CN101980022B - 可溶性的桥粒芯糖蛋白i蛋白物质用于筛选抗衰老活性剂的用途 - Google Patents
可溶性的桥粒芯糖蛋白i蛋白物质用于筛选抗衰老活性剂的用途 Download PDFInfo
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Abstract
本发明涉及一种或多种桥粒芯糖蛋白I的可溶性肽复合物或非复合物的用途,该肽可用作一种标记,用以评估活性剂和/或治疗、尤其是表皮的抗衰老活性剂和/或治疗的效果。
Description
技术领域
本发明涉及可溶性肽复合物或非复合物的应用,该肽至少部分地衍生于桥粒芯糖蛋白I,其对出现一个或多个皮肤衰老征兆的表皮表现出了潜在活性剂作用。
背景技术
上皮是一种组织,该组织中的细胞相互结合并连结于基膜上。该细胞可以形成一种外膜,如在皮肤表面、或者表皮、或在粘膜表面形成内膜,也可形成腺。
更具体地,该上皮是一种内环境稳定的组织,其内稳定环境源于在细胞增殖、转移与分化的所有阶段都实现了一套调整完好的细胞内与细胞外信号,并且该上皮组织还是各种不同细胞外基质成分的综合体。这些信号特别地源于角质形成细胞所产生的因子的运动。
保持正确的上皮生理功能涉及,特别地是上皮细胞终末分化和/或蛋白多糖合成。
至于更优选地表皮是一种上皮,通常分为角质形成细胞基底层、“刺状”层、“粒状”层和角质层。该角质形成细胞基底层作为表皮生发层的成分,包含特别地皮肤干细胞,“刺状”层是由许多基底层上的多面形细胞层组成的,“粒状”层包含一个或三个以前所知的扁平细胞层,该扁平细胞层包含不同的细胞质内含物和角质透明蛋白粒,最后是一组上层细胞,称为角质层(或者角质层),该角质层是由处于分化终末阶段的角质形成细胞(即comeocytes)构成。
角质层是皮肤的最外层,其作用是作为屏障、将皮肤组织与外界环境隔离开,毛干是毛囊的突出部分,其毛囊组成了浓浓的头发,角质层与毛干都代表了角质形成细胞分化过程的结果。基底层的角质形成细胞在成熟过程中分化并转移后,表皮出现分化,从而形成comeocytes,该角质细胞是一种彻底的角质化死细胞。这种分化是完全协调现象的产物,该现象形成了保持不变的表皮厚度,从而确保表皮内环境的稳定。
许多皮肤病或病理学条件起因于表皮内稳定环境的紊乱。
至于衰老皮肤,其紊乱一般会通过皱纹(小皱纹和深层皱纹)的出现、弹性的丧失、粗糙感和干燥来显现。从组织学的角度看,会发现真皮表皮连接处变扁及真皮与表皮的厚度变薄。胶原和葡萄糖胺聚糖含量减少。皮肤的屏障作用受到损坏。所有这些现象都会由于太阳下的慢性暴晒而增多。
同样地,这种紊乱在更年期妇女身上可能会更加厉害。
现在,众所周知的是,这些紊乱现象可能会特别地与角质层中某些蛋白的表达和/或其生物活性的不同调节有关。特别地是桥粒芯糖蛋白I的情况。
作为一种跨膜糖蛋白,桥粒芯糖蛋白I(也称作DGI)以其前蛋白原的形式存在,并包含1049种氨基酸,其分子量约为114Kda至150Kda,具体取决于该蛋白是否糖基化。蛋白序列在天冬酰胺残基上的糖基化位点是36、110和180位置,除此之外,该蛋白序列也包含钙结合部位。
该蛋白与钙粘素相关,并属于包括桥粒芯糖蛋白II和III的蛋白家族。DGI只以桥粒的形式存在,桥粒是DGI主要的结构元素之一。
专利文件US 2004/0142335报道了:通过转录组分析,与年轻人相比,年长的人皮肤上的mRNA(信使核糖核酸)表达有所增加,该mRNA(信使核糖核酸)编码桥粒芯糖蛋白I蛋白。该专利没有公开任何的可溶性桥粒芯糖蛋白I。
发明专利内容
近来,本发明人指出了在表皮自然老化过程中,角质层上的桥粒芯糖蛋白I表达明显增加,并且得到了积累。所以,桥粒芯糖蛋白I在角质层上的表达水平成为一种用以描述皮肤、优选地衰老皮肤的生理条件特征的有效指标。
就发明本身而言,本发明源于本发明人对人体角质层上可溶性肽的特征描述,该角质层经过了脱屑性治疗,并且该可溶性肽不同于、但却衍生于桥粒芯糖蛋白I。人们可认为本发明人所述肽衍生于或至少部分衍生于桥粒芯糖蛋白I的蛋白水解作用。
特别是,不同于全序列桥粒芯糖蛋白I,命名为SEQ ID NO2的可溶性蛋白。如下文所述,凭借特殊的ELISA(酶联免疫吸附测定)法的研制,优选以下实施例1中所述的方法,本发明人描述了该蛋白的可溶性肽复合物或非复合物的特征。因此,人们发现这些可溶性物质是一种特别有益的工具,可以用来筛选抗衰老活性剂,或者甚至描述预防和/或治疗皮肤衰老的治疗效果,特别地通过一种活动,或许是对皮肤衰老过程中角质层上所积累的桥粒芯糖蛋白I的降解活动。
在这两种情况中,活性剂的作用或本发明所述的治疗效果通过增加至少一种,或更多种本发明所述可溶性物质的释放得以验证。
所以,一方面,本发明涉及至少一种可溶性肽复合物或非复合物的使用,该肽衍生于或至少部分衍生于包含一种氨基酸序列的多肽,编码该氨基酸序列的核酸序列是由全部或部分SEQ ID No.1、或其类似物来表示的,该氨基酸序列可用作一种筛选工具,筛选能预防和/或治疗皮肤衰老的活性剂。
在一个优选的实施方案中,适用于本发明的可溶性蛋白不是由SEQ ID NO2序列表征的。
这些可溶性肽数量的增加是抗衰老治疗效果的指标。
特别地,检测上述肽的存在或其含量增加是活性剂的一种指标,表示该活性剂具有能预防和/或治疗皮肤衰老的特性。
本发明还涉及一种活性剂,优选地抗衰老活性剂的筛选方法,包括至少以下步骤:
a)适合上述可溶性肽释放的条件下,能将至少一种细胞类型与至少一种试验抗衰老活性剂相接触,该细胞类型能释放至少一种本发明所述可溶性物质,
b)确定上述可溶性肽的数量,以及
c)用上述可溶性物质的数量比较步骤b)所确定的数量,该可溶性物质的数量是在没有试验用化学化合物或生物化合物的情况下确定的。
优选地,在步骤c)的最后也可进行选择活性剂的步骤,可溶性物质数量的增加是为了选择活性剂。
另一方面,本发明还涉及一种非侵入性、优选地美容方法,该方法用于描述对个体美容或治疗的效果特征,该美容或治疗是为了预防和/或治疗与人体自然老化有关的皮肤衰老征兆,如皱纹和细纹,并且包含至少定性或定量的表征(characterization),描述本发明所述的桥粒芯糖蛋白I的至少一种可溶性肽的特征。
