CN114767613A - 新型鱼孢菌科微生物及其用途 - Google Patents
新型鱼孢菌科微生物及其用途 Download PDFInfo
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- CN114767613A CN114767613A CN202210228306.7A CN202210228306A CN114767613A CN 114767613 A CN114767613 A CN 114767613A CN 202210228306 A CN202210228306 A CN 202210228306A CN 114767613 A CN114767613 A CN 114767613A
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Abstract
本发明涉及属于鱼孢菌科的Epidermidibacterium属菌株或其培养液,或者用于预防、改善或治疗皮肤病症或炎症疾病的包含上述菌株或其培养液的组合物。
Description
相关申请的交叉引用
本申请是于2017年6月27日提交的申请号为201780003181.5的中国专利申请的分案申请。
技术领域
本发明涉及新型鱼孢菌科(Sporichthyaceae)微生物及其用途。
背景技术
皮肤生态系统为微生物提供了多种多样的生境,并且各种微生物占据了皮肤生态系统。已知这些微生物与其人类宿主有共生关系,并且对宿主有很多积极的影响。皮肤形成各种生境,如内陷、特定的生态位等,这些生境帮助各种微生物生长。皮肤的主要作用是形成物理屏障,并提供保护,防止来自外部环境和有毒物质的潜在威胁。皮肤是与外部环境的接口,并被各种微生物(真菌、细菌、病毒和小幼虫)定殖。根据物理和化学功能的选择,来选择适应微生物所居住的生态位的微生物。一般来说,皮肤是凉爽的、酸性,并保持干燥状态。在结构上,表皮在如下方面起作用:形成物理屏障以及抵抗微生物和毒素渗透,同时保持水分。表皮的最外层由角质层组成。表皮形成所谓的“砖和灰泥”结构,皮肤组织经历不断的自我更新,并且在分化的最后阶段,鳞屑不断从皮肤表面脱落。
益生菌被统称为对人体有益的微生物,并且是对我们的身体有益的微生物。迄今为止已知的大多数益生菌是乳酸菌。据报道,益生菌经由对人体的各种有益效果来显示出功效,但很少有关于皮肤菌群与皮肤之间相关性的研究。
皮肤屏障由死角质形成细胞和细胞间脂质组成。皮肤屏障是保护皮肤免受外部刺激并防止水分经由皮肤蒸发的皮肤保护层,并且在维持皮肤健康方面起着关键作用。也就是说,皮肤屏障可防止水分从体内过度流失,并防止化学物质或微生物等有害物质进入。构成死角质形成细胞的表面的角质形成细胞包膜在细胞间脂质的稳定性中起重要作用。角质形成细胞进行分化以经由角质化形成皮肤屏障。皮肤屏障的功能可能随着老化或由外部因素而受到破坏,并且皮肤屏障的损伤可能导致皮肤水分流失和皱纹。
因此,本发明人根据皮肤菌群的变化检查了皮肤中发生的变化,此外,发明人研究了是否可通过诱导皮肤菌群变化而潜在地改善皮肤环境。结果发现,从健康成人的皮肤中分离并鉴定了一种新型鱼孢菌科菌株,发现该菌株或其培养物可以诱导皮肤微生物群落的变化,从而改善皮肤环境,并且可以用于与皮肤有关的病症,从而完成了本发明。
发明内容
技术问题
一方面提供一种属于鱼孢菌科的新型Epidermidibacterium属菌株。
另一方面提供该菌株的培养液。
另外一个方面提供包含Epidermidibacterium属菌株或其培养液的组合物。
另外一个方面提供用于预防、改善或治疗受试者的病症的组合物,其包含Epidermidibacterium属菌株或其培养液。
另外一个方面提供Epidermidibacterium属菌株或其培养液在制备组合物中的用途。
另外一个方面提供Epidermidibacterium属菌株或其培养液在制备用于预防、改善或治疗受试者的病症的组合物中的用途。
另外一个方面提供预防、改善或治疗受试者的病症的方法,所述方法包括有需要的受试者施用Epidermidibacterium属菌株或其培养液。
技术方案
一方面提供属于鱼孢菌科的新型Epidermidibacterium属菌株。
Epidermidibacterium属菌株可具有以下菌学特征中的一者或多者:
(1)棒状(Rod-shaped);
(2)非运动性(non-motile);
(3)革兰氏阳性;
(4)无芽孢(non-spore forming);
(5)氧化酶阴性和/或过氧化氢酶阴性;
(6)能够从中检测出MK-9(H4);
(7)极性脂质是选自由磷脂酰乙醇胺(PE)、磷脂酰肌醇(PI)、磷脂酰甘油(PG)、磷脂酰胆碱(PC)和三种未鉴定的脂质(UL)所构成的组中的一者以上;以及
(8)DNA G+C含量是68.9摩尔%。
Epidermidibacterium属菌株与不同属的其他菌株之间在系统分类学特性和化学分类学特性方面存在明显的区别,因此该菌株被鉴定为新型Epidermidibacterium属菌株。
Epidermidibacterium属菌株可以包括Epidermidibacterium keratini。
Epidermidibacterium keratini可以具有以下菌学特征中的一者或多者:
(1)细胞长度为0.5μm至0.3μm,并且直径为0.3μm至0.1μm;
(2)菌落呈圆形、凸状且淡黄色;
(3)在R2A(Reasoner’s 2A)琼脂上观察到生长,但在营养琼脂(NA)、酵母提取物麦芽提取物琼脂(ISP 2)和胰酪胨大豆琼脂(TSA)上观察不到生长;
(4)在R2A琼脂上,在15℃至35℃(最适温度:25℃)下观察到生长,但在10℃或40℃下观察不到生长;
(5)在pH 5.0至6.5和至多10%的NaCl浓度(最适pH 6.0,0%NaCl)下观察到生长;
(6)硝酸盐还原成亚硝酸盐;
(7)酪蛋白和淀粉降解,但DNA和羧甲基纤维素不降解;
(8)观察到表1至3中描述的特征;
(9)对选自以下的一者或多者的同化表现为阳性:N-乙酰-D-氨基葡萄糖、N-乙酰-β-D-甘露糖胺、α-D-葡萄糖、D-甘露糖、D-果糖、D-半乳糖、糊精、D-岩藻糖、肌苷、乳酰胺、麦芽三糖、D-阿洛酮糖、D-核糖、α-酮戊酸、D-果糖-6-PO4、L-丝氨酸、果胶、丙酮酸、腺苷、胸苷、2'-脱氧腺苷、5'-一磷酸腺苷、对羟基苯乙酸、丙酮酸甲酯、D-乳酸甲酯、L-乳酸、柠檬酸、α-酮戊二酸、D-苹果酸、L-苹果酸、溴代琥珀酸、吐温40、吐温80、α-羟基丁酸、β-羟基-D,L-丁酸、α-酮丁酸、丙酸和乙酸活性;
(10)对选自以下的一者或多者的同化表现为阴性:D-麦芽糖、D-纤维二糖、龙胆二糖、蔗糖、D-松二糖、水苏糖、D-棉子糖、α-D-乳糖、D-蜜二糖、β哦-甲基-D-葡萄糖苷、D-水杨苷、N-乙酰-D-半乳糖胺、N-乙酰神经氨酸、D-山梨糖醇、D-甘露醇、D-阿拉伯糖醇、肌醇、甘油、D-葡萄糖-6-PO4、D-天冬氨酸、D-丝氨酸、明胶、甘氨酰-L-脯氨酸、L-丙氨酸、L-精氨酸、L-天冬氨酸、L-谷氨酸、L-组氨酸、L-焦谷氨酸、D-半乳糖醛酸、L-半乳糖酸内酯、D-葡萄糖酸、D-葡萄糖醛酸、葡糖醛酰胺、粘酸、奎宁酸、D-糖质酸、γ-氨基丁酸、甲酸、α-环糊精、β-环糊精、糖原、菊粉、甘露聚糖、N-乙酰-D-氨基葡萄糖、N-乙酰-β-D-甘露糖胺、扁桃苷、L-阿拉伯糖、熊果苷、L-岩藻糖、D-半乳糖、D-半乳糖醛酸、D-葡萄糖酸、乳果糖、D-松三糖、α-甲基-D-半乳糖苷、β-甲基-D-半乳糖苷、3-甲基葡萄糖、α-甲基-D-葡萄糖苷、β-甲基-D-葡萄糖苷、α-甲基-D-甘露糖苷、帕拉金糖、L-鼠李糖、水杨苷、景天庚醛聚糖、D-塔格糖、D-海藻糖、松二糖、木糖醇、D-木糖、乙酸、γ-羟基丁酸、对羟基苯乙酸、D-乳酸甲酯、D-苹果酸、L-苹果酸、丙酮酸甲酯、琥珀酸单甲酯、丙酸、琥珀酰胺酸、N-乙酰-L-谷氨酸、L-丙氨酸胺(alaninamine)、D-丙氨酸、L-丙氨酰甘油、甘氨酰-L-谷氨酸、L-焦谷氨酸、腐胺、2,3-丁二醇、尿苷、胸苷-5'-单磷酸盐、尿苷-5'-单磷酸盐、D-果糖-6-磷酸盐、α-D-葡萄糖-1-磷酸盐、D-葡萄糖-6-磷酸盐和D-L-α-甘油磷酸盐;
(11)存在选自如下的一种或多种活性:酯酶(C4)、酯酶脂肪酶(C8)、亮氨酸芳基酰胺酶、胱氨酸(crystine)芳基酰胺酶、酸性磷酸酶和萘酚-AS-BI-磷酸水解酶活性;
(12)存在弱碱性磷酸酶、缬氨酸芳基酰胺酶或α-胰凝乳蛋白酶活性;
(13)不存在选自以下的一种或多种活性:脂肪酶(C14)、胰蛋白酶、α-半乳糖苷酶、β-葡萄糖苷酸酶、β-葡萄糖苷酶、α-葡萄糖苷酶、N-乙酰-β-氨基葡萄糖苷酶、α-甘露糖苷酶和α-岩藻糖苷酶活性;以及
