CN114615898A - 利用植物乳杆菌菌株等的呼吸系统疾病改善用组合物 - Google Patents
利用植物乳杆菌菌株等的呼吸系统疾病改善用组合物 Download PDFInfo
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- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及一种利用植物乳杆菌KF511菌株、柳兰提取物或者茵陈蒿提取物的呼吸系统功能强化以及呼吸系统疾病改善用食品组合物;含有所述食品组合物的保健食品;以及作为有效成分含有茵陈蒿提取物的呼吸系统疾病预防或治疗用药物组合物。本发明的植物乳杆菌(lactobacillusplantarum)KF511菌株、柳兰提取物或者茵陈蒿提取物具有在利用人的呼吸系统上皮细胞(H292)的黏液高分泌模型中抑制MUC5AC的分泌,抑制中性粒细胞胞外诱捕网的Netosis激活,抑制支气管上皮细胞株NCI‑H292细胞因CSE的炎症细胞因子的表达,进一步地,在通过CSE和PPE诱导的呼吸系统疾病小鼠模型中抑制肺组织损伤,抑制BALF内总细胞、巨噬细胞、淋巴细胞、嗜酸性粒细胞、中性粒细胞等的免疫细胞浸润,在BALF以及肺组织中抑制炎症细胞因子和趋化因子的分泌的活性。
Description
技术领域
本发明涉及利用植物乳杆菌(lactobacillus plantarum)KF511菌株、柳兰(Epilobium angustifolium L.)提取物或者茵陈蒿(Artemisia capillaries Thunb.)提取物的呼吸系统功能强化以及呼吸系统疾病改善用食品组合物;含有所述食品组合物的保健食品;以及作为有效成分含有茵陈蒿提取物的呼吸系统疾病预防或治疗用药物组合物。
背景技术
支气管哮喘是以可逆性呼吸道梗阻、呼吸道过敏(呼吸道阻碍的增加)、黏液的过度分泌、血清中IgE数值高为特征的过敏性疾病。当通过吸入到呼吸道内的多个抗原而受到刺激的TH2(T helper 2)型免疫细胞生成IL-4、5、13等时,T细胞、嗜酸性粒细胞、肥大细胞等的炎症细胞发生增殖、分化以及激活,从而向呼吸道和呼吸道周围组织移动、浸润,因此,也被认为是慢性炎症疾病(J Clin Invest,11:291-297,2003;N Engl J.Med.2001;44(5):350-62;Toshio Hirano,Cytokine molecular biology,World Science,2002)。因此,在哮喘治疗剂的开发中,抑制嗜酸性粒细胞等炎症细胞的浸润等成为重要目标之一。
慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)作为伴随咳嗽、咳痰、呼吸困难、呼气流速下降、气体交换障碍等的慢性呼吸道疾病,每年全世界发病人口数在增加,而且预测到2020年可能会成为人类死亡原因中的第三种原因(Am J RespirCrit Care Med,2013,187:347-365;Am J Respir Crit Care Med,2009,180:396-406)。
COPD是因吸烟、大气污染、化学物质、职业因素、基因因素等各种原因而发病,其中吸烟被指认为是重要的原因,实际上有报告指出COPD患者的80%以上为吸烟人士(BiolPharm Bull,2012,35:1752-1760)。炎症、肺中的蛋白分解酶的激活、氧化应激(oxidativestress)等参与到COPD的发病机制中,而且参与炎症的细胞主要是中性粒细胞、巨噬细胞、T淋巴细胞等。所述炎症细胞生成活性氧簇(reactive oxygen species)、各种炎症细胞因子、引起组织损伤的各种蛋白分解酶(大韩民国肺结核以及呼吸系统学会呼吸系统学首尔:KOONJA出版社;2007,p301-5;Am J Respir Crit Care Med,1997155,1441-1447;Am JPhysiol Lung CellMol Physiol,2010,298:L262-L269)。尤其是,已知中性粒细胞向细胞外分泌弹性蛋白酶、胶原酶、MPO(髓过氧化物酶;myeloperoxidase)之类的蛋白质分解酶(proteasses)、花生四烯酸代谢物(arachidonate)、活性氧簇(reactive oxygen freeradical)等的物质,引起肺损伤,从而在COPD发病中起到重要作用,因此,在COPD治疗剂的开发中成为重要目标(Am J Respir Cell Mol Biol,2013,48:531-539;Eur Respir J,1998,12:1200-1208)。
最近,有报告指出中性粒细胞胞外诱捕网(Neutrophil extracellular traps)的Netosis激活参与到COPD在内的慢性肺/呼吸系统疾病的发病机制中(PLoS One.2014May15;9(5):e97784;Respir Res.2015May 22;16:59.;J Immunol Res.2017;2017:6710278;Respirology.2016Apr;21(3):467-75)。
目前,作为用于观察COPD、哮喘等疾病的进展过程等的手段,利用支气管肺泡灌洗术(bronchoalveolar lavage:BAL),在支气管肺泡灌洗术(bronchoalveolar lavage:BAL)内,炎症细胞因子、活性氧簇、白三烯、活化补体等炎症介质物质增加,而且在正常肺中占据不足5%的中性粒细胞增加到能够占据整个细胞的80%的程度(Am J Respir Crit CareMed 154(1):76-81,1996)。
目前为止,尚未有报告指出直接改善COPD或者哮喘的药物,作为目前的COPD或者哮喘治疗剂,主要使用支气管松弛剂(β2-作用剂、抗胆碱剂、methylxanthines(甲基黄嘌呤))和类固醇剂(吸入、口服)等来降低症状和并发症。
发明内容
技术问题
本发明的目的在于,提供作为有效成分含有植物乳杆菌(lactobacillusplantarum)KF511菌株、其培养液、其浓缩液或者其干燥物;柳兰(Epilobiumangustifolium L.)提取物;或者茵陈蒿(Artemisia capillaries Thunb.)提取物的呼吸系统功能强化以及呼吸系统疾病改善用食品组合物、含有所述组合物的保健食品。
本发明的另一目的在于,提供一种作为有效成分含有植物乳杆菌(lactobacillusplantarum)KF511菌株、其培养液、其浓缩液或者其干燥物;柳兰提取物或者茵陈蒿提取物的呼吸系统疾病预防或治疗用药物组合物。
技术方案
具体说明为如下。一方面,在本申请中公开的各个说明以及实施形态也可以各自应用到其他说明以及实施形态中。即,在本申请中公开的各种因素的所有组合属于本申请的范畴。另外,不应视为本申请的范畴受以下说明的具体叙述的限制。