特别地,按照本发明所述方法,检测或描述上述肽的存在或其含量增加的特征能反映上述活性剂的作用或上述治疗的效果。
在本发明的一种实施方案中,上述其中一种方法也可包含至少一个附加步骤,该附加步骤在桥粒芯糖蛋白I的至少一种可溶性肽的特征描述步骤的最后,即:将一种护理、优选地美容组合物施于个体上,该组合物是由上述可溶性物质中所获得的信息得以确定或选择的。优选地,上述附加步骤与特征描述步骤可以是连续的。在本发明的一种实施方案中,这种组合物可从一系列组合物中进行选择,该系列组合物均适合特征描述步骤最后所获得的信息类型。
所以,本发明的优势在于提出了一种简单而迅速的方法,首先,该方法能描述上皮以及优选地皮肤表皮的生理状态的特征,其次,该方法能相应地调整上述上皮或表皮的治疗。
所述术语“皮肤衰老征兆”是指由于自然老化,皮肤出现的任何外观变化,例如皱纹和细纹、皮肤干枯、皮肤失去弹性和/或紧张性、真皮变薄和/或胶原纤维降解,从而导致皮肤出现松弛和皱纹。
更优选地,上述非治疗方法的目的是描述治疗效果的特征,该治疗能预防和/或治疗个体皮肤衰老征兆,包含至少以下步骤:
i提供至少第一个代表上述个体的皮肤表面样品,
ii.在上述样品中,特别地通过ELISA(酶联免疫吸附测定)法,优选地通过以下实施例1所述的方法对本发明所述的至少一种可溶性肽定量,
iii对代表上述个体的第二个皮肤表面样品重复进行步骤i和ii,以及
iv比较步骤ii和iii最后所得结果,优选地由此推导出与至少一个治疗效果、与不同治疗阶段相对应的上述第一和第二个皮肤表面样品有关的信息。
步骤ii的参考值或数据是在开始上述治疗前从代表个体的上皮、优选地表皮中获得的数据,该个体是治疗受试者。
在本发明的一种优选的实施方案中,第一个样品代表治疗前的状态,第二个样品代表治疗期间或治疗后的状态。
在步骤iv中,检测上述可溶性肽的数量和增量能反映上述治疗效果。
在另一种实施方案中,本发明所述方法可进一步包括对上述个体进行上述治疗的调节步骤,通过使用一种美容护理组合物进行该治疗,通过步骤iv最后所得信息确定或选择该组合物。
另一方面,本发明还涉及使用至少一种本发明所述可溶性肽作为筛选工具,筛选能与桥粒芯糖蛋白I反应,优选地使其降解的生物化合物或化学化合物,从而引起并促使桥粒芯糖蛋白I的可溶性物质得到释放。
可溶性物质的特征描述对确定表皮状态的诊断也是有用的。
所以,本发明涉及一种本发明所述可溶性肽的使用,该可溶性肽可用作一种工具以描述上皮自然老化状态的体内和体外特征,检测上述肽的含量或减量是上皮组织自然老化状态的指标。
另一方面,本发明涉及一种非侵入性、尤其是美容性的体内或体外表征表皮自然状态的方法,包括对本发明所述桥粒芯糖蛋白I的可溶性肽进行至少定性或定量表征。
上皮状态的特征描述方法包含至少以下步骤:
a)特别地通过ELISA(酶联免疫吸附测定)法,确定该上皮的表面样品中至少一种本发明所述可溶性肽的数量,以及
b)用参考值比较步骤a)所确定的上述数量。
在本发明的另一个实施方案中,通过与至少上皮、优选地表皮中获得的参考数据段或值相比较,所得数据段或值能够得到评估,该数据段或值不同于特征描述的主题,并且具有已知状态。
本发明所述方法可在体外或体内进行。
按照以下所述描述,本发明所述方法在实施方面具有优选的优势,即不需要侵入性操作。
这是因为本发明人在角质层上定位了这些新的生物标记,从而使得通过简单的局部取样便能对上述标记进行定性或定量的特征描述。
优选地,可以通过简单的剥离对本发明的个体的角质层取样。取样方法可以是如剥离法,即将一部分胶带置于当前上皮组织上,如表皮。当拿开胶带时,会有一部分上皮如表皮部分得到剥离。提取蛋白后,可通过本发明所述ELISA(酶联免疫吸附测定)法分析上述剥离部分。
另一方面,本发明涉及一种本发明所述可溶性肽有效量的使用,用于制备和/或改进多层的细胞模型,优选地再造皮肤模型。
为达到本发明的目的,所述术语“有效量”是指获得预期效果所需的最小量。
另一方面,本发明涉及一种分离的再造皮肤的制备方法,该方法包含至少一个步骤,该步骤能将至少一种本发明所述可溶性肽与细胞相接触,其细胞能产生分离的再造皮肤,及优选地角质形成细胞。
桥粒芯糖蛋白I的“可溶性”的定义
为达到本发明的目的,所述术语“可溶性”是指:本发明所述的肽复合物或非复合物不需要蛋白变性物质便能在水或水介质中溶解,如促溶剂或离子型去垢剂,而天然的桥粒芯糖蛋白I与之相反,该蛋白只能在这种剂存在的情况下才能提取。
为达到本发明的目的,所述术语“复合物“是指本发明所述的其中一种肽与不同于桥粒芯糖蛋白I的蛋白或其蛋白片段、或另一种可溶性桥粒芯糖蛋白I蛋白或其衍生物的可溶性结合。
为达到本发明的目的,所述术语“桥粒芯糖蛋白I蛋白的衍生物“是指该蛋白的片段或类似物,如下文所述。
这些可溶性复合物可以是桥粒芯糖蛋白I蛋白或其片段与第二种蛋白相结合的产物,第二种蛋白也称作靶蛋白。
通过解释这些能与桥粒芯糖蛋白I和/或其片段相互反应的蛋白,可特别提及的有桥粒芯胶蛋白2a(Dsc 2),斑珠蛋白(Plakophilins)1、2和3,盘状球蛋白,激肽释放酶5,生长激素1(GH1),SSSCA1(27KD着丝粒自身抗原),RuvB-like 1,C3orfl0蛋白及VRK3(牛痘相关激酶3)。
如先前所述用途,本发明所述的可溶性物质衍生于、至少部分衍生于包含一种氨基酸序列的多肽,编码该氨基酸序列的核酸序列是由全部或部分SEQ ID No.1、或其类似物来表示的。
为达到本发明的目的,所述术语“核酸序列片段“是指能对多肽进行部分编码的核酸序列,及优选地用SEQ ID No.1或其类似物表示的核酸序列。本发明所述可溶性物质或其类似物衍生于该多肽。
所述术语“核酸序列的类似物“是指任选地产生于核酸编码的简并及对可溶性物质进行部分编码的任意核酸序列,该可溶性物质所含序列等于或类似于上述核酸序列部分编码的可溶性物质。
该核酸序列可以来自所有可能来源,即:动物、优选地哺乳动物、或者甚至更优选地人类、或植物、或微生物(病毒、噬菌体、细菌及其他)或者真菌,而无需事先判断该序列是否天然存在于上述有机体来源中。
按照本发明的另一种实施方案,本发明所述可溶性物质衍生于、至少部分衍生于包含一种氨基酸序列的多肽的蛋白水解作用,该氨基酸序列用SEQ ID No.2、或其类似物来表示。
