CN116083302A - 具有抗衰作用的口腔链球菌及其应用 - Google Patents
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Abstract
本发明涉及微生物技术领域,具体涉及具有抗衰作用的口腔链球菌及其应用。从儿童面部分离得到一株口腔链球菌,其保藏编号为CCTCC NO:M20221853。实验结果表明,其发酵产物中含有较高浓度的亚精胺,其发酵产物应用于皮肤防护中可促进负责皮肤屏障功能的桥粒胶蛋白2(DSC2)、ATP结合盒亚家族A成员12(ABCA12)和细胞外基质的主要成分之一I型胶原蛋白α1链(COL1A1)的合成,达到增强皮肤屏障、增强皮肤弹性和抗衰老的目的,同时所述的口腔链球菌无细胞毒性,安全可靠,可应用于化妆品中。
Description
技术领域
本发明涉及微生物技术领域,具体涉及具有抗衰作用的口腔链球菌及其应用。
背景技术
益生菌是对人体有益的微生物的统称,指对人体有益的微生物。目前国内外对于益生菌的功效研究趋于成熟,已被广泛应用于化妆品领域,并随着生物发酵技术的发展,维护皮肤“生态系统”平衡,让皮肤“城墙”变得更加牢固,从整体上修复皮肤微生态,从而重塑健康肌肤的“微生态护肤时代”已经到来。同时,随着护肤成分党崛起,抗衰功效走向年轻化并在市场上越来越受欢迎,Euromonitor数据显示,2020年中国护肤品市场中抗衰老护肤品规模达646亿元,占据护肤品市场份额的28.8%,据艾瑞咨询数据显示,在关注功效方面,整体样本排名第一的功效为抗衰,消费者更期待通过日常护肤起到减缓肌肤衰老速度、维持年轻态的需求。
迄今为止,已有很多益生菌应用于皮肤微生态制剂中,大多数带有功效的益生菌都来自于人体肠道微生物的分离,已有相关研究表明,皮肤微生态菌群与年龄密切相关,不同年龄阶段的皮肤微生物特征区别很大,如年老皮肤中,呈低比例丙酸杆菌,高微生物多样性,年轻皮肤中,呈高比例丙酸杆菌,低微生物多样性。中国专利CN202110049175.1公开了用于增强皮肤屏障、保湿皮肤或抗老化的组合物,其研究了肺炎链球菌、婴儿链球菌、缓症链球菌和嗜热链球菌四株链球菌对皮肤衰老的影响。但目前人们对皮肤菌群对皮肤的功效关系的深入研究较少,需要开发更多的优势菌株资源。
发明内容
有鉴于此,本发明要解决的技术问题在于提供具有抗衰作用的口腔链球菌及其应用。
本发明提供了保藏编号为CCTCC NO:M 20221853的口腔链球菌JWA714(Streptococcus oralis JWA714)。
本发明所述的口腔链球菌,其分离于儿童面部,经TSB培养基培养及PCR扩增及序列比对,确认其为口腔链球菌(Streptococcus oralis),保藏于中国典型培养物保藏中心,保藏编号为CCTCC NO:M 20221853。
进一步的,本发明提供了包括本发明所述的口腔链球菌的菌群。本发明所述的菌群包括与所述的口腔链球菌不存在相互拮抗或竞争关系的单个或多个菌形成的菌群,本发明对此不做限定。
更进一步的,本发明提供了含有所述的口腔链球菌或所述的菌群的菌剂。所述的菌剂的剂型包括颗粒、液体及干粉,本发明对此不做限定。本发明中,所述的菌剂还包括所述口腔链球菌的发酵液,菌体,上清及其中所含活性物质,本发明对此不做限定。
本发明提供了所述的口腔链球菌在制备含有亚精胺产品中的应用。
本发明的一些具体实施例中,分离得到两株口腔链球菌,本发明所述的口腔链球菌发酵液中的亚精胺浓度高于另外一株,发酵液中亚精胺的含量达到了2.59ng/ml。
本发明提供了亚精胺的制备方法,其为培养如本发明所述的口腔链球菌,获得含有亚精胺的培养物。
本发明提供了所述的口腔链球菌,和/或所述的菌群,和/或所述的菌剂,和/或权利要求5所述的制备方法制得的含有亚精胺的培养物在制备改善肤质的产品中的应用。
进一步的,所述改善肤质包括修复皮肤屏障或增强皮肤弹性中的至少一种。
本发明中,所述的口腔练球菌可修复皮肤屏障,所述修复皮肤屏障包括促进皮肤屏障功能基因的表达,所述皮肤屏障功能基因包括但不限于DSC2FLG、GBA和ABCA12,本发明对此不做限定。在本发明的一些具体实施例中,所述的口腔链球菌的发酵滤液可促进HSF细胞中DSC2基因、ABCA12基因FLG基因、和/或GBA基因的表达,起到促进皮肤屏障修护的功能。