如在以下的实施例以及实验例中所确认,本发明人确认到植物乳杆菌(lactobacillus plantarum)KF511菌株、柳兰(Epilobium angustifolium L.)提取物或者茵陈蒿(Artemisia capillaries Thunb.)提取物具有抑制通过PMA(佛波酯;phorbolmyristate acetate)诱导的中性粒细胞胞外诱捕网(Neutrophil extracelluLar traps)的Netosis激活,抑制作为支气管上皮细胞株的NCI-H292细胞因CSE(香烟烟雾提取物;Cigarette Smoke Extraction)的炎症细胞因子的表达,进一步地,在通过CSE和PPE诱导的呼吸系统疾病小鼠模型中抑制肺组织损伤,抑制BALF(支气管肺泡灌洗液)内总细胞(Totalcell)、巨噬细胞(macrophages)、淋巴细胞(Lymphocytes)、嗜酸性粒细胞(Eosinophil)、中性粒细胞(Neutrophil)等的免疫细胞浸润,在BALF以及肺组织中抑制炎症细胞因子和趋化因子的分泌的活性,由此完成了本发明。
为了达成所述目的,本发明的一实施方式为,提供作为有效成分含有植物乳杆菌(lactobacillus plantarum)KF511菌株、其培养液、其浓缩液或者其干燥物;柳兰提取物或者茵陈蒿提取物的呼吸系统功能强化以及呼吸系统疾病改善用食品组合物;以及含有所述组合物的保健食品。
在本发明中,术语“植物乳杆菌(lactobacillus plantarum)”是指,从各种发酵食品以及人的肠道中经常发现的乳杆菌属微生物,其属于革兰氏阳性菌。已知植物乳杆菌具有乳酸菌中最大的基因组(genome),生长以及增殖中需要的合适pH为3.4至8.8,合适温度范围为12℃至40℃。
在本发明中,所述植物乳杆菌菌株具体可以是“植物乳杆菌KF511”,更加具体为,可以是以保藏号KCCM 12573P保藏的菌株。所述菌株作为从发酵食品的泡菜分离以及鉴定的菌株,用于培养该菌株的培养基组分为MRS培养基,培养条件为pH6.5±0.2,在温度37℃下以及搅拌培养24小时,对氧的要求性为兼性厌氧菌,可以冷冻干燥保存或者通过细胞悬浮液冷冻进行菌株保存。一方面,本发明的植物乳杆菌KF511菌株具有1499kb长度的16srDNA序列(序列号1)。
本发明的所述植物乳杆菌KF511菌株是于2019年8月21日寄存到作为布达佩斯条约下的国际保藏机关的韩国微生物保存中心(KCCM),并得到保藏号KCCM 12573P。
在本申请中,术语“培养液”或者“培养物”是指,含有在培养基培养菌株,从而菌株摄入营养成分,并通过物质代谢产生的副产物或者菌株等的培养基,具体可以是植物乳杆菌KF511菌株的培养液或者培养物。另外,所述培养基的浓缩液或者稀释液、干燥所述培养基得到的干燥物、所述培养基的粗提纯物或者提纯物,或者其混合物也可以作为有效成分包含在本发明的组合物内。
在本发明中,术语“柳兰(Epilobium angustifolium L.)”作为双子叶植物桃金娘目柳叶菜科的多年本草植物,又被称作铁筷子、火烧兰。根茎等作为药用而出名,但是完全没有报告指出柳兰提取物或者分馏物对呼吸系统功能的强化、对呼吸系统疾病的改善、预防或治疗的活性。
在本发明中,术语“茵陈蒿(Artemisia capillaries Thunb.)”作为双子叶植物桔梗目菊科的多年本草植物,又被称作猪毛蒿、因陈蒿。公知嫩苗可食用且将整颗作为利尿剂来使用或者对黄疸有效果,但是完全没有报告指出茵陈蒿提取物或者分馏物对呼吸系统功能的强化、对呼吸系统疾病的改善、预防或治疗的活性。
在本发明中,术语“提取物”是指,将作为提取对象的植物,即柳兰或者茵陈蒿的茎、叶、果实、花朵、根、其混合物等使用水、碳原子数1至4的低级醇(甲醇、乙醇、丁醇等)、二氯甲烷、乙烯、丙醇、己烷、醚、氯仿、乙酸乙酯、乙酸丁酯、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、1,3-丁二醇、丙二醇或者其混合溶剂浸出而得到的提取物、使用二氧化碳、戊烷等超临界提取溶剂来得到的提取物或者分馏该提取物来得到的分馏物,提取方法可以是考虑活性物质的极性、提取物程度、保存程度而使用冷浸、回流、加温、超声波辐射、超临界提取等任意的方法。分馏的提取物表示包括将提取物悬浮到特定溶剂之后,与极性不同的溶剂进行混合·静置来得到的分馏物、将所述粗提取物吸附到填充有二氧化硅凝胶等的色谱柱之后,将疏水性溶剂、亲水性溶剂或者其混合溶剂作为移动相来得到的分馏物。另外,在所述提取物的含义中包括通过冷冻干燥、真空干燥、热风干燥、喷雾干燥等的方式去除提取溶剂的浓缩的液态提取物或者固态提取物。优选为,是指作为提取溶剂使用水、乙醇或者其混合溶剂来得到的提取物,更加优选为,是指作为提取溶剂使用水和乙醇的混合溶剂来得到的提取物。
在本发明中,术语“有效成分”是指能够单独显示所希望的活性或者其本身与没有活性的载体等一起显示所希望的活性的成分。
在本发明中,术语“呼吸系统功能强化”是指,以健康的状态维持鼻腔、咽头、喉头、气管、支气管以及肺等呼吸器官的原有功能,或者将因吸烟、微尘、中性粒细胞的Netosis激活或者其他呼吸系统疾病等的症状而降低的呼吸器官的功能改善为原有健康状态的所有行为。
另外,在本发明中,术语“呼吸系统疾病”是指,在鼻腔、咽头、喉头、气管、支气管以及肺等个体的呼吸器官中发生的疾病,具体为,所述呼吸系统疾病可以是指吸烟或者微尘引起的呼吸系统疾病;或者伴随Netosis的肺疾病,但不限于此。更加具体为,所述呼吸系统疾病可以是指伴随咳痰、呼吸困难、呼吸道过敏、呼吸道梗阻、黏液高分泌、呼气流速下降以及/或者气体交换障碍症状的肺疾病,更加具体为,可以是指选自由哮喘、慢性阻塞性肺疾病(COPD)、气管炎(tracheitis)、支气管炎(bronchitis)、弥漫性间质性肺炎、急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)、急性肺损伤、囊性纤维化(cystic fibrosis)、毛细支气管炎(bronchiolitis)、流感病毒感染(influenza virusinfection)、肺炎(pneumonia)、肺结核(tubercuLosis)以及输血相关的急性肺损伤(transfusion-related acute lung injury)而成的组中的一种以上,最具体为,可以是指哮喘或者COPD。
在本发明的组合物中,有效成分在能够显示呼吸系统功能强化以及呼吸系统疾病改善活性、对呼吸系统疾病的预防或治疗活性的情况下,可以根据其具体用途、制剂、调配目的等而含有任意的量(有效量),通常的有效量可以是以组合物总重量为基准,在0.001重量%至20.0重量%范围内决定。所述“有效量”是指,当在本领域的普通技术人员所提议的给药期间向作为本发明组合物的应用对象的个体给药本发明的组合物时,能够显示呼吸系统功能强化以及呼吸系统疾病改善、预防或治疗效果、哮喘或者COPD的改善效果等所意图的功能上、药理学上的效果的、包含在本发明的组合物中的有效成分的量。所述有效量可以是本领域的普通技术人员在通常的能力范围内通过实验决定。
可应用本发明的组合物的对象可以是狗、猫、牛、马、猪、人等的哺乳动物,可以优选为人。
本发明的食品组合物可以作为有效成分含有具有101至1012CFU菌数,优选为106至1012CFU菌数的植物乳杆菌KF511。
另外,本发明的组合物除了有效成分之外,可以进一步含有安全性已经得到验证且公知为具有相应活性的任意的化合物或者天然提取物以通过抗炎症活性、抗过敏活性等类似活性的附加来增进服用或者摄入的方便性。