(14)主要脂肪酸是C17:1ω8c、C16:0、异-C15:0或summed feature 3(C16:1ω6c和/或C16:1ω7c)。
Epidermidibacterium属菌株或Epidermidibacterium keratini可以具有如下形态特征中的一者或多者:
(1)棒状;
(2)非运动性;
(3)没有鞭毛;
(4)革兰氏阳性;
(5)无芽孢;
(6)细胞的长度为0.5μm至0.3μm,并且直径为0.3μm至0.1μm;以及
(7)菌落呈圆形、凸状和淡黄色。
Epidermidibacterium属菌株或Epidermidibacterium keratini可以具有如下的培养特征和生理特征中的一者或多者:
(1)好氧性;
(2)异养;
(3)氧化酶阴性和/或过氧化氢酶阴性
(4)表1的特征;
(5)在R2A琼脂上观察到生长,但在NA、ISP 2和TSA上观察不到生长;
(6)在R2A琼脂上,在15℃至35℃(最适温度:25℃)下观察到生长,但在10℃或40℃下观察不到生长;
(7)在pH 5.0至6.5和至多10%的NaCl浓度(最适pH 6.0,0%NaCl)下观察到生长;
(8)硝酸盐还原成亚硝酸盐;以及
(9)酪蛋白和淀粉降解,但DNA和羧甲基纤维素不降解。
Epidermidibacterium属菌株或Epidermidibacterium keratini可以具有如下生化特征中的一者或多者:
(1)具有9个单元的四氢化甲基萘醌(MK-9(H4))是唯一检测到的类异戊二烯醌;
(2)主要极性脂质是选自由磷脂酰乙醇胺(PE)、磷脂酰肌醇(PI)、三种未鉴定的磷脂质(UPL)、磷脂酰甘油(PG)、磷脂酰胆碱(PC)、两种未鉴定的氨基脂质(AL)和三种UL所构成的组中的一者或多者;
(3)DNA G+C含量是68.9摩尔%;以及
(4)表2的脂肪酸组成。
Epidermidibacterium keratini可以包含具有序列号为1的碱基序列的16s rRNA基因。
Epidermidibacterium keratini可以在被保藏在保藏号KCCM 11843P下。
此外,另一方面提供Epidermidibacterium属或Epidermidibacterium keratini的培养液。
本文中使用时,术语“培养液”是指通过培养菌株而获得的培养液、其浓缩物或其冻干产物,或者是通过从培养液中除去菌株而获得的培养上清液、其浓缩物或其冻干产物,并且“培养上清液”、“条件培养液”和“条件培养基”可以与其互换使用。
培养液可以通过如下获得:在高于10℃或低于40℃的任意温度下在R2A培养基中培养Epidermidibacterium属或Epidermidibacterium keratini预定的时间(例如4小时至50小时)。
在具体的实施方式中,菌株的培养上清液可以通过如下获得:通过离心分离或过滤从菌株的培养液中去除菌株。
在另一个具体的实施方式中,浓缩物可以通过将菌株培养液本身或上清液浓缩获得的,上清液是将培养液离心分离或者使用过滤器过滤培养液获得的。
本领域技术人员可以合适地选择或修改用于培养Epidermidibacterium属的培养基和培养条件。
另外一个方面提供Epidermidibacterium属或其培养液在制备组合物中的用途,并且尤其提供包含Epidermidibacterium属或其培养液的组合物。
Epidermidibacterium属或其培养液如上文中所描述。
在一个具体的实施方式中,Epidermidibacterium属菌株或其培养液可以提高皮肤细胞中丝聚蛋白、紧密连接蛋白(claudin)、αSMase、CerS3、转谷氨酰胺酶-1和HAS的表达,并且降低炎症相关因子和瘙痒症相关因子的表达。因此,Epidermidibacterium属菌株可以有效地用于皮肤相关病症或炎症相关病症。
皮肤相关病症的示例可以包括皮肤老化、伤口、皮炎、特应性皮炎、瘙痒症、湿疹性皮肤病、干性湿疹、红斑、荨麻疹、牛皮癣、药疹、丘疹鳞屑性(papulosquamous)疾病、昆虫和寄生虫介导的疾病、浅表皮肤真菌病、细菌感染性疾病、病毒性疾病、性传播疾病、自身免疫性大疱性疾病、结缔组织病、色素异常症(dyschromatosis)、着色性干皮病、痤疮等。
炎症相关病症可以包括皮炎、过敏症、特应性、结膜炎、牙周炎、鼻炎、中耳炎、咽喉炎、扁桃体炎、肺炎、胃溃疡、胃炎、克罗恩病、大肠炎、痛风、强直性脊柱炎、风湿热、狼疮、纤维肌痛、银屑病关节炎、骨关节炎、类风湿性关节炎、肩周炎、腱炎、腱鞘炎(tenosynovitis)、腱周围炎(peritendinitis)、肌炎、肝炎、膀胱炎、肾炎、干燥综合征、多发性硬化症、以及急性和慢性炎性疾病。
相对于组合物的总重量,组合物可以包含0.001重量%至80重量%的菌株或其培养液,例如0.01重量%至60重量%、0.01重量%至40重量%、0.01重量%至30重量%、0.01重量%至20重量%、0.01重量%至10重量%、0.01重量%至5重量%、0.05重量%至60重量%、0.05重量%至40重量%、0.05重量%至30重量%、0.05重量%至20重量%、0.05重量%至10重量%、0.05重量%至5重量%、0.1重量%至60重量%、0.1重量%至40重量%、0.1重量%至30重量%、0.1重量%至20重量%、0.1重量%至10重量%、或者0.1重量%至5重量%的菌株或其培养液。
在下文中,将详细描述根据组合物的Epidermidibacterium属菌株的用途。
组合物可以是化妆品组合物。
在具体的实施方式中,化妆品组合物可以增强皮肤屏障;预防、改善或抑制老化;预防或改善瘙痒症;并且预防或改善炎症。
本文中使用时,术语“皮肤老化”是指随着年龄增长而出现在皮肤上的有形的和无形的变化,例如表皮厚度减少,皮肤细胞或血管数量减少,修复DNA损伤的能力降低,细胞更新减少,伤口愈合延迟,皮肤屏障功能降低,表皮中保水性降低,汗液和皮脂分泌减少,维生素D产生减少,防御物理损伤减少,化学去除能力下降,免疫反应性下降,感觉功能下降,体温控制下降等。Epidermidibacterium属菌株或其培养液可以被用于改善由外生或内生因素引起的皮肤老化。外生因素指的是许多外部因素,例如紫外线(光线),而内生因素也被称为时序因素,是指主要随时间发生的因素。也就是说,皮肤老化特别包括不仅由外部刺激(如UV,空气污染,香烟烟雾,化学品等)引起的早期老化,而且还包括由于随着年龄的增长而皮肤细胞增殖减少而发生的自然老化。皮肤老化是包括如下所有内容的概念:皱纹、弹性丧失、皮肤松弛、干燥等。此外,皱纹包括由内部/外部因素的刺激引起的构成皮肤组织的组分变化引起的皱纹
因此,由于组合物可以具有上述效果,因此可以用于皮肤改善,例如皮肤润湿,预防皮肤老化,增强皮肤屏障,皮肤伤口愈合或皮肤炎症抑制。
化妆品组合物可以具有例如柔软化妆水、营养化妆水、按摩霜、营养霜、精华液、面膜、凝胶、安瓿(ampoule)、皮肤粘合剂类型的化妆品制剂。
除了组合物作为活性成分外,化妆品组合物还可以包含化妆品组合物中常用的组分,例如常见的添加剂和载体,诸如稳定剂、增溶剂、维生素、颜料和香料。
此外,组合物可以是皮肤外用剂组合物。
在本公开中,皮肤外用剂可以是霜剂、凝胶剂、软膏剂、皮肤乳化剂、皮肤悬浮液、透皮贴剂、含药物绷带、乳液或其组合。根据需要,上述皮肤外用剂可以适当地与在例如常见的化妆品或药品的皮肤外用剂中使用的组分混合,诸如水性组分、油性组分、粉末组分、醇类、润湿剂、增稠剂、UV吸收剂、增白剂、防腐剂、抗氧化剂、表面活性剂、香料、色素、各种皮肤营养剂或它们的组合。上述皮肤外用剂可以适当地与如下物质混合:螯合剂(例如乙二胺四乙酸二钠、乙二胺四乙酸三钠、柠檬酸钠、聚磷酸钠、偏磷酸钠、葡萄糖酸),咖啡因,丹宁酸,维拉帕米,甘草提取物,光甘草定,卡林(Calin)水果的热水提取物,各种草药,生育酚乙酸脂,甘草酸,氨甲环酸及其衍生物或其盐等的药剂,维生素C,抗坏血酸磷酸镁,抗坏血酸葡萄糖苷,熊果苷,曲酸,糖诸如葡萄糖、果糖、海藻糖等等。
在另一个具体的实施方式中,组合物可以是药物组合物。
药物组合物还可以包含药学上可接受的稀释剂或载体。稀释剂可以是乳糖,玉米淀粉、大豆油、微晶纤维素或甘露醇,润滑剂可以是硬脂酸镁、滑石或其组合。载体可以是赋形剂、崩解剂、粘合剂、润滑剂或其组合。赋形剂可以是微晶纤维素、乳糖、低取代羟基纤维素或其组合。崩解剂可以是羧甲基纤维素钙、羧甲淀粉钠、无水磷酸二氢钙或其组合。粘合剂可以是聚乙烯吡咯烷酮、低取代羟丙基纤维素、羟丙基纤维素或其组合。润滑剂可以是硬脂酸镁、二氧化硅、滑石或其组合。
药物组合物可以被配制成用于口服或肠胃外施用的制剂。用于口服施用的制剂可以是颗粒剂、粉剂、液体剂、片剂、胶囊剂、干糖浆剂或其组合。肠胃外施用的制剂可以是注射剂。
组合物可以是健康功能食品组合物。