为达到本发明的目的,除非特别说明,所述术语“桥粒芯糖蛋白I”通常是指经过或没有经过在天冬酰胺残基的36,110或180位置上N-乙酰糖基化翻译后修饰的蛋白质序列(SEQ ID No.2),并能修饰其表观分子量或等电点。
此外,众所周知地是:多肽的基本序列,即一系列氨基酸,确定了由蛋白酶特别识别的位置,如胰蛋白酶,一旦这些位置的识别生效,该基本序列将通过蛋白水解作用引起多肽分解。该蛋白水解作用会产生各种不同的肽、或者蛋白水解片段,当这些肽或片段呈可溶性时,则可代表本发明所述桥粒芯糖蛋白I的可溶性肽。
所以,按照本发明的一种优选的实施方案,本发明所述的可溶性物质衍生于包含一种氨基酸序列的多肽,该氨基酸序列选自SEQ ID No.3,SEQ ID No.4,SEQ ID No.5,SEQID No.6,SEQ ID No.7,SEQ ID No.8,SEQ ID No.9,SEQ ID No.10,SEQ ID No.11,SEQ IDNo.12,SEQ ID No.13,SEQ ID No.14,SEQ ID No.15,SEQ ID No.16,SEQ IDNo.17,SEQ IDNo.18,SEQI ID No.19,SEQ ID No.20,SEQ ID No.21,SEQ ID No.22,SEQID No.23,SEQ IDNo.24,SEQ ID No.25,SEQ ID No.26,SEQ ID No.27,SEQ ID No.28,SEQ ID No.29,SEQ IDNo.30,SEQ ID No.31,SEQ ID No.32,SEQ ID No.33,SEQ ID No.34,SEQ ID No.35,SEQ IDNo.36,SEQ ID No.37,SEQ ID No.38,SEQ ID No.39,SEQ IDNo.40,SEQ ID No.41,SEQ IDNo.42,SEQ ID No.43,SEQ ID No.44,SEQ ID No.45,SEQID No.46,SEQ ID No.47,SEQ IDNo.48,SEQ ID No.49,SEQ ID No.50,SEQ ID No.51,SEQ ID No.52,SEQIDNo.53,SEQ IDNo.54,SEQ ID No.55,SEQIDNo.56,SEQ ID No.57,SEQ ID No.58,SEQ ID No.59,SEQ IDNo.60,SEQ ID No.61,SEQ ID No.62,SEQ IDNo.63,SEQ ID No.64,SEQ ID No.65,SEQ IDNo.66,SEQ ID No.67,SEQ ID No.68,SEQID No.69,SEQ ID No.70,SEQ ID No.71,SEQ IDNo.72,SEQ ID No.73,SEQ ID No.74,SEQ ID No.75,SEQ ID No.76,SEQ ID No.77,SEQ IDNo.78,SEQ ID No.79,SEQ ID No.80,SEQ ID No.81,SEQ ID No.82,SEQ ID No.83,SEQ IDNo.84和SEQ ID No.85,及其混合物。
所述术语“多肽类似物“是指任何显示序列同源性、优选地上述多肽的其中一个特征序列的多肽,和任何显示相同性质的生物活性的多肽。这种类似物可能是一种肽类似物。
同源性可以至少为85%,如至少90%,以及如至少95%。该同源性可通过目测比较或者本领域内通常使用的任何计算机工具得到确定,如与缺省参数联用的BLAST程序(www.ncbi.nlm.nih.gov上有该程序)。
序列同源性可能衍生于一种修饰作用,该修饰作用源自本发明所述肽的序列突变或变异,该突变或变异产生于在本发明所述多肽的特征序列中删除、插入或替换一种或多种氨基酸。
为达到本发明的目的,所述术语“片段“是指任何肽部分,该肽部分包含至少4个、至少6个、优选地至少8个、及更优选地至少12个桥粒芯糖蛋白I的连续氨基酸,并且该肽部分实质上具有相似的的生物活性。一般地,多肽类似物包括天然氨基酸序列的保存性置换。
许多这种修饰可以进行合并。
通过本发明所述的突变例子,可提及的是:用包含相似水疗指数的氨基酸残基替代一个或多个氨基酸残基,但这实质上并没有影响桥粒芯糖蛋白I的天然生物特性。
水疗指数是指根据氨基酸的疏水性和电荷(Kyte et al.(1982),J.Mol.Biol.,157:105)分配得到的指数。
本发明所涉及的可溶性物质可以衍生于经过一种或多种翻译后修饰的多肽。
所述术语“翻译后修饰”是指:一种肽或蛋白在细胞内合成的最后所能进行的所有修饰,例如一种或多种磷酸化、一种或多种硫醇化、一种或多种乙酰化、一种或多种糖基化、一种或多种脂化,如法尼基化或棕榈酰化、结构重排如二硫桥的形成或肽序列的裂解。
此外,该类似物实质上具有与天然多肽相似的生物活性。
按照本发明的一种实施方案,适合于实施本发明的可溶性物质也可以是天然或合成的多肽,通过天然桥粒芯糖蛋白I的酶裂解或化学溶胞后、或者化学或生物合成或者生物组织的提取获得该可溶性物质,例如自然表达这些可溶性物质的皮肤、及其各种不同的翻译后形式。
按照本发明的一种实施方案,本发明所述的复合可溶性物质可以衍生于桥粒芯糖蛋白I或其片段与另外一种桥粒芯糖蛋白I蛋白或其片段、或靶蛋白的结合。
靶蛋白优选地选自桥粒芯胶蛋白2a(Dsc 2),亲斑蛋白质1、2和3,盘状球蛋白,激肽释放酶5,生长激素1(GH1),SSSCA1(27KD着丝粒自身抗原),RuvB-like1,C3orfl0蛋白及VRK3(牛痘相关激酶3)。
本领域技术人员可通过以重组DNA技术为基础的方法获得本发明所述可溶性物质,例如“分子克隆-实验室手册”(第2版)Sambrook et al.,1989,Vol.I-III,ColdspringHarbor Laboratory,
按照本发明的另一种实施方案,适合于实施本发明的可溶性物质也可以是一种与不同于上述定义的另一种多肽相融合的形式,亲水或疏水靶向剂、生物转化前驱物、或者发光、放射性的或比色标定剂。