在所述化合物或者提取物中,可以包括在各国药典(在韩国,“大韩民国药典”)、各国保健食品法典(在韩国,作为食品医药品安全处告示的“保健食品基准以及规格”)等的公定书中记载的化合物或者提取物、根据规定医药品的制造·销售的各国法律(在韩国,“药事法”)而得到品种许可的化合物或者提取物、根据规定保健食品的制造销售的各国法律(在韩国,“与保健食品有关的法律”)而功能性得到认可的化合物或者提取物。例如,根据韩国“与保健食品有关的法律”,抗炎症功能性得到认可的MSM(二甲基磺酰基甲烷;dimethylsμLfonylmethane)、N-乙酰氨基葡萄糖等和抗过敏功能性得到认可的粪肠球菌(Enterococcus faecalis)加热处理干燥粉末、番石榴叶提取物等的复合物、软枣猕猴桃提取物、苏叶提取物、picaopreto粉末等的复合物、PLAG(1-棕榈酰-2-油酰基-3-亚油酰-外消旋-甘油;1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol)等可以属于所述化合物或者提取物,但不特别限定于此。所述化合物或者天然提取物可以与该有效成分一起,在本发明的组合物中包含一个以上。
本发明的组合物在具体的形态中,可以作为食品组合物进行掌握,在所述食品中,可以包括保健(性)食品。
在本发明中,术语“保健食品”是指,使用具有对人体有用的功能性的原料或者成分来制成以及加工成片剂、胶囊、粉末、颗粒、液态以及丸等形态的食品。所述“功能性”是指,对人体的结构以及功能,调整营养素或者得到对生理学作用等之类的保健用途有用的效果。本发明的保健食品可以通过本领域中通常使用的方法来制备,在所述制备时,可以添加本领域中通常添加的原料以及成分来制备。另外,对于所述保健食品的剂型,只要是作为保健食品认可的剂型,则不受限制。本发明的食品组合物可以制成各种形态的剂型,与一般药品不同,将食品作为原料而具有没有长期服用药品时可以发生的副作用等的优点,而且携带方便,从而本发明的保健食品可以作为用于增进哮喘或者COPD改善效果,进一步地增进呼吸系统功能强化以及呼吸系统疾病改善效果的助剂来摄入。
本发明的食品组合物也可以制成任何形态,例如,可以制成茶;饮料、碳酸饮料、离子饮料等的饮料类;牛奶、酸奶等的加工乳类;口香糖类;年糕、韩国传统糕点、面包、饼干、面等的食品类;片剂、胶囊、丸、颗粒、液态、粉末、片状、糊状、糖浆、凝胶、果冻、条形等的保健食品制剂类等。另外,本发明的食品组合物在法律上·功能上的区分中,只要是符合制造·流通时刻的实施法规,则可以具有任意的产品区分。例如,可以是基于韩国“与保健食品有关的法律”的保健食品或者基于韩国“食品卫生法”的食品法典(食品医药品安全处告示的“保健食品基准以及规格”)上各个食品类型的饼干类、豆类、茶类、饮料类、特殊用途食品等。
另外,在本发明的食品组合物中,除了该有效成分之外,可以包括食品添加物。食品添加物可以理解为是在制造、加工或者保存食品中添加到食品中进行混合或者浸润的物质,由于是与食品一起每日且长时间摄入,因此其安全性应得到保障。在根据规定食品的制造·流通的各国法律(在韩国,“食品卫生法”)的食品添加物法典中,在成分方面或者功能方面限定规定着安全性得以保障的食品添加物。在韩国食品添加物法典(食品医药品安全处告示的“保健食品基准以及规格”)中,食品添加物在成分方面被区分为化学合成品、天然添加物以及混合制剂类进行规定,所述食品添加物在功能方面被分为甜味剂、风味剂、保存剂、乳化剂、酸味剂、增粘剂等。
所述甜味剂是为了使食品具有适当的甜味而使用的,可以使用天然或者合成的甜味剂。优选为,当使用天然甜味剂时,作为天然甜味剂,可以举出玉米糖浆固体、蜂蜜、蔗糖、果糖、乳糖、麦芽糖等的糖甜味剂。
所述风味剂可以是为了提高味道或者香味而使用,可以使用天然和合成的所有风味剂。优选地,使用天然风味剂。当使用天然风味剂时,除了风味之外,也可以同时实施营养强化的目的。作为天然风味剂,可以是从苹果、柠檬、柑橘、葡萄、草莓、桃等中得到的风味剂或者从绿茶叶、葳蕤、竹叶、桂皮、橘皮、茉莉花等中得到的风味剂。还可以使用从人参(红参)、竹笋、芦荟、银杏等中得到的风味剂。天然风味剂可以是液态的浓缩液或者固态的提取物。根据情况,可以使用合成风味剂,作为合成风味剂,可以使用酯、醇、醛、萜烯等。
作为所述保存剂,可以使用山梨酸钙、山梨酸钠、山梨酸钾、苯甲酸钙、苯甲酸钠、苯甲酸钾、EDTA(乙二胺四乙酸)等,作为乳化剂,可以使用阿拉伯胶、羧甲基纤维素、黄原胶、果胶等,作为酸味剂,可以使用柠檬酸、苹果酸、富马酸、己二酸、葡萄糖酸、酒石酸、抗坏血酸、醋酸、磷酸等。酸味剂除了增进味道的目的之外,作为能够抑制微生物的增殖的目的,可以添加到使食品组合物具有适当酸度。
作为所述增粘剂,可以使用悬浮剂、沉淀剂、凝胶形成剂、膨化剂等。
本发明的食品组合物除了前述的食品添加剂之外,作为补充、加强功能性和营养性的目的,可以包括本领域中公知且作为食品添加剂稳定性得到保障的生理活性物质或者矿物类。作为所述生理活性物质,可以举出绿茶等中包含的儿茶素类;维生素B1、维生素C、维生素E、维生素B12等的维生素类;生育酚;二苯甲酰硫胺素等,作为矿物类,可以举出柠檬酸钙等的钙制剂、硬脂酸镁等的镁制剂、柠檬酸铁等的铁制剂、氯化铬、碘化钾、硒、锗、钒、锌等。
在本发明的食品组合物中,可以根据产品类型,适量含有能够达成该目的的前述的食品添加物,针对能够包含在本发明的食品组合物中的其他食品添加物,可以参考各国食品法典或者食品添加物法典。
为了达成所述目的,根据本发明的另一形态为,提供一种作为有效成分含有植物乳杆菌(lactobacillus plantarum)KF511菌株、其培养液、其浓缩液或者其干燥物;柳兰提取物或者茵陈蒿提取物的呼吸系统疾病预防或治疗用药物组合物。植物乳杆菌、植物乳杆菌KF511、培养液、柳兰、茵陈蒿、提取物、有效成分以及呼吸系统疾病等所述术语为如上所述。
本发明的术语“预防”是指,通过给药根据本发明的含有植物乳杆菌KF511菌株的培养液等的组合物,从而抑制或者延缓由个体的呼吸系统疾病的症状的所有行为。
本发明的术语“治疗”是指,通过给药根据本发明的含有植物乳杆菌KF511菌株的培养液等的组合物,从而由个体的呼吸系统疾病的症状有变好转或者痊愈的所有行为。
本发明的药物组合物可以作为有效成分含有具有101至1012CFU菌数,优选为106至1012CFU菌数的植物乳杆菌KF511。
本发明的所述药物组合物除了有效成分之外,可以包括药学上可接受的载体,从而通过本领域中公知的常规方法,按照给药路径制成口服用剂型或者非口服用剂型。具体为,所述给药路径可以是包括局部路径、口服路径、静脉内路径、肌肉内路径以及通过粘膜组织的直接吸收的任意的合适路径,也可以组合两种以上的路径来使用。作为组合两种以上的路径的示例,作为根据给药路径而组合两种以上的剂型的药物的情况,例如是第一次是通过静脉内路径给药某种药物,第二次是通过局部路径给药另一种药物的情况。
药学上可接受的载体是根据给药路径或者剂型而在本领域中周知,具体为,可以参考包括“大韩民国药典”的各国药典。