本发明所述的口腔链球菌具有较强的修复皮肤屏障能力。在本发明的一些具体实施例中,所述的口腔链球菌的发酵液对HSF细胞修复皮肤屏障相关基因的表达量的影响显著高于其他菌株。
本发明中,所述的口腔链球菌可增强皮肤弹性,所述增强皮肤弹性包括促进细胞外基质合成相关基因的表达,所述细胞外基质合成相关基因包括蛋但不限于COL1A1。在本发明的一些具体实施例中,所述的口腔链球菌的发酵滤液可促进HaCaT细胞中COL1A1基因的表达,起到增强皮肤弹性的作用。
本发明的口腔链球菌安全无毒。在本发明的一些具体实施例中,所述的口腔链球菌发酵液浓度在4%(v/v)以下对成纤维细胞的细胞无细胞毒性;浓度在2%(v/v)以下,对成纤维细胞有促增殖的作用;且发酵液浓度在5%(v/v)以下对角质形成细胞无细胞毒性。
本发明提供了改善肤质的产品,其原料包括本发明所述的口腔链球菌,和/或本发明所述的菌群,和/或本发明所述的菌剂,和/或本发明所述的制备方法制得的含有亚精胺的培养物。
进一步的,本发明所述的产品包括食品、药品或化妆品,本发明对此不做限定。
进一步的,本发明所述的产品包括化妆品,所述的化妆品剂型包括:膏霜类、乳液类、水剂类、凝胶类、油剂类、粉剂类、散粉、泥类、气雾剂类、贴、膜类、冻干类中的至少一种。
本发明还提供了一种改善肌肤状态的方法,其包括使用本发明所述从产品。所述使用的方法包括涂抹、外敷或注射,本发明对此不做限定。
本发明提供了所述的口腔链球菌在促进HSF细胞中DSC2基因和ABCA12基因,和/或HaCaT细胞中COL1A1基因表达中的应用。
本发明所述的口腔链球菌安全无毒,其发酵液用于眼部刺激性实验,结果表明,其对眼无刺激性;且斑贴实验也证明本发明所述的口腔链球菌对皮肤无毒副作用。
本发明从儿童面部分离得到一株口腔链球菌,其保藏编号为CCTCC NO:M20221853。实验结果表明,其发酵产物中含有较高浓度的亚精胺,其发酵产物应用于皮肤防护中可促进负责皮肤屏障功能的桥粒胶蛋白2(DSC2)、ATP结合盒亚家族A成员12(ABCA12)和细胞外基质的主要成分之一I型胶原蛋白α1链(COL1A1)的合成,使其达到增强皮肤屏障、增强皮肤弹性和抗衰老的目的,同时所述的口腔链球菌无细胞毒性,安全可靠,可应用于化妆品中。
生物保藏说明
口腔链球菌JWA714(Streptococcus oralis JWA714),于2022年11月30日保藏在中国典型培养物保藏中心,地址为:中国,武汉,武汉大学,保藏编号为CCTCC NO:M20221853。
附图说明
图1示亚精胺标准曲线;
图2示5#和20#口腔链球菌对角质形成细胞基因表达的影响;
图3示5#口腔链球菌对成纤维细胞基因表达的影响。
具体实施方式
本发明提供了具有抗衰作用的口腔链球菌及其应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明采用的试材皆为普通市售品,皆可于市场购得。
下面结合实施例,进一步阐述本发明:
实施例1菌株分离鉴定与性能研究
1、菌株的分离、鉴定
使用无菌水清洗实验者的面部后,将无菌水喷洒到TSB上37℃有氧条件下生长。收集单个菌落并将其在96孔板的液体TSB培养基(胰蛋白胨大豆培养基)于37℃下培养72小时。以两排为单位收集培养物,以6000rpm的速度离心分离30分钟,收集沉淀物,提取DNA,通过婴儿链球菌的特异性引物进行PCR扩增:
ST2-F,5'-gcaagtagaacgctgaaggagg-3'(SEQ ID NO:8);
ST2-R,5'-caacatctcacgacacgagc-3'(SEQ ID NO:9)。