从非限制性方面看,可提及的荧光蛋白如“绿色荧光蛋白”,荧光化学化合物如若丹明、荧光素或德克萨斯红磷光化合物,放射性元素如3H、14C、35S、121I或125I,或者比色标定剂如发色底物,该发色底物对半乳糖苷酶、过氧物酶、氯霉素乙酰转移酶、荧光素酶或碱性磷酸酯酶的作用敏感。该荧光蛋白是一个能与本发明所述可溶性物质相耦合的化合物例子。
随着与本发明所述可溶性物质相耦合的化合物性质的不同,可以通过化学方法、优选地化学反应作用、或者本领域技术人员所熟知的分子生物学方法进行该耦合。通过多肽的检测方法,可提及的有蛋白质印法,狭线印迹法,点渍法,单重或多重ELISA(酶联免疫吸附测定)法,蛋白组学或糖组学法,在聚丙烯酰胺凝胶中用银基染料、考马斯蓝或者SYPRO染料进行的多肽染色法,免疫荧光法,紫外吸收法,常规、电子或共聚焦显微镜下的免疫组织化学法,FRET(荧光共振能量转移)法,TR-FRET(时间分辨荧光共振能量转移)法,FLIM(荧光寿命显微成像)法,FSPIM(荧光光谱显微成像)法,FRAP(荧光漂白恢复)法,报道基因法,AFM(原子力显微镜)法,表面等离子共振法,微量量热法,流式细胞法,生物传感器法,放射性免疫测定(RIA)法,等电聚焦法和酶分析法,使用肽芯片、糖芯片、抗体芯片的方法,质谱分析法、和SELDI-TOF(表面增强激光解吸电离-飞行时间光谱测定)法(Ciphergen)。
按照上述所述用途,优选地通过ELISA(酶联免疫吸附测定)法、及更优选地通过以下实施例1所述的方法描述本发明所述可溶性物质的特征。
使用本发明所述可溶性物质的目的是:筛选抗衰老活性剂和/或描述对皮肤衰老征兆进行治疗的效果特征。
按照以上所述用途,一方面,本发明涉及一种非侵入性方法,该方法用来描述、特别地从体外方面描述抗衰老活性剂或美容或治疗效果的特征,通过定性或定量分析本发明所述可溶性物质来描述该治疗效果的特征。
这些方法在其实施方面具有优选的有利性,即无需借助外科技术便可实施该方法,从而进行该特征描述。
如以下所述用途,本发明所述方法可在样品上进行,例如取自个体身上的上皮的、和优选地表皮的分离样品。
本发明所述方法也可以在上皮样品,及优选地表皮样品上进行从而确定其状态,该样品取自上皮细胞、及优选地表皮模型或再造的分离皮肤。
所以,通过简单的剥离便可以进行表皮提取,并且可以通过以下实施例1所述的ELISA(酶联免疫吸附测定)法对所提取的表皮直接进行分析。
剥离技术是将粘性表面应用于表皮表面,如3M公司生产的D′squam(CuDERM公司生产的商用胶粘剂)、或氰基丙烯酸酯粘合剂。通过这种剥离,可以对附着的角质细胞及其细胞间隙的数量进行取样,然后提取该样品,从而获得提取物中的蛋白质含量。
合适的取样方法也可以更直接地通过“清洗”皮肤表面来进行,采用例如叶式水轮机的配件或者与流体电路相结合的螺旋细胞(专利文件FR2 667 778中有所描述)、或者直接在皮肤表面加入/除去一滴缓冲液来“清洗”皮肤表面。
通过适合实施本发明的其他取样方法的指导,可提及的方法是以刮取角质层上部分为基础的方法,该角质层的上部分可通过双叶片系统或刮取活组织检查法进行刮取。这种方法能够收集鳞屑,并且可以通过各种不同的方法直接分析所收集的鳞屑,从而确定无机物、氨基酸或脂类的数量。
在取样最后,通过以下实施例1所述的ELISA(酶联免疫吸附测定)法描述该样品的特征。
该方法的基础优选地是抗体的使用,该抗体适用于检测本发明所述可溶性物质。
抗体可用作一种工具,用以评估表皮的状态。通过本领域技术人员所熟知的任何方法可以获得该抗体,具体在“抗体:实验室手册”,Cold Spring Harbor LaboratoryPress,ColdSpring Harbor,N.Y.(1990)中有所描述。优选地,所用抗体是重组抗体,如Antibodies-by-design(AbD)公司研制的重组抗体。
如以下实施例1所述用途,桥粒芯糖蛋白I的可溶性物质的检测方法需要优选地使用两种抗体,即:采用HuCAL技术(AbD克隆AbyD03984)研制的捕获抗体(人组合抗体库)与MSD指标所要求的带有“sulpho-tag”标签的检测抗体(单克隆抗体,克隆129204,R&D系统)。
生物化合物或化学化合物的筛选
本发明涉及一种筛选生物或化学化合物、或者甚至抗衰老活性剂、或物化因子的方法,该方法能在桥粒芯糖蛋白I上反应,并且最终影响本发明所述可溶性物质的释放,该方法包含至少以下步骤:
a)在适合上述可溶性肽释放的条件下,将至少一种细胞类型与至少一种试验化学或生物化合物相接触,该细胞类型能释放至少一种本发明所述可溶性肽,
b)确定上述可溶性肽的数量,以及
c)用上述可溶性物质的数量比较步骤b)所确定的数量,该可溶性物质的数量是在没有试验化学或生物化合物的情况下确定的。
优选地,在步骤c)最后也可进行选择活性剂的步骤,增加可溶性物质数量是为了选择活性剂。
步骤c)所做的比较能推导出修饰桥粒芯糖蛋白I的该实验化合物的特性信息,并且该特性能影响本发明所述可溶性物质的释放。
在这方面,对桥粒芯糖蛋白I产生作用的化合物能引起本发明所述桥粒芯糖蛋白I的可溶性物质的释放,该桥粒芯糖蛋白I会随着年龄的增长积累在角质层上。检测上述可溶性肽的存在或其含量增加可以作为化学或生物化合物的指标,该化合物能在桥粒芯糖蛋白I上反应。
更优选地,治疗效果的特征描述方法可包含至少以下步骤,该治疗能预防和/或治疗个体皮肤老化的信号:
i.提供至少第一个代表上述个体的皮肤表面样品,
ii.优选地通过ELISA(酶联免疫吸附测定)法对上述样品中至少一种本发明所述的可溶性肽定量,
iii.对代表上述个体的第二个皮肤表面样品重复进行步骤i和ii,以及
iv.比较步骤ii和iii最后所得结果,优选地由此推导出与至少一个治疗效果、与不同治疗阶段相对应的上述第一和第二个皮肤表面样品有关的信息。
如果在使用生物化合物或化学化合物、或者甚至抗衰老活性剂、或者供实验的物化因子之前测定了参考值,那么本发明所述方法也能适当地评估上述化合物的潜在效果。
本发明所述可溶性物质的释放可能不会受到上述化合物的影响,或者换言之,不会受到刺激影响。
如果出现了刺激效应,那么该实验化合物便可以用作如一种抗衰老活性剂。
本发明所述方法能在分离的细胞样品上进行。