当以口服用剂型制备本发明的药物组合物时,可以与合适的载体一起,通过本领域中公知的方法制备成粉末、颗粒、片剂、丸剂、糖衣片剂、胶囊剂、液剂、凝胶剂、糖浆剂、悬浮液、圆片等的剂型。此时,作为合适的载体的示例,可以举出乳糖、葡萄糖、蔗糖、右旋糖、山梨糖醇、甘露醇、木糖醇等的糖类;玉米淀粉、马铃薯淀粉、小麦淀粉等的淀粉类;甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素等的纤维素类;聚乙烯吡咯烷酮;水;甲基羟苯酸酯;丙基羟苯酸酯;硬脂酸镁;矿物油;麦芽;明胶;滑石;多元醇;植物油;乙醇;丙三醇等。当要制剂化时,可以根据需要,含有合适的耦合剂、润滑剂、崩解剂、着色剂、稀释剂等。作为合适的耦合剂,可以举出淀粉、硅酸镁铝、淀粉糊剂、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮、葡萄糖、玉米甜味剂、海藻酸钠、聚乙二醇、蜜蜡等,作为润滑剂,可以举出油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠、二氧化硅、滑石、硬脂酸、其镁盐和钙盐、聚乙二醇等,作为崩解剂,可以举出淀粉、甲基纤维素、琼脂(agar)、膨润土、黄原胶、淀粉、藻酸或者其钠盐等。另外,作为稀释剂,可以举出乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素、甘氨酸等。
当以非口服用剂型制备本发明的药物组合物时,可以与合适的载体一起,通过本领域中公知的方法制剂化为注射剂、透皮给药剂、鼻腔吸入剂以及栓剂的形态。当制剂化为注射剂时,作为合适的载体,可以使用水性等渗溶液或者悬浮液,具体为,可以使用含有三乙醇胺的PBS(磷酸盐缓冲液;phosphate buffered saline)或者注射用灭菌水、5%右旋糖之类的等渗溶液等。但制剂化为透皮给药剂时,可以制剂化为软膏剂、霜剂、乳液剂、凝胶剂、外用液剂、粘胶剂、擦剂、气溶胶剂等的形态。当为鼻腔吸入剂时,可以使用二氯氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳等的合适的推进剂来制剂化为气溶胶喷雾形态,当制剂化为栓剂时,作为该载体,可以使用维比索尔(witepsol)、吐温(tween)61、聚乙二醇类、可可脂、月桂酯(laurinum)、聚氧乙烯山梨糖醇酐脂肪酸酯类、聚氧乙烯硬脂酸酯类、山梨糖醇酐脂肪酸酯类等。
针对药物组合物的具体制剂化,是本领域中公知的,例如可以参考文献[Remington’s Pharmaceutical Sciences(19th ed.,1995)]等。所述文献作为本说明书的一部分。
本发明的药物组合物的优选给药量可以根据患者的状态、体重、性别、年龄、患者的疾病程度、给药路径而1日0.001mg/kg至10g/kg范围,优选为0.001mg/kg至1g/kg范围。可以按照1日1次或者数次完成给药。所述给药量在任何方面都不应解释为用于限制本发明的范围。
发明效果
本发明的植物乳杆菌(lactobacillus plantarum)KF511菌株、柳兰提取物或者因陈蒿提取物具有在利用人的呼吸系统上皮细胞(H292)的黏液高分泌模型中抑制MUC5AC的分泌,抑制中性粒细胞胞外诱捕网(Neutrophil extracelluLar traps)的Netosis激活,抑制支气管上皮细胞株NCI-H292细胞因CSE(香烟烟雾提取物;Cigarette SmokeExtraction)的炎症细胞因子的表达,进一步地,在通过CSE和PPE诱导的呼吸系统疾病小鼠模型中抑制肺组织损伤,抑制BALF内总细胞、巨噬细胞、淋巴细胞、嗜酸性粒细胞、中性粒细胞等的免疫细胞浸润,在BALF以及肺组织中抑制炎症细胞因子和趋化因子的分泌的活性。
附图说明
图1是示出对通过PPE/CSE诱导的呼吸系统疾病(COPD)小鼠模型给药本发明的植物乳杆菌KF511菌株以及作为阳性对照组的ROF之后,从支气管肺泡灌洗液(BALF)统计的总细胞数。
图2以及图3是示出通过迪夫快速染色液(Diff-Quick)染色来分析BALF内免疫细胞(巨噬细胞(macrophages)、淋巴细胞(Lymphocytes)、中性粒细胞(Neutrophil)以及嗜酸性粒细胞(Eosinophil))的结果。
图4是示出染色从呼吸系统疾病(COPD)小鼠模型摘除的肺组织的结果。
图5是分析呼吸系统疾病(COPD)小鼠模型的BALF内细胞因子(Cytokine)以及趋化因子(Chemokine;KC、MCP-1、MDC、MIP-2、TARC、GM-CSF、INF-gamma、IL-6、IL-10、IL-17)的结果。
图6是示出从呼吸系统疾病(COPD)小鼠模型的肺组织分析细胞因子(Cytokine)以及趋化因子(Chemokine;KC、MCP-1、MDC、MIP-2、TARC、GM-CSF、INF-gamma、IL-1beta、IL-6、IL-17)的结果。
图7是向来自呼吸系统疾病(COPD)小鼠模型的肺组织按照各个浓度处理植物乳杆菌KF511菌株之后,测定肺组织内B细胞(cell)的比率的结果。
图8是对呼吸系统疾病(COPD)小鼠模型按照各个浓度处理植物乳杆菌KF511菌株之后,测定BALF内IgA含量的结果。
图9是对作为人的呼吸系统上皮细胞的黏液上皮癌细胞株的NCI-H292细胞按照各个浓度处理植物乳杆菌KF511菌株之后,测定MUC5AC的表达程度的结果。
图10是示出对通过PPE/CSE诱导的呼吸系统疾病(COPD)小鼠模型给药本发明的柳兰提取物以及作为阳性对照组的ROF之后,从支气管肺泡灌洗液(BALF)统计的总细胞数。
图11是示出通过迪夫快速染色液(Diff-Quick)染色来分析BALF内免疫细胞(巨噬细胞(macrophages)、淋巴细胞(Lymphocytes)、中性粒细胞(Neutrophil)以及嗜酸性粒细胞(Eosinophil))的结果。
图12是示出染色从呼吸系统疾病(COPD)小鼠模型摘除的肺组织的结果。
图13是评价随着处理柳兰提取物而在NCI-H292细胞中MUC5AC抑制活性的结果。
图14是评价随着柳兰提取物的处理浓度而在A549细胞中炎症细胞因子(IL-8)的抑制活性的结果。
图15以及16是示出对通过PPE/CSE诱导的呼吸系统疾病(COPD)小鼠模型给药本发明的茵陈蒿提取物以及作为阳性对照组的ROF之后,从支气管肺泡灌洗液(BALF)统计的总细胞数;以及通过迪夫快速染色液(Diff-Quick)染色来分析BALF内免疫细胞(巨噬细胞(macrophages)、淋巴细胞(Lymphocytes)、中性粒细胞(Neutrophil)以及嗜酸性粒细胞(Eosinophil))的结果。
图17是示出染色从呼吸系统疾病(COPD)小鼠模型摘除的肺组织的结果。
图18是示出随着处理茵陈蒿提取物而确认通过微尘诱导的NCI-H292细胞的损伤抑制活性的结果。
图19是示出测定随着处理茵陈蒿提取物而在NCI-H292细胞中MUC5AC mRNA的表达量的结果。
具体实施方式
以下,通过以下实施例更加详细说明本发明。然而,所述实施例是用于示例性地说明本发明,本发明的范围不仅限于所述实施例。
实施例1:植物乳杆菌KF511菌株的分离以及鉴定
根据本发明的植物乳杆菌菌株是利用乳杆菌MRS琼脂培养基(MRS培养基,BD288130,Difco公司,美国)从通过传统方式制造的泡菜进行了分离,并通过16S rDNA排序鉴定所述分离的菌株。鉴定结果,所述菌株的16S rDNA核酸序列(序列号1)与以往的植物乳杆菌ATCC14917(T)菌株具有99.93%的同源性。用于培养所述菌株的培养基组分为MRS培养基,培养条件为pH6.5±0.2,在温度37℃下以及搅拌培养24小时,对氧的要求性为兼性厌氧菌,可以冷冻干燥保存或者通过细胞悬浮液冷冻进行菌株保存。
本发明人将所述菌株命名为植物乳杆菌(lactobacillus plantarum)KF511,并于2019年8月21日寄存到作为国际保藏机关的韩国微生物保存中心(KCCM),并得到保藏号KCCM 12573P。
