实施例中,以如下方式进行实验,以评估鼠李糖乳杆菌来源的囊泡对由病毒致病因素引起的免疫功能障碍的免疫调节作用。即,在实施例5所述的免疫疾病小鼠模型中,通过ELISA法测量气道灌洗液中的炎性细胞因子TNF-α和IL-6。使用上述ELISA方法。
结果,如图11a和11b所示,与阴性对照(NC)组相比,poly(I:C)施用组的气道灌洗液中的TNF-α和IL-6浓度增加。另一方面,在施用鼠李糖乳杆菌来源的囊泡的组中,通过poly(I:C)增加的TNF-α和IL-6的分泌显著减少至阴性对照组的水平,并且与地塞米松施用组(Dexa)相比,抑制效果更好。
6-2.脾T细胞的炎性细胞因子分泌的确认
通过评估脾T细胞中的细胞因子分泌模式,评估鼠李糖乳杆菌来源的囊泡对poly(I:C)引起的全身免疫功能障碍的治疗效果。
如图12a和12b所示,与阴性对照组相比,在poly(I:C)施用组中,Th1细胞因子IFN-γ和Th17细胞因子IL-6的分泌增加。另一方面,鼠李糖乳杆菌来源的囊泡显著抑制了IFN-γ和IL-6水平的增加。同时,地塞米松(Dexa)无效。
通过上述结果可以看出,鼠李糖乳杆菌来源的囊泡能够有效抑制由病毒致病因素引起的免疫功能障碍,并且比常规免疫抑制剂地塞米松具有更优异的治疗效果。
实施例7.鼠李糖乳杆菌来源的囊泡调节病毒致病因素poly(I:C)引起的免疫功能
障碍的分子生物学作用机制的确认
作为核转录因子的核因子-κB(NF-κB)是一种炎症调节因子,其诱导诱导型一氧化氮合酶(iNOS)的转录并增加各种促炎细胞因子的分泌。
因此,为了评估鼠李糖乳杆菌来源的囊泡通过NF-κB激活对炎症性反应的影响,利用小鼠肺组织通过蛋白质印迹法进行了实验。
如图13所示,在施用poly(I:C)的情况下,NF-κB的磷酸化(p-NF-κB、p-p65)和iNOS表达增加。此外,poly(I:C)增加的NF-κB磷酸化(p-NF-κB、p-p65)受到地塞米松(Dex)和鼠李糖乳杆菌来源的囊泡的抑制。另外,与地塞米松相比,在施用鼠李糖乳杆菌来源的囊泡的情况下,由poly(I:C)增加的iNOS表达被更有效地抑制。
通过上述结果可以看出,鼠李糖乳杆菌来源的囊泡有效抑制NF-κB信号(由致病因素引起的免疫功能障碍的关键)及其下游信号iNOS的表达,以控制由病毒致病因素引起的免疫超敏反应。
通过上述结果,证实了本发明的鼠李糖乳杆菌来源的囊泡不仅能够通过AMPK信号传导增加细胞稳态来抑制细胞衰老和细胞凋亡,而且还可以通过抑制NF-κB信号传导来抑制由生物致病因素引起的免疫功能障碍,从而有效治疗免疫疾病和细胞衰老相关疾病(参见图14)。因此,预期本发明的鼠李糖乳杆菌来源的囊泡可用于减轻、预防或治疗与免疫功能障碍和细胞衰老相关疾病。
以上对本发明的描述只是为了说明的目的,应当理解,本领域的普通技术人员可以很容易地将本发明修改为其它具体形式而不改变本发明的技术构思或本质特征。因此,上述实施方案在所有方面都应当被理解为说明性的而非限制性的。
[工业实用性]
根据本发明的鼠李糖乳杆菌来源的囊泡可以抑制体重增加,改善肾功能和肺功能,并且激活AMPK(诱导细胞稳态的关键信号),抑制全身炎症性反应,并显著抑制免疫超敏反应引起的肺部炎症。因此,其具有工业实用性,因为其可以有效地用于开发用于预防、减轻或治疗免疫疾病(包括病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病)以及细胞衰老相关疾病的药物或健康功能食品。
Claims (24)
1.一种用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的药物组合物,包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
2.根据权利要求1所述的药物组合物,其中所述免疫疾病是选自由病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病组成的组中的一种或多种。
3.根据权利要求2所述的药物组合物,其中所述病毒感染性疾病是选自由病毒性肺炎、病毒性肝炎、病毒性心脏炎、病毒性肠炎、病毒性肾炎、病毒性血栓栓塞、带状疱疹和梅尼埃病组成的组中的一种或多种。