通过特定地ELISA(酶联免疫吸附测定)法可以确定本发明所述可溶性物质的数量,该方法在以下实施例1中有所描述。
本发明还涉及一种本发明所述可溶性物质的有效量的使用,用于制备和/或改进多层的细胞模型,优选地表皮或粘膜细胞模型,及优选地再造皮肤模型。
为达到本发明的目的,所述术语“再造皮肤模型”是指各种不同的细胞类型相结合的模型,该细胞类型如,优选地皮肤的天然成分,例如角质形成细胞、成纤维细胞、朗格汉斯细胞和黑素细胞。
成纤维细胞可以或没有受到辐射。
该模型及其制备为本领域技术人员所熟知。
所以,本发明还涉及一种分离的再造皮肤的制备方法,该方法包括至少一个步骤,该步骤能将至少一个本发明所述可溶性物质与细胞相接触,其细胞能产生分离的再造皮肤,及优选地角质形成细胞。
为达到本发明的目的,另一方面,上述桥粒芯糖蛋白I的可溶性物质可以用于一种美容或治疗组合物中。
众所周知的是:本发明所述的所有美容或治疗组合物都采用了一种生理上可接受的介质。
为达到本发明的目的,所述术语“生理上可接受的介质”是指能将一种组合物应用于上皮或角蛋白材料上的合适介质,该角蛋白材料如皮肤、头皮、嘴唇、粘膜和角蛋白纤维如头发、指甲与体毛,或者适当地通过口服或肠外应用该组合物。按照本发明的一种优选的实施方案,本发明可以是一种美容或治疗组合物。
除了可溶性物质,本发明所述的组合物可以包含至少一种美容和/或治疗的活性剂。
在本发明所述的活性剂的例子中,可提及的有美容油,如硅油、甘油三酯植物油、羟基油如Parleam油和脂肪酸酯及脂肪醇酯。
也可使用其他能改善皮肤条件的活性剂,如保湿活性剂或能改善天然类脂屏障的活性剂,如神经酰胺、胆固醇硫酸盐和/或脂肪酸、及其混合物。
也可使用在皮肤上有活性的酶,如蛋白酶、脂肪酶、葡萄糖苷酶、酰胺酶、脑甙酶和/或melanases酶、及其混合物。
一般地,本发明所述任何组合物都可以应用于皮肤(在身体的任何皮肤部位)或粘膜(口腔、颧骨、牙龈、生殖器、结膜等)上。
众所周知地,一种美容组合物也可包含该领域常用的辅助剂,如亲水或亲脂胶凝剂、亲水或亲脂添加剂、防腐剂、抗氧化剂、溶剂、芳香剂、填充剂、遮蔽剂、吸味剂和染料。
本发明所述组合物中各种成分的含量是本领域的常规用量。
另一方面,本发明涉及一种美容治疗皮肤衰老征兆的方法,该方法包含至少一个步骤,该步骤将至少一种本发明所述化妆品组合物应用于至少部分皮肤、粘膜和/或角蛋白纤维上。
另一方面,本发明还涉及使用、优选地美容和/或治疗性使用桥粒芯糖蛋白I的可溶性肽、或其类似物、或者多肽的活性、表达和/或稳定性的调节剂,从而特别地阻止皮肤衰老征兆、优选地预防和/或治疗衰老皮肤。
按照本发明的另一种实施方案,本发明涉及一种调节剂的使用,该调节剂能调节本发明所述可溶性物质。
为达到本发明的目的,所述术语“调节”是指从指定效果的角度出发,能够刺激或抑制该指定效果的活动。
为达到本发明的目的,所述术语“调节剂或能调节生物活性和/或表达的化学或生物化合物”是指:任何能直接或间接对本发明所述可溶性物质产生反应的化合物,或者对可溶性物质进行部分编码的核酸序列,或者直接或间接对胞内或胞外信号途径元件产生反应的化合物,或者对涉及上述可溶性物质的代谢途径元件产生反应的化合物,或者对核酸序列的转录和/或翻译及上述可溶性物质的稳定性的调节元件产生反应的化合物,该核酸序列能编码上述可溶性物质。
该调节剂可以抑制或激活本发明所述可溶性物质的表达,或者调节上述可溶性物质的稳定性。
更优选地,该调节剂可以是本发明所述的可溶性物质表达的活性剂。
按照本发明的一种优选的实施方案,通过抑制其蛋白水解性降解作用,该调节剂可以促进本发明所述可溶性物质的稳定性。
以下所示实施例对本发明进行了非限制性说明。
附图说明
图1:该图说明了通过本发明所述的高灵敏度ELISA(酶联免疫吸附测定)法监测活性剂的效果,该活性剂能作用于桥粒芯糖蛋白I的降解作用上。
图2:该图说明了血清对本发明所述可溶性肽的数量的作用,该血清是由10%的bifidiobiotic(CLR复合物)及0.002%的植物鞘氨醇-SLC(“G”处理)组成的。
具体实施方式
实施例1:
研制高灵敏度的ELISA(酶联免疫吸附测定)法是为了检测本发明所述桥粒芯糖蛋
白I的可溶性
采用MesoScale Discovery(MSD)公司的技术研制开发了“桥粒芯糖蛋白”-特定的96-孔板。
通过采用HuCAL(人组合抗体库)技术(公司:Antibodies by Design)、并借助于重组桥粒芯糖蛋白所进行的筛选研制开发了重组捕获抗体(克隆AbyD03984),该捕获抗体可用于抑制桥粒芯糖蛋白的胞外域。
在200μg/ml的浓度条件下,该捕获抗体滴在标准96-微孔板上。
利用重组桥粒芯糖蛋白可以确定参考曲线(400至6ng/ml)。在室温条件下,用一种封闭液(MesoScale)封闭每块孔板1小时。各取三份样品与标准品,每份各25μl,然后放在室温下搅拌培养1小时。然后用三羟甲基氨基甲烷缓冲液(MesoScale)冲洗该孔板4次。在室温条件下,用25μl的检测抗体(单克隆抗体,克隆129204,R&D系统)、通过搅拌培养该孔板1小时,该检测抗体的浓度为1μg/ml,并带有MSD指标所要求的“sulpho-tag”标签。在加入150μl的1X read buffer T(MesoScale)之前,先用三羟甲基氨基甲烷缓冲液(MesoScale)清洗该孔板4次。用″Sector Imager 6000″读取该孔板。用Bradford试剂盒(Bio-Rad)测定ng/μg(每ng桥粒芯糖蛋白在每μg总蛋白的含量),并对该数据进行标准化处理。
实施例2:
使用高灵敏度ELISA(酶联免疫吸附测定)法筛选活性剂,该活性剂能作用于桥粒芯糖蛋白I的降解作用上。
将6mg碾细的角质层(PSC)分散在96-多孔板筛选0.22μm过滤系统(Millipore)的每个孔内。每种测定进行三次。
将100μlEDTA(浓度为0.2和2%)加入到pH值为8的0.1M氨基丁三醇中,然后再将该混合物加入到PSC中。在室温条件下培养该孔板10分钟,然后过滤该孔板,用200μl的PBS缓冲液清洗孔5次。然后再将200μl的0.1M三羟甲基氨基甲烷(pH值为8)加入到每个孔中。在30℃下,通过搅拌,培养该孔板2小时,然后将该孔板过滤到接收板中,从而收集到每种反应介质。