实施例2:柳兰提取物以及茵陈蒿提取物的准备
制造柳兰提取物(提取部位:地上部),确认了肺疾病改善活性。提取物是向各个提取对象天然物的干燥粉末添加10倍重量的70%乙醇,在50℃下每隔6小时反复提取2次进行过滤之后,进行减压浓缩以及冷冻干燥,由此得到粉末状。
另外,制造茵陈蒿(提取部位:地上部),确认了肺疾病改善活性。提取物是向各个提取对象天然物的干燥粉末添加10倍重量的70%乙醇,在50℃下每隔6小时反复提取2次进行过滤之后,进行减压浓缩以及冷冻干燥,由此得到粉末状。
实验例1:通过PPE+CSE诱导的(PPE+CSE-induced)呼吸系统疾病(COPD)小鼠模型
从Orient Bio公司购入BALB/C小鼠(雄性(male),5周龄),驯化1周,并按照n=10进行分组。对于样品处理组,从开始COPD诱导1周之前到解剖之前为止口服给药107至109CFU/head的样品24天,对于原始(Naive)和COPD组给药等量的PBS。此时,对于作为阳性对照组的罗氟司特(Roflumilast;ROF)组,在开始诱导之后,每日口服给药10mg/kg浓度。在COPD诱导中使用了1.2单位(unit)的猪胰弹性蛋白酶(Porcine Pancreatic Elastase;PPE)和100%香烟烟雾提取物(Cigarette Smoke Extraction;CSE)。每隔7日通过鼻腔(intra nasal)给药1.2单位的PPE共3次,从处理PPE的第二天开始通过鼻腔(intra nasal)处理20μL的CSE3天,且在最后处理PPE之后,不处理CSE而在第二天进行解剖。利用吸入麻醉器,利用异氟烷(isoflurane)麻醉之后,进行解剖。在实验期间,以自助餐形态提供饲料和饮用水,在24℃、湿度60%的环境下进行饲养。
实验例2:在BALF内浸润的总细胞数以及通过Diff-Quick染色的BALF内免疫细胞的分析
2-1:在BALF内浸润的总细胞数
通过呼吸系统疾病(COPD)小鼠模型的呼吸道注入1mL的PBS之后,轻柔按摩,回收700μL的支气管肺泡灌洗液(bronchoalveolar lavage fluid;BALF)。将回收的10uL的BALF液与Accustain T溶液(solution)等量混合,向Accuchip channel注入12uL之后,利用细胞计数器(cell counter;ADAM-MC、NANOENTEK.INC,Korea(韩国))自动计数总细胞(totalcell)(图1)。
2-2:通过Diff-Quick染色的BALF内免疫细胞的分析
对于回收的BALF,在300Xg、5分钟条件下,通过离心分离分离出上清液和细胞沉淀物(pellet)。对于细胞沉淀物(cell pellet),添加700μL的PBS进行再悬浮,利用细胞离心涂片机(Cytospin device;Centrifuge 5403,Eppendorf,Hamburg,Germany)在1000rpm、10min(分钟)、4℃条件下离心分离150μL的所述BALF悬浮液,在载片(slide)粘贴BALF细胞。然后,使用迪夫快速染色试剂(Diff-Quick staining reagent)并依据制造商(1-5-1Wakinohamakaigandori,chuo-ku,Kobe,Japan)的协议,染色细胞之后,利用显微镜进行观察(图2以及图3)。
实验例3:组织分析(Histological examination)
从解剖的呼吸系统疾病(COPD)小鼠模型中摘除肺组织,去除肺的间质之后,在10%的中性福尔马林固定液(neutral buffered formalin)固定3天。利用乙醇(ethylalcohol)和二甲苯(xylene)使固定的组织脱水之后,利用石蜡包埋之后进行切削,并以5um厚度进行切片。将准备的切片粘贴到载片上之后,为了确认一般形态,利用H&E染色之后,利用显微镜进行观察(图4、图12、图17)。
实验例4:BALF内细胞因子(Cytokines)以及趋化因子(Chemokines)的分析
通过呼吸系统疾病(COPD)小鼠模型的呼吸道注入1mL的PBS之后,轻柔按摩,回收700μL的支气管肺泡灌洗液(bronchoalveolar lavage fluid;BALF)。在300Xg、5分钟条件下离心分离经回收的BALF,分离出上清液之后,用到细胞因子(Cytokines)以及趋化因子(Chemokines)的分析中(KC、MCP-1、MDC、MIP-2、TARC、GM-CSF、INF-gamma、IL-6、IL-10、IL-17)。为了细胞因子(Cytokines)以及趋化因子(Chemokines)的分析,取出30uL的上清液之后,依据多因子ELISA检测试剂盒(Q-plex ELISA array kit)的制造商(Quansisbiosciences公司)协议,进行实验。在图5中按照各个细胞因子(Cytokines)或者趋化因子(Chemokines)示出该结果。
实验例5:肺组织的细胞因子(Cytokines)以及趋化因子(Chemokines)的分析
添加相当于呼吸系统疾病(COPD)小鼠模型肺组织重量的10倍的PBS,利用均质器(homogenizer)进行粉碎之后,在12000rpm、20分钟(min)条件下进行离心分离。回收的上清液用于细胞因子以及趋化因子的分析中(KC、MCP-1、MDC、MIP-2、TARC、GM-CSF、INF-gamma、IL-1beta、IL-6、IL-17)。为了细胞因子以及趋化因子的分析,取出30uL的上清液之后,依据多因子ELISA检测试剂盒(Q-plex ELISA array kit)的制造商(Quansis biosciences公司)协议,进行实验。在图6中按照各个细胞因子或者趋化因子示出该结果。
实验例6:肺组织内免疫细胞比率的测定
从呼吸系统疾病(COPD)小鼠模型中回收肺组织,利用解剖用剪刀细切肺组织。向GentleMACS C管放入细切的肺组织,并依据制造商(miltenyi Biotec公司)的协议,处理酶D(enzyme D)和A,通过MACS组织处理器(MACS dissociator)将组织单细胞化。对单细胞化的细胞处理红细胞裂解液(red blood cell lysis)并静置之后,按照各个组测定细胞数。制成1×107cells/mL浓度的细胞,向96孔V型底板(V-bottom plate)向每个孔(well)分注200μL。在染色与免疫细胞相关的表面标记之前,利用FACS缓冲液(FACS buffer;PBS+8%NaHCO3+1%FBS+10%NaN3),以0.8μL/20μL/well处理Fc blockTM之后进行移液,在4℃冷藏室静置15分钟。为了清洗,在1800rpm下离心分离3分钟,去除上清液。为了染色各种免疫细胞的表面标记,按照制造商(Biolegend公司)的染色浓度推荐量,各自计算相关抗体,并利用FACS缓冲液进行稀释,由此进行准备。