在健康功能食品组合物中,根据一般方法,Epidermidibacterium属菌株或其培养液可以单独使用或者与其他食品或食品成分组合使用。有效成分的混合比例可以根据使用目的(预防、健康或治疗)来确定。通常,为了生产食品或饮料,本公开的组合物可以相对于原料以15重量份或更少的量加入。健康功能食品的种类没有特别的限制。在各种健康功能食品中,饮料组合物可以包含各种调味剂或天然碳水化合物作为附加成分,像普通饮料那样。天然碳水化合物包括诸如葡萄糖和果糖的单糖,诸如麦芽糖和蔗糖的二糖,诸如糊精和环糊精的多糖以及诸如木糖醇、山梨糖醇和赤藓糖醇的糖醇。作为甜味剂,可以使用天然甜味剂,诸如奇异果甜蛋白和甜叶菊提取物,或者使用合成甜味剂,诸如糖精和阿斯巴甜。健康食品组合物可包含营养剂、维生素、电解质、调味剂、着色剂、果胶酸及其盐、藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油剂、醇、碳酸饮料中使用的碳酸化剂或其组合。健康功能食品组合物还可以包括天然果汁、果汁饮料、用于制备蔬菜饮料的果肉或其组合。
此外,另外一个方面提供预防、改善或治疗受试者的病症的方法,所述方法包括给有需要的受试者治疗或施用有效量的Epidermidibacterium属菌株、其培养液或包含其的组合物。
受试者的病症可以是皮肤相关病症或炎症相关病症。组合物与上文所描述的相同。受试者可以是哺乳动物,例如人、牛、马、猪、狗、绵羊、山羊或猫。
有益效果
根据一个方面,新型鱼孢菌科菌株具有与不同科或相同科的不同属的其他菌株不同的系统分类学特征和化学分类学特征,因此,新型鱼孢菌科菌株或其培养液可以有效地用于预防、改善或治疗皮肤相关病症或炎症相关病症。
附图说明
图1是显示EPI-7的系统分类结果的图;
图2是显示EPI-7的形态学特征的图;
图3是显示根据EPI-7治疗的皮肤菌群变化的图;
图4是显示根据EPI-7治疗的皮肤菌群变化的图;
图5是显示EPI-7对在人角质形成细胞和阳性对照组中丝聚蛋白表达的影响的对比的图;
图6是显示EPI-7对在人角质形成细胞和阳性对照组中紧密连接蛋白4表达的影响的对比的图;
图7是显示不同剂量的EPI-7对在人角质形成细胞中紧密连接蛋白4表达的影响的图;
图8是显示EPI-7对在人角质形成细胞和阳性对照组中CerS3表达的影响的对比的图;
图9是显示不同剂量的EPI-7对在人角质形成细胞中CerS3表达的影响的图;
图10是显示EPI-7对在人角质形成细胞和阳性对照组中αSMase表达的影响的对比的图;
图11是显示不同剂量的EPI-7对在人角质形成细胞中αSMase表达的影响的图;
图12是显示EPI-7对在人角质形成细胞和阳性对照组中HAS表达的影响的对比的图;
图13是显示不同剂量的EPI-7对在人角质形成细胞中HAS表达的影响的图;
图14是显示EPI-7对在人角质形成细胞和阳性对照组中谷氨酰胺转氨酶1表达的影响的对比的图;
图15是显示不同剂量的EPI-7对在人角质形成细胞中紧密连接蛋白1表达的影响的图;
图16是显示不同剂量的EPI-7对在人角质形成细胞中水通道蛋白3表达的影响的图;
图17显示EPI-7对炎症性因子的影响的图;
图18是显示不同剂量的EPI-7对人角质形成细胞中TSLP表达的影响的图;
图19是显示不同剂量的EPI-7对人角质形成细胞中TARC表达的影响的图;并且
图20是显示EPI-7对细胞活力的影响的图。
具体实施方式
在下文中,将参考实施例更详细地描述本公开。然而,这些实施例仅用于说明的目的,并且本公开的范围并非旨在受这些实施例的限制。
实施例1.菌株的分离
将通过用无菌蒸馏水洗涤健康女性的皮肤而获得的样品(人表皮角质形成细胞)接种于Reasoner’s 2A(R2A)培养基(Becton Dickinson,Cockeysville,MD)中。接种后,将样品在28℃下在孵育箱中培养48小时,分离并培养100个菌落,然后在28℃下在孵育箱中再培养48小时。完成培养的菌落通过16s rRNA基因测序来鉴定。此时使用的引物(序列号2和3)被设计为仅在细菌中反应和扩增。PCR扩增进行30个循环,在每个循环中在95℃下1分钟,55℃下1分钟和75℃下1分30秒,最后在72℃下8分钟。产品储存在4℃下。通过使用ABI-3730XL(ABI,美国)测定PCR反应后分离和培养的物种的DNA序列。将在分离和培养的微生物的菌落中确定的16S rRNA区域的碱基序列与通过国家生物技术信息中心(NCBI)主页提供的BLAST程序中登记的其他菌株的碱基序列进行比较。仅选择和使用具有97%或更低同源性的新型物种,并且在它们中选择具有94%或更低同源性的新型微生物(以下称为“EPI-7”)。EPI-7具有序列号为1(互补DNA)的16s rRNA序列。
实施例2.新型微生物的分类学特征和菌学特征
2.1.分类学特征
使用ExTaxon-e服务器(Yoon S.H等,(2017))计算16S rRNA同源性分析。使用软件包BioEdit(Hall T.A.(1999))对序列数据进行比对,并使用MEGA版本5.05(Tamura,K等,(2011))进行系统分析。系统树使用Neighbor-joining分析(Sitouand Nei(1987)),最大似然估计和最大简约法算法来构建,系统树的稳定性通过bootstrap分析(1000次重复)(Felsenstein 1985)进行评估。
结果发现,EPI-7与Modestobacter lapidis MON 3.1、Sporichthya polymorphaDSM 43042、Modestobacter marinus 42H12-1、Modestobacter roseus KLBMP1279和Modestobacter versicolor CP153-2分别具有93.4%、93.2%、93.0%、93.0%和92.9%同源性。如图1中所示,构建的系统树的结果显示EPI-7是属于鱼孢菌科的新型微生物,其尚未被报道过。
2.2.菌学特征
2.2.1.形态学特征
如下分析EPI-7的形态学特征。
首先,在25℃下在R2A培养基中培养细胞5天后,在放大1000倍的Olympus显微镜(GX71)下观察EPI-7的细胞形态。
通过在R2A培养基中将悬滴技术应用于新鲜的EPI-7细胞来研究滑行运动(gliding motility)。
对于扫描电子显微镜(SEM),样品如下进行预处理。将EPI-7接种在R2A(BectonDickinson,Cockeysville,MD)固体培养基上并培养3天,然后将膜过滤器附着到形成的菌落上。将附着有菌落的膜过滤器分离并固定在2.5%戊二醛溶液中2小时,然后用PBS洗涤5分钟两次。此后,将膜过滤器用2%四氧化锇溶液处理1小时,并用40%、50%、60%、70%、80%、90%和100%乙醇脱水。将脱水样品用乙酸异戊酯处理以从中除去乙醇。将预处理后的样品自然干燥,并通过使用溅射涂布机(SC502,Polaron)溅射金。之后,使用SEM(HitachiS4300N,日立,日本)以10000倍率和100000倍率对样品进行拍照,结果示于图2中。
为了区分革兰氏阳性和革兰氏阴性细菌,进行实验如下。具体而言,将在R2A固体培养基上良好培养的EPI-7的一个菌落收集并固定在载玻片上。将载玻片完全干燥,然后用结晶紫染色1至2分钟,并用流水洗涤并再次干燥。将干燥的载玻片用碘-碘化钾染色1分钟。此后,将载玻片用乙醇脱色,并用流水洗涤,然后干燥。为了确定样品是革兰氏阳性还是阴性,使用红色染色染料如番红进行二次染色1至3分钟,并将载玻片用水洗涤并在显微镜(Olympus microscope,12GX71)下观察。
结果发现,EPI-7具有如下形态学特征:
(1)棒状;
(2)非运动性;
(3)没有鞭毛;
(4)革兰氏阳性;
(5)无芽孢;
(6)细胞的长度为0.5μm至0.3μm,并且直径为0.3μm至0.1μm;以及
(7)菌落呈圆形、凸状和淡黄色。
2.2.2.培养和生理学特征
为了研究EPI-7的培养条件,通过将最佳生长温度设定为5℃至40℃(5℃间隔)来确定最佳培养温度,并且通过向培养基添加0%(w/v)至15%(w/v)(0.5%间隔)的NaCl,然后在25℃培养5天。通过使用以下缓冲体系确定pH值:乙酸钠/乙酸(pH<6),Tris/HCl(pH 6至pH 9)和甘氨酸/氢氧化钠(pH>9)。
此外,通过分析3%(v/v)H2O2中的泡沫产生来确定过氧化氢酶活性,并且通过使用1%(v/v)四甲基苯二胺来测定氧化酶活性。
此外,为了测试生长培养基,使用营养琼脂(NA)、酵母提取物麦芽提取物琼脂(ISP2)和胰酪胨大豆琼脂培养基(BD,美国)在25℃下培养5天。
此外,使用BioLog GP2、BioLog Gen III、API 20NE和API ZYM(法国梅里埃,法国)来研究EPI-7的物质利用。根据制造商提供的手册进行使用方法。当发生阳性反应时,会产生紫色。肉眼检查后,使用微孔板分光光度计精确测定生长的程度。在25℃下培养4小时后分析API ZYM测试,并且在25℃下培养至少48小时后分析另一API测试。与其他物种比较的结果显示在下表1中。