在Mesoscale MA6000DB016板上检测桥粒芯糖蛋白I肽,之前已描述过该板的研制。
每次测定都直接用25μl的反应介质进行。在相同条件下,用重组桥粒芯糖蛋白(R&D系统)制备标准量程。结果可用AU(任意单位=在“sector imager000”上获得的信号)或者用ng/μg(每ng桥粒芯糖蛋白I在每μg总蛋白的含量)来表示。
图1能实际测定桥粒芯糖蛋白I的可溶性物质的释放,该释放是由如EDTA家族的螯合剂的治疗引起的,这种治疗能促使角质桥粒降解。
所以,该检测适用于评估桥粒芯糖蛋白I的降解-刺激效应,通过测定体外所释放的可溶性物质进行该评估。
所以,该测定能监测分子或美容组合物、优选地抗衰老活性剂的效果,从而补偿桥粒芯糖蛋白I在衰老的角质层中出现的异常积累。
实施例3:
通过剥离法,描述各种不同样品中桥粒芯糖蛋白I的可溶性物质的数量特征
通过实施例1所述的ELISA(酶联免疫吸附测定)法进行该特征描述。
用前臂上所取样品进行产品研究,该研究持续超过56天,即:2个月(1组中有24位拥有白种人皮肤且年龄在40-45岁的女性)。
该产品是一种血清,该血清是由10%的Bifidiobiotic(CLR复合物)及0.002%的植物鞘氨醇-SLC(“G”处理)组成的。
CLR复合物与一种溶胞产物相关,该溶胞产物所注册的INCI名称为比菲德氏菌、EINECS名称为长双歧杆菌,EINECS编号为306-168-4及其CAS号为96507-89-0。该溶胞产物特别地是由K.Richter GmbH公司以Repair Complex名称出售的。
植物鞘氨醇-水杨酸的衍生物是由Evonick Goldschmidt公司以植物鞘氨醇-SLC名称出售的。
在该研究中,从前臂(后面)提取了D-squame样品。
a)从D-squame角质盘中提取蛋白质:
将角质盘置于2ml的埃彭道夫管中,并将粘性表面向内放置。在该管中加入550μl的“Native+”抽提缓冲液(TBS,1%聚乙二醇辛基苯基醚,1M氯化钠)及一个不锈钢管。然后将该管放在MM400振动磨(Retsch)的架体上。通过振动磨以每圈2分钟(30Hz)的速度进行该提取。然后回收介质,并通过0.45μm的Millipore Ultrafree柱对所回收的介质进行过滤,然后在5000g、4℃条件下,对过滤后的介质进行离心分离5分钟。最后将待分析的上清液储存在-20℃条件下。
b)统计学分析
从处理效应出发,用变量分析的混合模型分析成对的活性剂-空白差异,其中时间因素为固定效应和主体因素为随机效应。
通过对比,检测在D0和D56时的处理效应。
必要时,该变量是预先对数变换的,从而使得其分布更具有正态分布性。
使用SPSS软件(第14版)进行描述性分析(方法曲线图和箱形图(graphs ofthemeans and box plots)),以及SAS企业指导软件(第3版)用于干扰部分。
在双边法中,第一种阿尔法风险定在5%。
图2说明了本研究的结果。
图2表现了实验产品对可溶性物质的数量的作用。桥粒芯糖蛋白I的可溶性物质的释放显著增加,从而表明了该产品对桥粒芯糖蛋白I释放具有刺激效应。实验产品具有真正的抗衰老作用,因为该产品能抵消随着年龄的增长出现的桥粒芯糖蛋白I的积累。
序列表
<110>欧莱雅
<120>可溶性的桥粒芯糖蛋白I蛋白物质用于筛选抗衰老活性剂的用途
<130>BR87469/96082/KLP/PLC/cf
<160>85
<170>PatentIn version 3.3
<210>1
<211>4512
<212>DNA
<213>智人
<400>1
cccagcccaa gtttttaggg tggggatcca gactggttat acgtaccttc agtccttctc 60
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ccttggtctt ggatgtaaga gaatccagca gagatggact ggagtttctt cagagtagtt 240
gcagtgctgt tcatttttct ggtggtggta gaagttaaca gtgaattccg aatccaggta 300
agagattata acactaaaaa tggcaccatc aaatggcatt caatccgaag gcagaaacgt 360
gaatggatca agttcgcagc agcctgtcgt gaaggtgaag acaactcaaa gaggaaccca 420
atcgccaaaa ttcactcaga ttgtgctgca aaccagcaag ttacataccg catctctgga 480
gtaggaattg atcagccacc atatgggatc tttgtcatta atcagaaaac tggtgaaatt 540
aatataacat ccatagttga tcgagaggtc actcctttct tcattatcta ctgccgagct 600
ctgaactcaa tgggccaaga tttagagagg cctctagagc tcagagtcag ggttttggat 660
ataaatgaca accctccagt gttttcaatg gctacatttg caggacaaat agaagaaaat 720
tctaatgcaa atacactggt gatgatactc aatgctactg acgcagatga accgaacaat 780
ttgaactcaa aaatagcctt caagattata agacaagaac cttcagattc accaatgttt 840
attatcaaca gaaatactgg agaaattcga acgatgaata attttctaga cagagagcaa 900
tacggccagt atgctcttgc tgtaagaggc tctgaccgag atggtggggc agatggcatg 960