在实验中,使用了FITC抗小鼠I-A/I-E(FITC anti-mouse I-A/I-E)、PE抗小鼠CD11c(PE anti-mouse CD11c)、PerCP/Cy5.5抗小鼠Ly-6C抗体(PerCP/Cy5.5 anti-mouseLy-6C antibody)、APC抗小鼠CD64(FcγRI)(APC anti-mouse CD64(FcγRI))、AlexaFluor 700抗小鼠Ly-6G(Alexa Fluor 700anti-mouse Ly-6G)、APC/Fire 750抗小鼠CD45抗体(APC/Fire 750anti-mouse CD45 antibody)、Brilliant Violet 421抗小鼠CD24(Brilliant Violet 421anti-mouse CD24)、Brilliant Violet 510抗小鼠/人CD11b抗体(Brilliant Violet 510anti-mouse/human CD11b antibody)。以20μL/well处理经稀释的抗体,在常温下反应30分钟。然后,利用PBS进行清洗,使细胞在PBS悬浮。利用作为流式细胞分析仪的Cytoflex(Beckman CouLer公司)分析悬浮的细胞。在图7中按照植物乳杆菌KF511(LPKF511)菌株各自的处理浓度示出该结果。
实验例7:BALF内IgA含量的测定
IgA的测定是按照ELISA试剂盒(ELISA kit;eBioscience,USA)的实验方法进行的测定。利用包被缓冲液(Coating Buffer)稀释捕获抗体(Capture antibody),向96孔非无菌板(Immunoplate)按每个孔分注100μ之后,在4℃下静置1天左右。第二天,利用冲洗缓冲液(Washing buffer)冲洗(Washing)2次之后,向每个孔分注250μ的封闭缓冲液(Blockingbuffer),在常温下静置2小时。封闭(Blocking)过程结束之后,冲洗4次,然后,利用分析缓冲液(Assay Buffer)稀释标准(Standard)试料和各个组的BALF溶液,向每个孔分注100μ,在常温下静置2小时。将溶液冲洗4次之后,利用分析缓冲液(Assay Buffer)稀释检测抗体(Detection-Antibody),向每个孔分注100μL,在常温下静置1小时。将溶液冲洗4次之后,向每个孔分注100μL的底物溶液(Substrate solution)之后,在常温下静置15分钟,向每个孔添加100μL的终止液(Stop solution),使反应终止。然后,在450nm的波长下测定吸光度,通过利用标准(Standard)的标准曲线进行定量。在图8中按照植物乳杆菌KF511(LPKF511)菌株各自的处理浓度示出该结果。
实验例8:利用NCI-H292的MUC5AC抑制功能的确认
作为黏液内糖蛋白的黏蛋白是通过黏液基因而生成,尤其是,作为分泌型粘液素的MUC5AC的表达在呼吸系统领域起到重要的作用。为此,在本实验中,想要利用作为人的呼吸系统上皮细胞的黏液上皮癌细胞株的NCI-H292细胞来确认植物乳杆菌KF511菌株的MUC5AC抑制功能。
8-1:H292细胞的培养
H292细胞的培养是使用了含有10%FBS(胎牛血清;Fetal bovine serum)、100unit/ml的青霉素(penicillin)和100mg/ml的链霉素(streptomycin)的RPM 1640培养基。在48孔细胞培养板(cell culture plate)以4×104cell/well(细胞/孔)浓度接种H292细胞,在37℃、提供5%的二氧化碳(CO2)的条件下培养24小时。培养24小时之后,在培养基的组分中替换成将FBS的浓度降为0.2%的培养基,在37℃、提供5%的二氧化碳(CO2)的条件下饥饿(starvation)24小时。然后,样品以及刺激物质的处理全部是使用了未添加血清(serum)的RPM 1640培养基。刺激物质是使用了PMA(12-豆蔻酸-13-乙酸佛波醇;Phorbol12-myristate 13-acetate),使最终浓度成为2ng/mL,并与106-9cell/well的KF511同时处理之后,培养24小时。回收培养上清液,使用在利用ELISA分析方法的MUC5AC测定中。
8-2:MUC5AC测定
向96孔非无菌板(immunoplate)分别分注100μL的培养上清液,在50℃的干燥箱中全部干燥之后,利用添加有0.05%吐温(tween)20的PBS清洗3次。然后,在所有步骤之间使用与以上相同的清洗方法。向每个孔分注200μL的1%BSA(牛血清白蛋白;Bovine serumalbumin),封闭1小时之后,进行清洗。将MUC5AC抗体(abcam)稀释500倍,向每个孔分注100μL,反应2小时。清洗之后,将山羊抗小鼠IgG HRP(goat anti-mouse IgG HRP;abcam)稀释2000倍,向每个孔分注100μL之后,遮光并反应1小时。向每个孔分注100μL的底物溶液(substrate solution;BD)之后,遮光并反应30分钟之后,向每个孔添加50μL的终止液(stop solution),使反应终止。利用ELISA酶标仪(reader),在450nm下测定吸光度,MUC5AC的抑制功能是通过如下程度来表示的,即当以未处理任何东西的对照组细胞为基准时,相对于基于PMA的MUC5AC的生成功能,处理样品时被抑制的程度。
确认MUC5AC的生成功能的结果,确认到与未给刺激的对照组细胞进行比较,PMA增加MUC5AC的生成2.5倍左右。与此相反地,当处理植物乳杆菌KF511(LPKF511)时,确认到MUC5AC的生成相对于该处理浓度以依赖性地显著减少(图9)。
实验例9:在BALF内浸润的总细胞数以及通过Diff-Quick染色的BALF内免疫细胞的分析
9-1:在BALF内浸润的总细胞数
通过呼吸系统疾病(COPD)小鼠模型的呼吸道注入1mL的PBS之后,轻柔按摩,回收700μL的支气管肺泡灌洗液(bronchoalveolar lavage fluid;BALF)。将回收的10μL的BALF液与Accustain T溶液(solution)等量混合,向Accuchip channel注入12uL之后,利用细胞计数器(cell counter;ADAM-MC、NANOENTEK.INC,Korea(韩国))自动计数总细胞(totalcell)(图10、图15)。
9-2:通过Diff-Quick染色的BALF内免疫细胞的分析
对于回收的BALF,在300Xg、5分钟条件下,通过离心分离分离出上清液和细胞沉淀物(pellet)。对于细胞沉淀物(cell pellet),添加700μL的PBS进行再悬浮,利用细胞离心涂片机(Cytospin device;Centrifuge 5403,Eppendorf,Hamburg,Germany)在1000rpm、10分钟(min)、4℃条件下离心分离150μL的所述BALF悬浮液,在载片(slide)粘贴BALF细胞。然后,使用迪夫快速染色试剂(Diff-Quick staining reagent),依据制造商(1-5-1Wakinohamakaigandori,chuo-ku,Kobe,Japan)的协议,染色细胞之后,利用显微镜进行观察(图11、图16)。
实验例10:利用NCI-H292细胞的MUC5AC抑制活性的测定