4.根据权利要求2所述的药物组合物,其中所述自身免疫性疾病是选自由系统性红斑狼疮、类风湿性关节炎、干燥综合征、白塞病、强直性脊柱炎和多发性硬化症组成的组中的一种或多种。
5.根据权利要求2所述的药物组合物,其中所述过敏性免疫疾病是选自由特应性皮炎、银屑病、过敏性结膜炎、过敏性鼻炎、过敏性哮喘、超敏性肺炎、食物过敏、乳糜泻、肠易激综合征和过敏反应组成的组中的一种或多种。
6.根据权利要求1所述的药物组合物,其中所述细胞衰老相关疾病是选自由以下组成的组中的一种或多种:
选自由心绞痛、心肌梗死、心肌病、血栓栓塞和中风组成的组中的一种或多种心血管疾病;
选自由酒精性脂肪性肝炎、肝硬化、慢性胆管炎、慢性胆囊炎和慢性胰腺炎组成的组中的一种或多种肝胆胰疾病;
选自由痛风、骨关节炎和骨质疏松症组成的组中的一种或多种肌肉骨骼疾病;和
选自由阿尔茨海默病、帕金森病和黄斑变性组成的组中的一种或多种神经性疾病。
7.根据权利要求1所述的药物组合物,其中所述囊泡具有10至1000nm的平均直径。
8.根据权利要求1所述的药物组合物,其中所述囊泡是从鼠李糖乳杆菌的培养基中分离的。
9.根据权利要求1所述的药物组合物,其中所述囊泡是从通过添加鼠李糖乳杆菌制备的食品中分离的。
10.根据权利要求1所述的药物组合物,其中所述囊泡由鼠李糖乳杆菌天然分泌或人工产生。
11.一种用于预防或减轻选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的食品组合物,包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
12.根据权利要求11所述的食品组合物,其中所述免疫疾病是选自由病毒感染性疾病、过敏性免疫疾病和自身免疫性疾病组成的组中的一种或多种。
13.根据权利要求11所述的食品组合物,其中所述囊泡是从鼠李糖乳杆菌的培养基中分离的。
14.根据权利要求11所述的食品组合物,其中所述囊泡是从通过添加鼠李糖乳杆菌制备的食品中分离的。
15.根据权利要求11所述的食品组合物,其中所述囊泡由鼠李糖乳杆菌天然分泌或人工产生。
16.一种用于预防或治疗衰老的药物组合物,包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
17.一种用于预防或减轻衰老的食品组合物,包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
18.一种用于预防或减轻衰老的化妆品组合物,包含来源于鼠李糖乳杆菌的囊泡作为活性成分。
19.一种用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的方法,所述方法包括向有此需要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
20.包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的用途。
21.来源于鼠李糖乳杆菌的囊泡在制备用于治疗选自由免疫疾病和细胞衰老相关疾病组成的组中的一种或多种的治疗剂中的用途。
22.一种用于预防或治疗衰老的方法,所述方法包括向有此需要的受试者施用包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物。
23.包含来源于鼠李糖乳杆菌的囊泡作为活性成分的组合物用于预防或治疗衰老的用途。
24.来源于鼠李糖乳杆菌的囊泡在制备用于治疗衰老的治疗剂中的用途。
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KR10-2021-0173139 | 2021-12-06 | ||
PCT/KR2022/007768 WO2022255784A1 (ko) | 2021-06-03 | 2022-05-31 | 락토바실러스 람노수스 유래 소포 및 이의 용도 |
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