以实验室嗜热链球菌为阳性对照,痤疮丙酸杆菌为阴性对照,跑胶筛选阳性样本,选取电泳条带亮的菌株进一步通过TSB培养基进行喷板筛选,挑选单菌落培养,进一步分离鉴定,经过几轮筛选获得平板及液体中均能生长的链球菌纯培养物,选取其中菌落形态不一样的菌进行鉴定,得到两株口腔链球菌,如下表1所示。其中5#的16s序列如下所示:cgggcttgctataatgcaagtagaacgctgaaggaggagcttgcttctctggatgagttgcgaacgggtgagtaacgcgtaggtaacctgcctggtagcgggggataactattggaaacgatagctaataccgcataagagtagatgttgcatgacatttgcttaaaaggtgcaattgcatcactaccagatggacctgcgttgtattagctagttggtgaggtaacggctcaccaaggcaacgatacatagccgacctgagagggtgatcggccacactgggactgagacacggcccagactcctacgggaggcagcagtagggaatcttcggcaatggacggaagtctgaccgagcaacgccgcgtgagtgaagaaggttttcggatcgtaaagctctgttgtaagagaagaacgagtgtgagagtggaaagttcacactgtgacggtatcttaccagaaagggacggctaactacgtgccagcagccgcggtaatacgtaggtcccgagcgttgtccggatttattgggcgtaaagcgagcgcaggcggttagataagtctgaagttaaaggctgtggcttaaccatagtacgctttggaaactgtttaacttgagtgcaagaggggagagtggaattccatgtgtagcggtgaaatgcgtagatatatggaggaacaccggtggcgaaagcggctctctggcttgtaactgacgctgaggctcgaaagcgtggggagcaaacaggattagataccctggtagtccacgccgtaaacgatgagtgctaggtgttagaccctttccggggtttagtgccgcagctaacgcattaagcactccgcctggggagtacgaccgcaaggttgaaactcaaaggaattgacgggggcccgcacaagcggtggagcatgtggtttaattcgaagcaacgcgaagaaccttaccaggtcttgacatccctctgaccgctctagagatagagttttccttcgggacaaaaggtgacaggt(SEQ ID NO:1)。
表1.分离菌株
拉丁文名称 | 同源性 | 样本编号 | 来源 |
Streptococcus oralis | 99.08% | 5# | 儿童1#面部 |
Streptococcus oralis | 98.98% | 20# | 儿童1#面部 |
2、发酵液的制备
纯化的链球菌以体积分数5%的接种量接种至TSB培养基中,在150rpm/min摇瓶培养24h,获得链球菌培养物,经6000rpm/min离心10min,获得上清经过滤除菌即得无菌的链球菌代谢物样本。
3、发酵液中亚精胺的定量分析
实验方法:无菌的链球菌代谢物样本可直接进行检测,具体实施方法按照亚精胺(SMD)酶联免疫吸附检测试剂盒说明书进行(ELK Biotechnology),具体的:
(1)实验开始前,各试剂均应平衡至室温,提配置好所有试剂。试剂或样品稀释时,均需混匀,混匀时尽量避免起泡。
(2)加样:分别设标准孔、待测样本孔。加标准品或待测样木50μL,注意不要有气泡,加样将样本加于酶标板孔底部,尽量不触及孔壁,接着每孔加生物素结合物(1×)50L,轻轻晃动混匀,酶标板加上盖或覆膜,37℃温育1小时。
(3)为保证实验结果有效性,每次实验使用新的标准品溶液。
(4)温育1小时后,弃去孔内液体,甩干,洗板3次,每孔加洗涤液(1×)200μL,每次浸泡1~2分钟,甩干。
(5)接着每孔加链霉素-HRP(1×)100μL,轻轻晃动混匀,酶标板覆膜,37℃温育1小时后.弃去孔内液体,甩干,洗板5次,每孔加洗涤液(1×)200μL,每次浸泡1~2分钟,甩干。
(6)依序每孔加TMB显色剂90μL,37℃避光显色15~20分钟(20分钟内,此时肉眼可见标准品的前3~4孔有明显的梯度蓝色,后3~4孔梯度不明显,即可终止)。
(7)依序每孔加终止液50μL,终止反应(此时蓝色立转黄色)。终止液的加入顺序应尽量与底物液的加入顺序相同。为了保证实验结果的准确性,底物反应时间到后应尽快加入终止液。