H292细胞的培养是使用了含有10%FBS(胎牛血清;Fetal bovine serum)、100unit/ml的青霉素(penicillin)和100mg/ml的链霉素(streptomycin)的RPM 1640培养基。在48孔细胞培养板(cell culture plate)以4×104cell/well(细胞/孔)浓度接种H292细胞,在37℃、提供5%的二氧化碳(CO2)的条件下培养24小时。培养24小时之后,在培养基的组分中替换成将FBS的浓度降为0.2%的培养基,在37℃、提供5%的二氧化碳(CO2)的条件下饥饿(starvation)24小时。然后,样品以及刺激物质的处理全部是使用了未添加血清(serum)的RPM 1640培养基。刺激物质是使用了PMA(12-豆蔻酸-13-乙酸佛波醇;Phorbol12-myristate 13-acetate),使最终浓度成为2ng/mL,并与柳兰同时处理之后,培养24小时。向96孔非无菌板(immunoplate)分别分注100μL的培养上清液,在50℃的干燥箱中全部干燥之后,利用添加有0.05%吐温(tween)20的PBS清洗3次。然后,在所有步骤之间使用与以上相同的清洗方法。向每个孔分注200μL的1%BSA(牛血清白蛋白;Bovine serumalbumin),封闭1小时之后,进行清洗。将MUC5AC抗体(antibody;abcam)稀释500倍,向每个孔分注100μL,反应2小时。清洗之后,将山羊抗小鼠IgG HRP(goat anti-mouse IgG HRP;abcam)稀释2000倍,向每个孔分注100μL之后,遮光并反应1小时。向每个孔分注100μL的底物溶液(substrate solution;BD)之后,遮光并反应30分钟之后,向每个孔添加50μL的终止液(stop solution),使反应终止。利用ELISA酶标仪(reader),在450nm下测定吸光度,MUC5AC的抑制功能是通过如下程度来表示的,即当以未处理任何东西的对照组细胞为基准时,相对于基于PMA的MUC5AC的生成功能,处理样品时被抑制的程度。回收上清液之后,向剩余细胞以500μL/well处理利用RPM1640+10%FBS+1%P/S培养基稀释1/10的四氮唑盐水溶液(Water solution tetrazolium salt;WST)试剂,在37℃、5%CO2的培养箱反应50分钟之后,在450nm下测定吸光度,确认细胞存活率(WST),在MUC5AC分析中排除了存活率相比对照组降低的浓度。在图13中按照柳兰提取物的各个处理浓度示出该结果,确认到随着柳兰提取物的处理而抑制MUC5AC生产。
实验例11:利用A549细胞的炎症细胞因子(IL-8)抑制活性的评价
在96孔板(well plate)以200μL/well传代培养以1×105cells/mL浓度准备的A549细胞24小时之后,利用MEM+10%FBS+1%P/S培养基,对刺激物质(TNF-α;最终5ng/mL)和样品(最终;3.12、6.25、12.5、25μg/mL)以所需的最终浓度进行反应并稀释之后,向每个孔处理20uL。培养一晚之后,回收培养上清液,使用到IL-8测定中。通过ELISA方法测定人(Human)的IL-8,并依据制造商(BD公司)的协议进行的。此时,将IL-8测定用上清液稀释40倍并进行了分析。回收上清液,向剩余的细胞利用MEM+10%FBS+1%P/S培养基以100μL/well进行处理,并以20μL/well处理以2mg/mL浓度准备的MTT(噻唑蓝溴化四唑;Thiazolylblue tetrazolium bromide,Sigma公司)试剂,在37℃、5%CO2的培养箱反应4小时之后,以100μL/well处理10%SDS溶液,第二天在570nm下测定吸光度,确认细胞存活率(MTT),在细胞因子分析中排除了存活率相比对照组降低的浓度。该结果,确认到处理柳兰时以浓度依赖性地抑制炎症细胞因子(IL-8)水平(图14)。
实验例12:通过微尘诱导的NCI-H292细胞损伤抑制活性
H292细胞是向6孔细胞培养板(cell culture plate)的每个孔放入盖玻片(coverglass)之后,涂布胶原蛋白来使用。胶原蛋白涂层是将细胞基质I-C型(Cell matrix typeI-C)在0.02N HCl稀释15倍而在每个孔处理30分钟之后,利用DPBS清洗3次之后来使用。以3×105cell/well(细胞/孔)浓度接种H292细胞,在37℃、提供5%的二氧化碳(CO2)的条件下培养24小时。培养24小时之后,在培养基的组分中替换成将FBS的浓度降为0.2%的培养基,在37℃、提供5%的二氧化碳(CO2)的条件下饥饿(starvation)24小时。然后,样品以及刺激物质的处理全部是使用了未添加血清(serum)的RPM 1640培养基。刺激物质是使用了CRM(Urban aerosols No.28,NIES),使最终浓度成为100μg/mL,并与茵陈蒿同时处理之后,培养24小时。结束培养之后,利用DPBS清洗2次,回收盖玻片(cover glass),进行Diff Quick(Sysmex)染色。染色是依据制造商(Sysmex公司)的协议而依次染色3种染色液(Solution)来进行的。结束染色之后,通过显微镜观察,比较基于CRM的细胞的损伤程度,由此确认保护效果(图18)。
实验例13:利用NCI-H292细胞的MUC5AC mRNA表达量的分析
按照实验例1的方法,向NCI-H292细胞处理微尘(CRM)和茵陈蒿试剂进行培养之后,使用QiAzol Lysis Reagent(QIAGEN)回收细胞。使用RNeasy迷你试剂盒(Mini kit;QIAGEN)并依据制造商的协议进行RNA提取,cDNA合成是使用了Maxime RT Premix(iNtRoN)。利用合成的cDNA、实时荧光定量反转录PCR试剂盒(SYBR Green PCR kit;QIAGEN)以及引物对来扩增基因。在分析中使用了MUC5AC引物(primer)(Forward(正向):TCAACGGAGACTGCGAGTACAC,Reverse(反向)CTTGATGGCCTTGGAGCA)。实时PCR(Real-timePCR)是在95℃下反应15分钟、在95℃下反应15秒、在60℃下反应15秒、在72℃下反应15秒,并反复50个循环。MUC5AC的mRNA表达量是通过如下程度来确认的,即当以未处理任何东西的对照组细胞为基准时,相对于基于CRM的MUC5AC的生成功能,处理样品时被抑制的程度。该结果,确认到MUC5AC mRNA表达量在处理茵陈蒿提取物的情况中,以与未处理任何东西的对照组类似的水平在减少(图19)。
从以上的说明中,本发明所属技术领域的技术人员可以理解本发明在不改变其技术构思或者必要特征的情况下可以实施为其他具体形态。针对此,应理解以上说明的实施例在所有面上属于示例而不用于限定。本发明的范围应被解释为相比所述具体实施方式而从专利权利要求书的含义、范围以及其等效概念导出的所有变更或者变形的形态包含在本发明的范围中。
<110> 韩国食品研究院
Korea Food Research Institute
<120> 利用植物乳杆菌菌株等的呼吸系统疾病改善用组合物
<130> PPkfri202001-PCT
<150> KR 10-2019-0124486
<151> 2019-10-08
<150> KR 10-2019-0124489
<151> 2019-10-08
<150> KR 10-2019-0124492
<151> 2019-10-08
<160> 1
<170> KoPatentIn 3.0
<210> 1
<211> 1499
<212> DNA
<213> 植物乳杆菌
<400> 1