通过向R2A培养基中加入巯基乙酸钠(1g/l)并用氮气置换上部空气层,在血清瓶中检查好氧生长。
在25℃下培养7天后,进行DNA、酪蛋白、淀粉、吐温80和羧甲基纤维素降解性的测试。
[表1]
1:EPI-7
2:Modestobacter lapidis MON 3.1
3:Sporichthya polymorpha DSM 43042
4:Modestobacter marinus 42H12-1
+:阳性,-:阴性
结果发现,EPI-7具有如下培养和生理学特征:
(1)好氧性;
(2)异养;
(3)氧化酶阴性和/或过氧化氢酶阴性
(4)表1的特征;
(5)在R2A琼脂上观察到生长,但在NA、ISP 2和TSA上观察不到生长;
(6)在R2A琼脂上,在15℃至35℃(最适温度:25℃)下观察到生长,但在10℃或40℃下观察不到生长;
(7)在pH 5.0至6.5和至多10%的NaCl浓度(最适pH 6.0,0%NaCl)下观察到生长;
(8)硝酸盐还原成亚硝酸盐;以及
(9)酪蛋白和淀粉降解,但DNA和羧甲基纤维素不降解。
2.2.3.生化特征
通过HPLC分析EPI-7的DNA G+C含量。具体而言,用于分析细胞脂肪酸组成、G+C组成和醌的实验方法和条件如下。
首先,根据米勒方法(Miller’s method)分析分离的菌株的细胞脂肪酸组成。将大约40mg培养的细胞转移至管中,加入1ml通过向50%甲醇中加入15%NaOH而制备的溶液,并将管在100℃下加热30分钟并在室温下冷却。向管中加入2ml甲醇-HCl(325ml 6.0N HCl和275ml甲醇的混合物),然后在80℃下加热10分钟,然后迅速冷却。向其中加入1.25ml己烷/甲基叔丁基醚(1:1,v/v),并充分混合10分钟。在室温下放置后,当反应溶液分成2层时,除去下层,加入3ml稀释的NaOH(10.8g氢氧化钠/900ml的蒸馏水),并充分混合10分钟后,放置于室温下。将大约2/3的上清液转移到带螺旋盖的样品瓶(12×32mm,安捷伦科技公司)中,盖上盖子,然后用作样品。根据Sherlock MIS软件的标准方案对样品进行皂化、甲基化和提取。使用安捷伦科技公司6890气相色谱仪和A30 m×0.320mm×0.25μm交联的甲基硅氧烷柱(HP-1)分析脂肪酸,并且使用MIS包的TSBA40数据库(MIDI,版本4.5)来鉴定脂肪酸。所有实验重复至少三次,结果显示在下表2中。
此外,分析G+C摩尔%如下。将从菌株中提取的DNA溶液转移到微管中,并以14000rpm离心分离5分钟。此后,收集100μl上清液并转移到新的管中,并在100℃下进行DNA变性5分钟,然后冷却。向其中加入10μl(0.1mg/mL)P1核酸酶,并使其在50℃下反应3小时。向其中加入碱性磷酸酶(10μl缓冲液和5μl磷酸酶),然后在37℃孵育过夜。以14000rpm离心分离5分钟后,在以下条件下进行分析:
HPLC:YOUNG LIN YL9100(YL9111二元泵)
检测器:YOUNG LIN YL9120 UV/Vis检测器
色谱数据系统:YOUNG LIN Autochro-3000
分析柱:Waters Spherisorb 5um ODS2 4.6mm×250mm柱
洗脱液:0.02M NH4H2PO4(pH未调节)-乙腈(20:1,v/v)
流速:0.5mL/min
检测波长:270nm
如下分析醌:将菌株在R2A培养基中于25℃下培养96小时,然后从中仅收集细胞并冷冻干燥。将冷冻干燥的样品在下列条件下提取:加入氯仿:甲醇(2:1)溶液并振荡3至4小时。使用滤纸(Whatman No.2)过滤出细胞并浓缩滤液。之后,将浓缩物溶解在100μl氯仿:甲醇(8.5:1.5)中,然后以14000rpm离心分离5分钟以收集上清液,其通过HPLC进行分析。HPLC条件如下:
HPLC:YOUNG LIN YL9100(YL9111二元泵)
检测器:YOUNG LIN YL9120 UV/Vis检测器
色谱数据系统:YOUNG LIN Autochro-3000
分析柱:Waters Spherisorb 5um ODS2 4.6mm×150mm柱
(柱温40℃)
分析溶剂:甲醇:异丙基醚(4:1)
流速:1.0mL/min
检测波长:254mm。
在R2A培养基中在25℃下培养菌株96小时后,进行极性脂质分析。首先,按照Minnikin D.E.等(1984)(J Microbiol Methods 2,233-241)中所描述的方法从菌株中提取极性脂质。此后,通过二维TLC法(Komakata K等,1987,Methods Microbiol 19,161-206)鉴定极性脂质。
[表2]
1:EPI-7
2:Modestobacter lapidis MON 3.1
3:Sporichthya polymorpha DSM 43042
4:Modestobacter marinus 42H12-1)
Summed Feature 3:C16:1ω6c和/或C16:1ω7c
Summed Feature 4:反异B-C17:1和/或异I-C17:1
Summed Feature 7:C19:1ω6c和/或ω7c和/或环C19:0
Summed Feature 8:C18:1ω6c
Summed Feature 9:异-C17:1ω9c
结果发现,EPI-7具有如下生化特征:
(1)具有9个单元的四氢化甲基萘醌(MK-9(H4))是唯一检测到的类异戊二烯醌;
(2)主要极性脂质是磷脂酰乙醇胺(PE)、磷脂酰肌醇(PI)、三种未鉴定的磷脂质(UPL)、磷脂酰甘油(PG)、磷脂酰胆碱(PC)、两种未鉴定的氨基脂质(AL)和三种UL;
(3)DNA G+C含量是68.9摩尔%;以及
(4)表2的脂肪酸组成。
此外,将其特征与其他微生物的特征进行比较,并总结在下表3中。
[表3]
如表3中所示,EPI-7在主要生物化学特征方面不同于最接近的物种,并且实施例2.1的这些系统分类结果和化学分类学结果证明EPI-7是一种新物种。
总体来看,证明了从人表皮角质形成细胞分离的EPI-7是属于鱼孢菌科的新属的微生物,并根据系统学会命名法命名为Epidermidibacterium属(Epidermidibacteriumgen.nov.)。
Epidermidibacterium[E.pi.der.mi.di.bac.te’ri.um.N.L.n.表皮,-idis皮肤;L.neut.n.细菌,(小棒或棍);N.L.neut.(Epidermidibacterium来自皮肤的小棒)]。
此外,如实施例2中所证实,Epidermidibacterium属具有如下特征:
(1)棒状;
(2)非运动性;
(3)革兰氏阳性;
(4)无芽孢;
(5)氧化酶阴性和/或过氧化氢酶阴性;
(7)能够从中检测出MK-9(H4);
(8)主要极性脂质是PE、PI、PG、PC和三种UL;并且
(9)DNA G+C含量为68.9mol%。
随后,上述结果表明,从人表皮角质形成细胞分离的Epidermidibacterium属(Epidermidibacterium gen.nov.)菌株是一个物种,其根据系统学会命名法被命名为Epidermidibacterium keratini(Epidermidibacterium keratini sp.nov)。
Epidermidibacterium keratini(ke.ra.ti’ni.N.L.gen.neut.n.keratini属于角蛋白)。
此外,如实施例2中所证实,除了Epidermidibacterium属的特征之外,Epidermidibacterium keratini还具有如下特征:
(1)细胞长度为0.5μm至0.3μm,并且直径为0.3μm至0.1μm;
(2)菌落呈圆形、凸状且淡黄色;
(3)在R2A(Reasoner’s 2A)琼脂上观察到生长,但在营养琼脂(NA)、酵母提取物麦芽提取物琼脂(ISP 2)和胰酪胨大豆琼脂(TSA)上观察不到生长;
(4)在R2A琼脂上,在15℃至35℃(最适温度:25℃)下观察到生长,但在10℃或40℃下观察不到生长;
(5)在pH 5.0至6.5和至多10%的NaCl浓度(最适pH 6.0,0%NaCl)下观察到生长;
(6)硝酸盐还原成亚硝酸盐;
(7)酪蛋白和淀粉降解,但DNA和羧甲基纤维素不降解;
(8)观察到表1至3中描述的特征;
(9)对选自以下的一者或多者的同化表现为阳性:N-乙酰-D-氨基葡萄糖、N-乙酰-β-D-甘露糖胺、α-D-葡萄糖、D-甘露糖、D-果糖、D-半乳糖、糊精、D-岩藻糖、肌苷、乳酰胺、麦芽三糖、D-阿洛酮糖、D-核糖、α-酮戊酸、D-果糖-6-PO4、L-丝氨酸、果胶、丙酮酸、腺苷、胸苷、2'-脱氧腺苷、5'-一磷酸腺苷、对羟基苯乙酸、丙酮酸甲酯、D-乳酸甲酯、L-乳酸、柠檬酸、α-酮戊二酸、D-苹果酸、L-苹果酸、溴代琥珀酸、吐温40、吐温80、α-羟基丁酸、β-羟基-D,L-丁酸、α-酮丁酸、丙酸和乙酸活性;