(8)用酶联仪在450nm波长依序测量各孔的光密度(OD值)。在加终止液后5分钟以内进行检测。
结果:
使用专业曲线绘制软件进行标曲绘制(四参数Logistic曲线拟合):方程:y=(A-D)/[1+(x/C)^B]+D(A=228.04177;B=2.60302;C=0.11253;D=1.09873)R2=0.99920。链球菌发酵液样本中亚精胺含量如表2所示:
表2.链球菌发酵液样本中亚精胺含量
OD450nm | SMD(ng/ml) | |
样本 | X值 | Y值 |
5#(本方案的链球菌) | 0.7736 | 2.59 |
20# | 0.9287 | 2.03 |
5#和20#口腔链球菌发酵液上清液中均含有亚精胺,说明其具有亚精胺的生产能力。其中5#亚精胺生产能力更强。
4、5#链球菌发酵液细胞毒性实验:
不同浓度链球菌发酵液与角质形成细胞及成纤维细胞共孵育24h,MTT法检测菌株培养液对角质形成细胞及成纤维细胞的细胞毒性,具体的:1×104个细胞/孔的密度接种在96孔板中,培养24h后,更换新鲜的培养基(无血清),并添加链球菌发酵液处理细胞24h,弃除上清,加入100μL MTT溶液,培养箱孵育4h后加入110μL的DMSO溶解甲臜结晶,490nm处检测吸光值。细胞毒性结果如表3和表4所示:
表3.链球菌对HSF毒性影响
表4.链球菌对HaCaT毒性影响
5#口腔链球菌的发酵液在4%(v/v)浓度以下对成纤维细胞的细胞无细胞毒性,且在较低浓度,如1%(v/v)和2%(v/v)浓度,对成纤维细胞有促增殖的作用,其发酵液在5%(v/v)浓度以下对角质形成细胞无细胞毒性。
5、评估真皮结构基因的表达水平
细胞培养和St溶液处理:
HSF在成纤维细胞培养体系中培养,待细胞80%汇合时接种到6孔板中,并在37℃,5% CO2的气氛中孵育24小时后,用磷酸盐缓冲盐水(PBS)洗涤细胞一次,并将含5%(v/v)链球菌发酵液的培养基与无补充的培养基加入细胞孔中分别作为实验组和对照组,孵育24小时。
HaCaT在DMEM培养基(添加10%(v/v)FBS,双抗)中培养,待细胞80%汇合时接种到6孔板中,并在37℃,5% CO2的气氛中孵育24小时后,用磷酸盐缓冲盐水(PBS)洗涤细胞一次,并将含4%(v/v)链球菌发酵液的培养基与无补充的培养基加入细胞孔中分别作为实验组和对照组,孵育24小时。
RNA提取及实时荧光定量PCR:
根据制造商的说明(诺唯赞RNA isolater(Vazyme Cat.R401-01 100ml)),从细胞中分离出总RNA。使用逆转录预混料(HiScript II 1st Strand cDNA Synthesis Kit(Vazyme))从1μg总RNA合成cDNA。使用qPCRSYBRGreenMasterMix(Vazyme)进行实时荧光定量PCR扩增反应,对基因表达进行定量,设备:CFX Real-Time PCR System(BIO-RAD,USA)。反应条件如下:在95℃下启动5分钟,然后在95℃下循环10秒,在55℃下20秒,在72℃下20秒,循环40次。β-肌动蛋白被用作内部对照。
引物序列如下:
桥粒芯蛋白2(DSC2):
forward:5′-AGTGTGAGTTTGTTCATCACAGGTC-3′(SEQ ID NO:2);
Reverse:5′-CCATGGCCTCACAGCCTTTA-3′(SEQ ID NO:3);
ABCA12:
Forward:5′-ACAGGAATGGCCTTCATCAC-3′(SEQ ID NO:4);
Reverse:5′-AACATGGTGCCCTGAGAAAC-3′(SEQ ID NO:5);
I型胶原蛋白α1(COL1A1):
Forward:5′-GAGGGCCAAGACGAAGACATC-3′(SEQ ID NO:6);
Reverse:5′-CAGATCACGTCATCGCACAAC-3′(SEQ ID NO:7);
GBA:
Forward:5-GCTAGGCTCCTGGGATCGAG-3′(SEQ ID NO:10);
Reverse:5′-GTTCAGGGCAAGGTTCCAGTCA-3′(SEQ ID NO:11);
FLG:
Forward:5′-AGTGCACTCAGGGGGCTCACA-3′(SEQ ID NO:12);