ggctcaggac gaacgctggc ggcgtgccta atacatgcaa gtcgaacgaa ctctggtatt 60
gattggtgct tgcatcatga tttacatttg agtgagtggc gaactggtga gtaacacgtg 120
ggaaacctgc ccagaagcgg gggataacac ctggaaacag atgctaatac cgcataacaa 180
cttggaccgc atggtccgag tttgaaagat ggcttcggct atcacttttg gatggtcccg 240
cggcgtatta gctagatggt ggggtaacgg ctcaccatgg caatgatacg tagccgacct 300
gagagggtaa tcggccacat tgggactgag acacggccca aactcctacg ggaggcagca 360
gtagggaatc ttccacaatg gacgaaagtc tgatggagca acgccgcgtg agtgaagaag 420
ggtttcggct cgtaaaactc tgttgttaaa gaagaacata tctgagagta actgttcagg 480
tattgacggt atttaaccag aaagccacgg ctaactacgt gccagcagcc gcggtaatac 540
gtaggtggca agcgttgtcc ggatttattg ggcgtaaagc gagcgcaggc ggttttttaa 600
gtctgatgtg aaagccttcg gctcaaccga agaagtgcat cggaaactgg gaaacttgag 660
tgcagaagag gacagtggaa ctccatgtgt agcggtgaaa tgcgtagata tatggaagaa 720
caccagtggc gaaggcggct gtctggtctg taacctgacg ctgaggctcg aaagtatggg 780
tagcaaacag gattagatac cctggtagtc cataccgtaa acgatgaatg ctaagtgttg 840
gagggtttcc gcccttcagt gctgcagcta acgcattaag cattccgcct ggggagtacg 900
gccgcaaggc tgaaactcaa aggaattgac gggggcccgc acaagcggtg gagcatgtgg 960
tttaattcga agctacgcga agaaccttac caggtcttga catactatgc aaatctaaga 1020
gattagacgt tcccttcggg gacatggata caggtggtgc atggttgtcg tcagctcgtg 1080
tcgtgagatg ttgggttaag tcccgcaacg agcgcaaccc ttattatcag ttgccagcat 1140
taagttgggc actctggtga gactgccggt gacaaaccgg aggaaggtgg ggatgacgtc 1200
aaatcatcat gccccttatg acctgggcta cacacgtgct acaatggatg gtacaacgag 1260
ttgcgaactc gcgagagtaa gctaatctct taaagccatt ctcagttcgg attgtaggct 1320
gcaactcgcc tacatgaagt cggaatcgct agtaatcgcg gatcagcatg ccgcggtgaa 1380
tacgttcccg ggccttgtac acaccgcccg tcacaccatg agagtttgta acacccaaag 1440
tcggtggggt aaccttttag gaaccagccg cctaaggtgg gacagatgat tagggtgaa 1499
Claims (12)
1.一种呼吸系统功能强化以及呼吸系统疾病改善用食品组合物,其特征在于,所述组合物作为有效成分含有植物乳杆菌菌株、其培养液、其浓缩液或者其干燥物;柳兰提取物;或者茵陈蒿提取物。
2.根据权利要求1所述的组合物,其特征在于,所述植物乳杆菌是以保藏号KCCM12573P保藏的植物乳杆菌KF511菌株。
3.根据权利要求1所述的组合物,其特征在于,所述提取物为水、乙醇或者其混合溶剂提取物。
4.根据权利要求1所述的组合物,其特征在于,所述呼吸系统疾病是伴随咳嗽、咳痰、呼吸困难、呼吸道过敏、呼吸道梗阻、黏液高分泌、呼气流速下降以及/或者气体交换障碍症状的肺疾病。
5.根据权利要求1所述的组合物,其特征在于,所述呼吸系统疾病为哮喘、COPD、弥漫性间质性肺炎、急性呼吸窘迫综合征或者急性肺损伤。
6.根据权利要求5所述的组合物,其特征在于,所述呼吸系统疾病为哮喘或者COPD。
7.一种保健食品,其特征在于,含有权利要求1至6中任一项所述的食品组合物。
8.一种呼吸系统疾病预防或治疗用药物组合物,所述组合物作为有效成分含有植物乳杆菌菌株、其培养液、其浓缩液或者其干燥物;柳兰提取物;或者茵陈蒿提取物。
9.根据权利要求8所述的组合物,其特征在于,所述植物乳杆菌是以保藏号KCCM12573P保藏的植物乳杆菌KF511菌株。
10.根据权利要求8所述的组合物,其特征在于,所述提取物为水、乙醇或者其混合溶剂提取物。
11.根据权利要求8所述的组合物,其特征在于,所述呼吸系统疾病为哮喘、COPD、弥漫性间质性肺炎、急性呼吸窘迫综合征或者急性肺损伤。
12.根据权利要求11所述的组合物,其特征在于,所述呼吸系统疾病为哮喘或者COPD。
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KR20130046897A (ko) * | 2011-10-28 | 2013-05-08 | 대상에프앤에프 주식회사 | 락토바실러스 플란타륨 dsr ck10또는 락토바실러스 플란타륨 dsr m2를 유효성분으로 함유하는 염증질환 치료용 조성물 |
CN106262931A (zh) * | 2016-08-04 | 2017-01-04 | 吉林省农业科学院 | 植物乳杆菌在制备抗过敏产品中的应用 |
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KR20130046897A (ko) * | 2011-10-28 | 2013-05-08 | 대상에프앤에프 주식회사 | 락토바실러스 플란타륨 dsr ck10또는 락토바실러스 플란타륨 dsr m2를 유효성분으로 함유하는 염증질환 치료용 조성물 |
CN106262931A (zh) * | 2016-08-04 | 2017-01-04 | 吉林省农业科学院 | 植物乳杆菌在制备抗过敏产品中的应用 |
KR20180123259A (ko) * | 2017-05-08 | 2018-11-16 | 전남대학교산학협력단 | 락토바실러스 플란타럼으로부터 유래된 당단백질 l67을 포함하는 알레르기 질환의 예방 또는 치료용 조성물 |
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