(10)对选自以下的一者或多者的同化表现为阴性:D-麦芽糖、D-纤维二糖、龙胆二糖、蔗糖、D-松二糖、水苏糖、D-棉子糖、α-D-乳糖、D-蜜二糖、β哦-甲基-D-葡萄糖苷、D-水杨苷、N-乙酰-D-半乳糖胺、N-乙酰神经氨酸、D-山梨糖醇、D-甘露醇、D-阿拉伯糖醇、肌醇、甘油、D-葡萄糖-6-PO4、D-天冬氨酸、D-丝氨酸、明胶、甘氨酰-L-脯氨酸、L-丙氨酸、L-精氨酸、L-天冬氨酸、L-谷氨酸、L-组氨酸、L-焦谷氨酸、D-半乳糖醛酸、L-半乳糖酸内酯、D-葡萄糖酸、D-葡萄糖醛酸、葡糖醛酰胺、粘酸、奎宁酸、D-糖质酸、γ-氨基丁酸、甲酸、α-环糊精、β-环糊精、糖原、菊粉、甘露聚糖、N-乙酰-D-氨基葡萄糖、N-乙酰-β-D-甘露糖胺、扁桃苷、L-阿拉伯糖、熊果苷、L-岩藻糖、D-半乳糖、D-半乳糖醛酸、D-葡萄糖酸、乳果糖、D-松三糖、α-甲基-D-半乳糖苷、β-甲基-D-半乳糖苷、3-甲基葡萄糖、α-甲基-D-葡萄糖苷、β-甲基-D-葡萄糖苷、α-甲基-D-甘露糖苷、帕拉金糖、L-鼠李糖、水杨苷、景天庚醛聚糖、D-塔格糖、D-海藻糖、松二糖、木糖醇、D-木糖、乙酸、γ-羟基丁酸、对羟基苯乙酸、D-乳酸甲酯、D-苹果酸、L-苹果酸、丙酮酸甲酯、琥珀酸单甲酯、丙酸、琥珀酰胺酸、N-乙酰-L-谷氨酸、L-丙氨酸胺(alaninamine)、D-丙氨酸、L-丙氨酰甘油、甘氨酰-L-谷氨酸、L-焦谷氨酸、腐胺、2,3-丁二醇、尿苷、胸苷-5'-单磷酸盐、尿苷-5'-单磷酸盐、D-果糖-6-磷酸盐、α-D-葡萄糖-1-磷酸盐、D-葡萄糖-6-磷酸盐和D-L-α-甘油磷酸盐;
(11)存在选自如下的一种或多种活性:酯酶(C4)、酯酶脂肪酶(C8)、亮氨酸芳基酰胺酶、胱氨酸(crystine)芳基酰胺酶、酸性磷酸酶和萘酚-AS-BI-磷酸水解酶活性;
(12)存在弱碱性磷酸酶、缬氨酸芳基酰胺酶或α-胰凝乳蛋白酶活性;
(13)不存在选自以下的一种或多种活性:脂肪酶(C14)、胰蛋白酶、α-半乳糖苷酶、β-葡萄糖苷酸酶、β-葡萄糖苷酶、α-葡萄糖苷酶、N-乙酰-β-氨基葡萄糖苷酶、α-甘露糖苷酶和α-岩藻糖苷酶活性;以及
(14)主要脂肪酸是C17:1ω8c、C16:0、异-C15:0或summed feature 3(C16:1ω6c和/或C16:1ω7c)。
本发明人于2016年6月8日在韩国微生物保藏中心(KCCM)以保藏号KCCM11843P保藏了属于Epidermidibacterium属的Epidermidibacterium keratini菌株。
实施例3.菌株的活性
3.1.皮肤-微生物组变化的分析
为了测定EPI-7对皮肤菌群的变化的影响,分析受试者的皮肤微生物组的变化。
具体来说,以6小时的间隔将EPI-7培养物施用于受试者的皮肤持续共72小时,收集皮肤样品并分析。在培养物处理之前(表皮A)和处理后72小时(表皮B)收集样品。样品采用无菌水和刮刀收集,所有程序均在洁净的工作台上进行。将从皮肤收集的样品悬浮在0.85%NaCl中,将上清液进行离心分离(17000rpm/m)以从中收集细胞。细胞用无菌生理盐水洗涤一次。此后,使用FastDNA SPIN KIT(MP Biomedical,法国)提取DNA。为了扩增提取的DNA的16S核糖体DNA基因,使用了附有GC封条(序列号为4)的341F(序列号为5)和518R(序列号为6)。对于PCR反应,将0.4mM dNTP、0.5单位Taq聚合酶和10μl含4mM Mg2+的TakaraPerfect Premix(Takara,日本)与1μl DNA模板(20μg/mL)以及1μl 1.0μM正向引物和1μl1.0μM反向引物混合。向混合物中加入蒸馏水至总体积为20μl。通过降落PCR方法在C1000-Dual(Bio-Rad,美国)中进行PCR反应,在降落PCR方法中在将温度从64℃降至59℃的同时每两个周期实施扩增,并且PCR混合物最终在72℃下处理8分钟,并储存在4℃。此后,将所得PCR产物用于变性梯度凝胶电泳(DGGE)分析。在DGGE分析中,使用了D-code系统(Bio-rad,美国)。使用浓度为8%的聚丙烯酰胺凝胶,并使用40%聚丙烯酰胺双溶液(29:1,3.3%C)(Bio-Rad,美国)来制备垂直浓度梯度为40-60%的凝胶。此时,使用7M尿素和40%(w/v)甲酰胺(Sigma,美国)作为变性剂。用约7L TAE缓冲液(20mM Tris,10mM乙酸,0.5mM EDTA,pH8.0)填充D-code系统,并将等量的2X加载染料(0.05%溴酚蓝,0.05%二甲苯蓝,70%甘油)和PCR产物混合并在50V下电泳800分钟。将电泳的聚丙烯酰胺凝胶用Redsafe(Intron,韩国)溶液染色15分钟,分析出现的特定带。结果示于图3中。此外,使用GelCompar2(Bionumeric,比利时)量化和分析DGGE带的图像以产生直方图。为了测序分析,将DGGE凝胶带送至Macrogen公司,结果示于图4中。
如图3和4中所示,与表皮A相比(培养物处理之前),在表皮B(培养物处理后)中观察到带数量减少和具体带的强烈表达。带的表达增加表明群体增加。大多数强度增加的DGGE带表示属于与皮肤共生的皮肤菌群的葡萄球菌(staphylococcus)属微生物,其有效地增强了皮肤屏障并使皮肤润湿。
这些结果表明EPI-7通过增加微生物影响皮肤屏障的增强和皮肤润湿。
3.2.分析皮肤伤口愈合、皮肤屏障增强和润湿活性
为了分析皮肤伤口愈合、皮肤屏障增强和润湿活性,在人角质形成细胞系(HaCaT)中,根据EPI-7处理,通过RT-PCR检查作为与皮肤屏障增强和润湿活性相关的因子的丝聚蛋白、透明质酸合酶(HAS3)、紧密连接蛋白1、紧密连接蛋白4、αSMase、水通道蛋白3(AQP3)谷氨酰胺转氨酶1和CerS3的表达量。
具体而言,将作为人角质形成细胞的HaCaT细胞在含有10%胎牛血清的DMEM培养基(Dulbecco's modified Eagle's培养基,Gibco 1210-0038)中培养,并且培养在37℃和5%的CO2的孵育箱中进行。作为阳性对照组,用1mM视黄醇处理培养的细胞系。作为另一个阳性对照组,将20ml细胞培养液用浓度为1%的动物双歧杆菌(UB)和嗜酸乳杆菌(AB)的培养液处理。此外,以0.1%、0.5%或1.0%的浓度用EPI-7培养液进行处理。
此后,将HaCaT细胞进一步孵育24小时并回收,并向其中加入1ml三唑(RNAiso,DAKARA,日本)以分离RNA。此外,对于RT-PCR,通过使用Nanodrop 2000(Thermo,美国)对RNA进行定量,并且在42℃下反应55分钟并且在70℃下反应15分钟以合成cDNA(逆转录酶混合,ELPIS biotech,韩国)。通过使用Step One Plus(Applied Biosystems,美国)进行RT-PCR,并且将SYBR Green supermix(Applied Biosystems,美国)与引物和cDNA一起加入。将聚合酶在94℃下活化5分钟,然后在95℃下30秒、在54℃下1分钟和在72℃下1分钟下进行40个循环的聚合。将序列号为7和8的引物用于丝聚蛋白,序列号为9和10的引物用于HAS3,序列号为11和12的引物用于紧密连接蛋白1,序列号为13和14的引物用于紧密连接蛋白4,序列号为15和16的引物用于αSMase,序列号为17和18的引物用于AQP3,序列号为19和20的引物用于转谷氨酰胺酶1,序列号为21和22的引物用于CerS3,序列号为23和24的引物用于β-肌动蛋白。
图5是显示EPI-7对在人角质形成细胞和阳性对照组中丝聚蛋白表达的影响的对比的图。
图6是显示EPI-7对在人角质形成细胞和阳性对照组中紧密连接蛋白4表达的影响的对比的图。
图7是显示不同剂量的EPI-7对在人角质形成细胞中紧密连接蛋白4表达的影响的图。
图8是显示EPI-7对在人角质形成细胞和阳性对照组中CerS3表达的影响的对比的图。
图9是显示不同剂量的EPI-7对在人角质形成细胞中CerS3表达的影响的图。
图10是显示EPI-7对在人角质形成细胞和阳性对照组中αSMase表达的影响的对比的图。
图11是显示不同剂量的EPI-7对在人角质形成细胞中αSMase表达的影响的图。
图12是显示EPI-7对在人角质形成细胞和阳性对照组中HAS表达的影响的对比的图。
图13是显示不同剂量的EPI-7对在人角质形成细胞中HAS表达的影响的图。
图14是显示EPI-7对在人角质形成细胞和阳性对照组中谷氨酰胺转氨酶1表达的影响的对比的图。
图15是显示不同剂量的EPI-7对在人角质形成细胞中紧密连接蛋白1表达的影响的图。