Reverse:5′-CCGGCTTGGCCGTAATGTGT-3′(SEQ ID NO:13);
如图2所示,链球菌5#及链球菌20#培养上清液处理角质形成细胞,与正常组对比,负责皮肤屏障功能的桥粒胶蛋白2(DSC2)和丝聚蛋白(FLG)的表达水平,葡萄糖神经酰胺酶β(GBA)和ATP结合盒亚家族A成员12(ABCA12)(层状体和神经酰胺的合成能够形成脂质屏障)水平在链球菌5#中有上升趋势(GBA的数据,由于数据离散太大,显著性分析没有显著性),其中桥粒胶蛋白2(DSC2)及ATP结合盒亚家族A成员12(ABCA12)基因表达量与对照相比有显著上升。桥粒胶蛋白2和葡萄糖神经酰胺酶β在链球菌20#中与对照组相当,无上升趋势。
链球菌5#处理成纤维细胞还显著增加了细胞外基质的主要成分之一I型胶原蛋白α1链(COL1A1)的表达量(如图3所示)。
6、5#链球菌发酵液的急性眼刺激性/腐蚀性试验
依据《化妆品安全技术规范》(2015年版)第六章5急性眼刺激性试验,取10%(v/v)浓度的发酵液0.1m作为受试物,滴入家兔左侧眼结膜囊内,闭合1s,给药后不冲洗。右侧眼不做处理作为自身对照,在滴入受试物后1、24、48、72h对动物眼睛进行检查,如果72h未出现刺激反应,即可终止试验,除了对角膜、虹膜、结膜进行观察外,其他损害效应均应当记录并报告,在每次检查中均应按检测依据表5眼损害的评分标准记录眼部刺激反应的积分。
表5.眼损害的评分标准
表6.眼刺激性试验观察结果
给受试物后动物角膜、虹膜或结膜各自在24、48和72h观察时点的刺激反应积分0,按检测依据表5化妆品原料眼刺激性反应分级判定,样品对眼刺激强度(未冲洗)为无刺激性。
7、5#链球菌发酵液的斑贴实验
依据《化妆品安全技术规范》(2015年版)对5#链球菌的发酵液进行皮肤封闭型斑贴试验,将20μl受试物(体积分数分别为1%、2%和4%的发酵液)滴加于斑试贴内,将加有受试物的斑试器贴敷于受试者的前臂曲侧,用手掌轻压使之均匀地贴敷于皮肤上,持续24h,同时留一个空白的斑试器作为空白对照。24h后去除受试物斑试器,于0.5h、24h和48h分别观察一次皮肤反应。按表7(皮肤不良反应分级标准表)记录反应结果,皮肤封闭型斑贴试验结果解释:受试者中出现1级皮肤不良反应的人数多于5例,或2级皮肤不良反应的人数多于2例(除臭产品斑贴试验2级反应的人数多于5例),或出现任何1例3级或3级以上皮肤不良反应时,判定受试物对人体有皮肤不良反应。
表7.皮肤不良反应分级标准
表8.皮肤封闭型斑贴试验皮肤反应分级标准
共30名志愿者完成了3个样品的斑贴实验,结果未出现阳性反应,说明5#链球菌发酵液样品较为安全。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.保藏编号为CCTCC NO:M 20221853的口腔链球菌(Streptococcus oralis)。
2.包括权利要求1所述的口腔链球菌的菌群。
3.包括权利要求1所述的口腔链球菌或权利要求2所述的菌群的菌剂。
4.权利要求1所述的口腔链球菌在制备含有亚精胺产品中的应用。
5.亚精胺的制备方法,其为培养如权利要求1所述的口腔链球菌,获得含有亚精胺的培养物。
6.权利要求1所述的口腔链球菌、权利要求2所述的菌群、权利要求3所述的菌剂、和/或权利要求5所述的制备方法制得的含有亚精胺的培养物在制备改善肤质的产品中的应用。
7.根据权利要求6所述的应用,其特征在于,所述改善肤质包括修复皮肤屏障或增强皮肤弹性中的至少一种。
8.根据权利要求7所述的应用,其特征在于,所述修复皮肤屏障包括促进皮肤屏障功能基因的表达,所述皮肤屏障功能基因包括DSC2和ABCA12。
9.根据权利要求7所述的应用,其特征在于,所述增强皮肤弹性包括促进细胞外基质合成相关基因的表达,所述细胞外基质合成相关基因包括COL1A1。
10.改善肤质的产品,其特征在于,其原料包括权利要求1所述的口腔链球菌、权利要求2所述的菌群、权利要求3所述的菌剂、和/或权利要求5所述的制备方法制得的含有亚精胺的培养物。
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