tcagcggaat gtgagtgcaa cattaaaatc ctcgatgtca atgataatat cccttacatg 1020
gaacagtctt catataccat agaaattcaa gaaaatactc taaattcaaa tttgctcgag 1080
attagagtaa ttgatttgga tgaagagttc tcagctaact ggatggcagt aattttcttt 1140
atctctggaa atgaaggaaa ttggtttgag atagaaatga atgaaagaac aaatgtggga 1200
attttaaagg ttgttaagcc cttagattat gaagctatgc agagtctgca actcagtatt 1260
ggtgtcagaa ataaagctga atttcatcat tcaattatgt ctcaatataa actgaaagca 1320
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aagacatatg ttgtaactgg taatatggga tcaaatgata aagtgggaga ctttgtagct 1440
actgacctgg acacaggtag accttcaacg actgttaggt atgtaatggg aaataatcca 1500
gctgacctgc tagctgttga ttcaagaaca ggcaaactca ctttgaaaaa taaagttacc 1560
aaggaacagt acaatatgct cggaggaaaa taccaaggaa cgattctctc tatagatgat 1620
aatcttcaaa gaacttgcac tggtacaatt aatattaaca ttcaaagttt tggtaatgac 1680
gacaggacta atacagagcc gaacactaaa attactacca atactggcag acaagaaagt 1740
acttcttcca ctaactatga taccagcaca acttctactg actctagcca agtatattct 1800
tctgaacccg gaaacggagc caaagatttg ttatcagaca atgtacattt tggtcctgct 1860
ggcattggac tcctcatcat gggattcttg gtcttaggat tggtcccatt tttgatgatc 1920
tgttgtgatt gtggaggtgc tcctcgtagt gcagctggct ttgagcctgt tcccgaatgt 1980
tcagatggag caattcattc atgggcagta gaaggaccac agcctgaacc cagggatata 2040
accactgtca taccacaaat accacctgat aacgcaaata taattgaatg cattgacaac 2100
tcaggagttt atacaaatga gtatggtggc agagaaatgc aagatctggg aggaggagag 2160
agaatgacag gatttgaact aacagaggga gttaaaactt caggaatgcc tgagatatgt 2220
caagaatact ctggaacatt aagaagaaat tctatgaggg aatgtagaga aggaggtctg 2280
aatatgaatt tcatggaaag ctacttctgt cagaaagcat atgcttacgc agatgaagat 2340
gaaggacgcc catctaatga ctgtttgctc atatatgaca tcgaaggtgt aggttcccct 2400
gctggctctg tgggttgttg tagcttcatt ggagaagacc tggatgacag cttcttggat 2460
accctgggac ctaaatttaa gaagttggca gacatcagcc taggaaaaga atcatatcca 2520
gaccttgatc cttcttggcc accacaaagc actgaaccag tttgccttcc tcaggaaaca 2580
gagcccgttg ttagtggaca cccaccaatc tccccacatt tcggcactac cacagtaatt 2640
tctgagagca cctatccctc gggacctggt gtactgcatc ctaagcctat tctcgatcct 2700
ctgggctatg gtaatgtcac tgtgaccgag tcttacacca cctctgacac tctgaagccc 2760
tctgtgcacg ttcacgataa ccgaccagca tcaaacgtgg tagtgacaga gagagtggtc 2820
ggcccaatct ctggcgctga tttgcatgga atgttagaga tgcctgactt gcgagatggg 2880
tcgaatgtta tagtgacaga aagggtaata gcaccaagct ctagtctacc cacctctctg 2940
actatccatc atcctagaga gtcttcaaat gtggtagtga cagaaagagt aatccaacca 3000
acttccggca tgataggtag tctgagtatg caccccgagt tagccaatgc ccacaatgtc 3060
attgtgacag agagggttgt ttctggtgct ggcgtaactg gaattagtgg caccactggg 3120
atcagcggtg gcataggcag cagtggcctg gttggcacca gcatgggtgc tgggagcggt 3180
gccctgagtg gagctggcat aagtggtggt ggcattggcc tgagcagctt gggagggaca 3240