图16是显示不同剂量的EPI-7对在人角质形成细胞中水通道蛋白3表达的影响的图。
如图5中所示,发现EPI-7显着增加丝聚蛋白的表达,丝聚蛋白是角质形成细胞分化标记物和负责润湿皮肤表面的天然润湿因子的前体蛋白。
如图6、7和15中所示,发现EPI-7显着增加紧密连接蛋白1和4的表达,紧密连接蛋白1和4是负责保护内部器官免受外部环境的影响并维持人体的体内稳态的紧密连接结构。
如图8和11中所示,发现EPI-7显著增加CerS3和aSMase的表达,CerS3和aSMase是用于神经酰胺合成的必需的酶。
如图12和13中所示,发现EPI-7培养物显著增加HAS3基因的表达,HAS3负责合成透明质酸,透明质酸是维持皮肤水分的细胞外基质组分,并且EPI-7显示出比阳性对照(视黄醇)更高的效力。
如图14中所示,发现EPI-7显著增加谷氨酰胺转氨酶1的表达,谷氨酰胺转氨酶1在形成角化包膜中起关键作用。
如图16中所示,发现EPI-7显著增加AQP3的表达,AQP3在为人类皮肤提供水方面发挥作用,起到促进细胞迁移的水通道的作用,并且起到甘油转运体的作用以调节角质形成细胞增殖和分化,从而治疗伤口。
总体来看,可以看出,EPI-7增强了皮肤的柔韧性和坚固性,改善了皮肤的保水能力,从而表现出皮肤润湿作用,通过更有效地控制细胞间粘附和含水溶质和水通过周质间隙迁移来增强皮肤屏障功能,并且增加角质形成细胞的增殖、分化和迁移,以对伤口愈合显示出显着的作用。
3.3.分析皮肤中的抗炎活性
为了分析EPI-7的抗炎活性,用作为炎症诱导剂的金黄色葡萄球菌(S.aureus)处理HaCaT细胞,并且将表皮葡萄球菌和EPI-7与人HaCaT细胞共同培养,然后评估炎症性因子的mRNA表达水平。
具体而言,将HaCaT细胞培养并接种于6孔板上。24小时后,将微膜孔置于细胞单层的顶部上,然后将活细胞(SA:金黄色葡萄球菌,SA_SE:金黄色葡萄球菌+表皮葡萄球菌,SA_EPI-7:金黄色葡萄球菌+EPI-7)以1.0×1014的细胞密度接种。将细胞进一步共培养24小时,然后除去细胞和培养基。以与实施例3.2相同的方式进行RT-PCR,除了分别使用序列号25和26的组合,序列号27和28的组合,序列号29和30的组合和序列号为31和32的组合分别用作TNF-α、IL-1a、TSLP和DDIT3的引物。结果示于图17中。
图17是显示EPI-7对炎症性因子的影响的图。
如图17中所示,发现EPI-7显着抑制作为皮肤炎症性因子的TNF-α、L-1a、TSLP和DDIT3的表达。该结果表明EPI-7及其培养液可用于皮肤炎症相关的疾病。
3.4.分析皮肤中止痒活性
为了分析EPI-7的止痒活性,评估作为瘙痒因子的TSLP(胸腺基质淋巴细胞生成素)和TARC(胸腺和活化调节趋化因子)的mRNA表达水平。详细地说,用聚肌苷酸:聚胞苷酸(Poly I:C)处理HaCaT细胞,其是诱导干扰素产生的合成的核糖核酸,然后培养24小时以刺激HaCaT细胞。通过刺激的老化细胞用浓度为0.1%、0.5%或1.0%的EPI-7培养液处理,并进一步培养24小时。除了使用序列号33和34的组合作为TARC引物之外,以与实施例3.3中相同的方式进行RT-PCR。
结果示于图18和19中。
图18是显示不同剂量的EPI-7对人角质形成细胞中TSLP表达的影响的图。
图19是显示不同剂量的EPI-7对人角质形成细胞中TARC表达的影响的图。
如图18和19中所示,发现EPI-7显着降低作为瘙痒因子的TSLP和TARC的表达。该结果表明EPI-7及其培养液可用于皮肤炎症相关的疾病和瘙痒症。
3.5.细胞毒性分析
为了检查EPI-7的细胞毒性,进行MTT试验。
具体而言,以实施例3.1中相同的方式制备HaCaT细胞,并且以3×104个细胞/孔的密度分配到96孔板中。24小时后,更换无FBS的培养基。用不含FBS的培养基以0.01%、0.1%、1%、10%和50%的浓度稀释EPI-7培养液并用于处理细胞。孵育24小时后,去除培养基,加入0.5μg/mL的MTT(Sigma-Aldrich,St.Louis,MO)溶液以使细胞结晶,然后再孵育4小时。去除MTT试剂后,将晶体溶于二甲基亚砜(DMSO,Sigma-Aldrich,St.Louis,MO)中。测量540nm处的吸光度,并与未处理的组进行比较以测量细胞活力。结果示于图20中。
图20是显示EPI-7对细胞活力的影响的图。
如图20中所示,发现EPI-7即使在高浓度下也没有细胞毒性。
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<110> 科丝美诗株式会社
<120> 新型鱼孢菌科微生物及其用途
<130> PX054386
<150> KR 10-2016-0080231
<151> 2016-06-27
<150> KR 10-2016-0155981
<151> 2016-11-22
<150> KR 10-2017-0076819
<151> 2017-06-16
<150> KR 10-2017-0076820
<151> 2017-06-16
<160> 34
<170> PatentIn version 3.5
<210> 1
<211> 1450
<212> DNA
<213> Epidermidibacterium keratini
<400> 1
caggacgaac gctggcggcg tgcttaacac atgcaagtcg agcgaagctc tcctcttcgg 60
aggagatgac ttagcggcga acgggtgagt aacacgtggg caacctgccc ttagctctgg 120
gataagcgat ggaaacgtcg tctaataccg gatacgacac ggaacggcat cattaccgtg 180
tggaaagaat ttcggctaag gatgggcccg cggcctatca gcttgttggt ggggtaatgg 240
cctaccaagg cttcgacggg taaccggcct gagagggcga ccggtcacac tgggactgag 300
acacggccca gactcctacg ggaggcagca gtggggaata ttgcacaatg ggcgaaagcc 360
tgatgcagcg acgccgcgtg agggatgacg gccttcgggt tgtaaacctc tttcagcagg 420
gacgaagcga aagtgacggt acctgcagaa gaagcgccgg ccaactacgt gccagcagcc 480
gcggtaatac gtagggcgca agcgttgtcc ggaattattg ggcgtaaaga gctcgtaggc 540
ggtttatcac gtcggctgtg aaatcccgag gcttaacctc gggcctgcag tcgatacggg 600
ttgactagag tgaagcaggg gagactggaa ttcctggtgt agcggtgaaa tgcgcagata 660
tcaggaggaa caccggtggc gaaggcgggt ctctgggctt taactgacgc tgaggagcga 720
aagcgtgggt agcgaacagg attagatacc ctggtagtcc acgccgtaaa cggtgggcgc 780
taggtgtggg gaccattcca cggtctccgt gccgcagcta acgcattaag cgccccgcct 840
ggggagtacg gccgcaaggc taaaactcaa aggaattgac gggggcccgc acaagcggcg 900
gagtatgttg cttaattcga tgcaacgcga agaaccttac caaggcttga catataccga 960
aaactcatag agatatgagg tccttttggg cggtatacag gtggtgcatg gttgtcgtca 1020
gctcgtgtcg tgagatgttg ggttaagtcc cgcaacgagc gcaaccctcg ttctatgttg 1080
ccagcacgta atggtgggga ctcataggag actgccgggg tcaactcgga ggaaggtggg 1140
gatgacgtca aatcatcatg ccccttatgt cttgggctgc aaacatacta caatggccgg 1200
tacaaagggc tgcgataccg taaggtggag cgaatcccaa aaagccggtc tcagttcgga 1260
ttggggtctg caactcgacc ccatgaagtc ggagtcgcta gtaatcgcag atcagcaacg 1320
ctgcggtgaa tacgttcccg ggccttgtac acaccgcccg tcaagtcatg aaagtcggta 1380
acacccgaag ccggtggcct aacctttttg gagggagccg tcgaaggtgg gactggcgat 1440
taggactaag 1450
<210> 2
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 细菌引物
<400> 2
agagtttgat cmtggctcag 20
<210> 3
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 细菌引物
<400> 3
tacggytacc ttgttacgac tt 22
<210> 4
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增16s核糖体基因的GC封条
<400> 4
cgcccggggc gcgccccggg cggggcgggg gcacgggggg 40
<210> 5
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增16s核糖体基因的正向引物
<400> 5
cctacgggag gcagcag 17
<210> 6
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 用于扩增16s核糖体基因的反向引物
<400> 6
attaccgcgg ctgctgg 17
<210> 7
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 用于丝聚蛋白的正向引物
<400> 7
agtgcactca gggggctcac a 21
<210> 8
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于丝聚蛋白的反向引物
<400> 8
ccggcttggc cgtaatgtgt 20
<210> 9
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于HAS3的正向引物
<400> 9
cttaagggtt gcttgcttgc 20
<210> 10
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于HAS3的反向引物
<400> 10
gttcgtggga gatgaaggaa 20
<210> 11
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 用于紧密连接蛋白1的正向引物
<400> 11
gctctagaat tctcacacgt agtctttccc gct 33
<210> 12
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 用于紧密连接蛋白1的反向引物
<400> 12
gctctagaat tctcacacgt agtctttccc gct 33
<210> 13
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 用于紧密连接蛋白4的正向引物
<400> 13
gctctagaat tccgagcgag tcatggccaa cgc 33
<210> 14
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 用于紧密连接蛋白4的反向引物
<400> 14
gctctagaat tctcacacgt agtctttccc gct 33
<210> 15
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 用于aSMase的正向引物
<400> 15
actttgataa ctgctcctct gac 23
<210> 16
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于aSMase的反向引物
<400> 16
ttcgtgtcca gcagagtacc 20
<210> 17
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于AQP3的正向引物
<400> 17
agacagcccc ttcaggattt 20
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于AQP3的反向引物
<400> 18
tcccttgccc tgaatatctg 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于TG1的正向引物
<400> 19
ccccaagaga ctagcagtgg 20
<210> 20
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于TG1的反向引物
<400> 20
agaccaggcc attcttgatg 20
<210> 21
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 用于CerS3的正向引物
<400> 21
acattccaca aggcaaccat tg 22
<210> 22
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于CerS3的反向引物
<400> 22
ctcttgattc cgccgactcc 20
<210> 23
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于β-肌动蛋白的正向引物
<400> 23
ggccatctct tgctcgaagt 20
<210> 24
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于β-肌动蛋白的反向引物
<400> 24
gacaccttca acaccccagc 20
<210> 25
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于TNF-a的正向引物
<400> 25
cttctccttc ctgatcgtgg 20
<210> 26
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 用于TNF-a的反向引物
<400> 26
gctggttatc tctcagctcc a 21
<210> 27
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 用于IL-1a的正向引物
<400> 27
tggctcattt tccctcaaaa gttg 24
<210> 28
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 用于IL-1a的反向引物
<400> 28
agaaatcgtg aaatccgaag tcaag 25
<210> 29
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 用于TSLP的正向引物
<400> 29
gctatctggt gcccaggcta t 21
<210> 30
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 用于TSLP的反向引物
<400> 30
cgacgccaca atccttgtaa t 21
<210> 31
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于DDIT3的正向引物
<400> 31
tgcctttctc ttcggacact 20
<210> 32
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 用于DDIT3的反向引物
<400> 32
tgtgacctct gctggttctg 20
<210> 33
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 用于TARC的正向引物
<400> 33
cttctctgca gcacatcc 18
<210> 34
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 用于TARC的反向引物
<400> 34
aagacctctc aaggctttg 19
Claims (5)
1.一种化妆品组合物,其用于加强皮肤屏障、预防或改善皮肤老化、使皮肤保湿、改善皮肤伤口、或者预防或改善皮肤炎症,所述化妆品组合物包含被保藏在保藏号KCCM 11843P下的Epidermidibacterium keratini菌株或通过培养所述菌株获得的培养液。
2.一种化妆品组合物,其用于预防或改善选自由皮肤伤口、皮炎、特应性皮炎、瘙痒症、湿疹性皮肤病、干性湿疹、红斑、荨麻疹、牛皮癣、药疹和痤疮所构成的组中的任一者,所述化妆品组合物包含被保藏在保藏号KCCM 11843P下的Epidermidibacterium keratini菌株或通过培养所述菌株获得的培养液。
3.一种皮肤外用剂组合物,其用于预防、改善或治疗皮肤病症,所述皮肤外用剂组合物包含被保藏在保藏号KCCM 11843P下的Epidermidibacterium keratini菌株或通过培养所述菌株获得的培养液。
4.根据权利要求3所述的皮肤外用剂组合物,其中所述皮肤病症是选自由皮肤伤口、皮炎、特应性皮炎、瘙痒症、湿疹性皮肤病、干性湿疹、红斑、荨麻疹、牛皮癣、药疹和痤疮所构成的组中的一者以上。
5.一种药物组合物,其用于预防和治疗皮肤疾病,所述药物组合物包含被保藏在保藏号KCCM 11843P下的Epidermidibacterium keratini菌株或通过培养所述菌株获得的培养液,其中所述皮肤疾病是选自由皮肤伤口、皮炎、特应性皮炎、瘙痒症、湿疹性皮肤病、干性湿疹、红斑、荨麻疹、牛皮癣、药疹和痤疮所构成的组中的一者以上。
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
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KR20160080231 | 2016-06-27 | ||
KR10-2016-0080231 | 2016-06-27 | ||
KR10-2016-0155981 | 2016-11-22 | ||
KR20160155981 | 2016-11-22 | ||
KR1020170076820A KR101910791B1 (ko) | 2016-06-27 | 2017-06-16 | 스포리치아과 미생물의 용도 |
KR10-2017-0076819 | 2017-06-16 | ||
KR10-2017-0076820 | 2017-06-16 | ||
KR1020170076819A KR101910790B1 (ko) | 2016-06-27 | 2017-06-16 | 신규 스포리치아과 미생물 |
PCT/KR2017/006741 WO2018004224A2 (ko) | 2016-06-27 | 2017-06-27 | 신규 스포리치아과 미생물 및 그의 용도 |
CN201780003181.5A CN109415682B (zh) | 2016-06-27 | 2017-06-27 | 新型鱼孢菌科微生物及其用途 |
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CN202210228306.7A Pending CN114767613A (zh) | 2016-06-27 | 2017-06-27 | 新型鱼孢菌科微生物及其用途 |
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US (2) | US11261421B2 (zh) |
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US11261421B2 (en) | 2016-06-27 | 2022-03-01 | Cosmax Co., Ltd. | Sporichthyaceae microorganism and use thereof |
KR102204477B1 (ko) * | 2019-01-11 | 2021-01-19 | 코스맥스 주식회사 | 신규 바이우라실, 이의 용도, 및 이의 제조방법 |
KR102174525B1 (ko) * | 2019-09-17 | 2020-11-05 | 코스맥스 주식회사 | 신규한 판토에아 왈리시 루미테리아 균주 및 그 균주 배양액을 포함하는 피부 미용 개선용 조성물 |
KR102335647B1 (ko) * | 2020-05-26 | 2021-12-08 | 주식회사 유나이티드엑티브 | 발효나노유화제 조성물 및 그 제조방법 |
WO2023054973A1 (ko) * | 2021-09-29 | 2023-04-06 | 코스맥스 주식회사 | 에피더미디박테리움 케라티니 균주의 추출물을 포함하는 섬유유연제 조성물 |
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CN105358164A (zh) * | 2013-06-28 | 2016-02-24 | 乐斯福公司 | 治疗和/或预防慢性炎症疾病的菌株 |
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CA2654008C (en) | 2006-06-01 | 2015-11-24 | Therapeutic Peptides, Inc. | Polymeric biosurfactants |
CN102387772A (zh) | 2008-05-29 | 2012-03-21 | 唐纳德·欧文 | 皮肤美容组合物中的寡聚生物表面活性剂 |
KR20100064516A (ko) | 2008-12-05 | 2010-06-15 | 서울대학교산학협력단 | 마이크로rna를 유효성분으로 포함하는 항암제 및 그 제조방법 |
CN104671956A (zh) * | 2013-11-28 | 2015-06-03 | 大连三科生物工程有限公司 | 用于板栗种植微生物添加剂的制备方法 |
US11261421B2 (en) | 2016-06-27 | 2022-03-01 | Cosmax Co., Ltd. | Sporichthyaceae microorganism and use thereof |
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2017
- 2017-06-27 US US15/759,688 patent/US11261421B2/en active Active
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- 2017-06-27 CN CN202210228306.7A patent/CN114767613A/zh active Pending
- 2017-06-27 WO PCT/KR2017/006741 patent/WO2018004224A2/ko unknown
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2021
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CN105358164A (zh) * | 2013-06-28 | 2016-02-24 | 乐斯福公司 | 治疗和/或预防慢性炎症疾病的菌株 |
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Also Published As
Publication number | Publication date |
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US20190040475A1 (en) | 2019-02-07 |
US11261421B2 (en) | 2022-03-01 |
CN109415682A (zh) | 2019-03-01 |
CN109415682B (zh) | 2022-03-25 |
US20220142912A1 (en) | 2022-05-12 |
WO2018004224A2 (ko) | 2018-01-04 |
US11634685B2 (en) | 2023-04-25 |
WO2018004224A3 (ko) | 2018-02-22 |
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