gccagcattg gccacatgag gagttcctct gaccatcact ttaaccaaac cattgggtcc 3300
gcctccccta gcacagctcg aagtcgaatc acaaagtata gtaccgtgca atatagcaag 3360
tagtcaggac cccagctcac tttttcatag tcattgtggt ttagatccaa ttcccaccac 3420
taaaaaacta acaatgtgat ttataacgca caacttcgtg ctcaggtcat ctaggagcaa 3480
ggtgagaaat cacaatgaga aaaataaatg gaaacaccac tgctagggga gagctctcct 3540
tagcattcat aaacttttct cttatattag gactaaggaa ctaaaacttg aggcagagtc 3600
ttctttgtgc ctgagtggcc tgtagtccat ctccagcatg taactggcct tacgatggca 3660
attggcatca ttctccttgc tctgttttgc ttttccatat agctcgagca aaattcaaaa 3720
agaactaaat atgcaatata tgttcatatc tatgggaaaa atctaaaatg tgtgccagat 3780
gccctgttgg tttcacagat aacataaata aaaattcaac cacagattta tacaagggtt 3840
aaccattttt tttaagtttg actacatagt caagtccaca agccatcaag cactcctacc 3900
ttaattattg cactagagaa aataaattcc aaattaggaa gtgtttccta ggaggaaaat 3960
tccattagag agtggcaata ggatgaggtt tcttcagggt aaactagcaa tgcctgagcc 4020
tgaaccttaa tgtggggcct cagttaatat ccctgtggag tcaaggattc ttctgattct 4080
agtgtgtgtt tagtgataga tgtagtcttg acgaatattg cttactggtg aggttgagga 4140
atatcacact cgtctttccc tttaccactg tggttttgac ttaagaaagc aaaactcact 4200
aagtttactt ctcgaattga agcaagtgag gcctgacatg gttgtcatca ctagtggcaa 4260
atgaccttcc aagtaagcag atgggaactg aattgtgttt tcaggttttg tttttagtag 4320
gtgatattca ttcgtatcca gctctttatt acatagctct gaagttaaaa tgatttacat 4380
aggccgagct gtggacaaaa aaaaagaagc agcagcttgt agtatgctta agctttgggg 4440
aatttttttt taaggggatc taaaaaaatg tttttagaac atgtaaaatg tttaatggtg 4500
aaagttggaa aa 4512
<210>2
<211>1049
<212>PRT
<213>智人
<400>2
Met Asp Trp Ser Phe Phe Arg Val Val Ala Val Leu Phe Ile Phe Leu
1 5 10 15
Val Val Val Glu Val Asn Ser Glu Phe Arg Ile Gln Val Arg Asp Tyr
20 25 30
Asn Thr Lys Asn Gly Thr Ile Lys Trp His Ser Ile Arg Arg Gln Lys
35 40 45
Arg Glu Trp Ile Lys Phe Ala Ala Ala Cys Arg Glu Gly Glu Asp Asn
50 55 60
Ser Lys Arg Asn Pro Ile Ala Lys Ile His Ser Asp Cys Ala Ala Asn
65 70 75 80
Gln Gln Val Thr Tyr Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro
85 90 95
Tyr Gly Ile Phe Val Ile Asn Gln Lys Thr Gly Glu Ile Asn Ile Thr
100 105 110
Ser Ile Val Asp Arg Glu Val Thr Pro Phe Phe Ile Ile Tyr Cys Arg
115 120 125
Ala Leu Asn Ser Met Gly Gln Asp Leu Glu Arg Pro Leu Glu Leu Arg
130 135 140
Val Arg Val Leu Asp Ile Asn Asp Asn Pro Pro Val Phe Ser Met Ala
145 150 155 160
Thr Phe Ala Gly Gln Ile Glu Glu Asn Ser Asn Ala Asn Thr Leu Val
165 170 175
Met Ile Leu Asn Ala Thr Asp Ala Asp Glu Pro Asn Asn Leu Asn Ser
180 185 190
Lys Ile Ala Phe Lys Ile Ile Arg Gln Glu Pro Ser Asp Ser Pro Met
195 200 205
Phe Ile Ile Asn Arg Asn Thr Gly Glu Ile Arg Thr Met Asn Asn Phe
210 215 220
Leu Asp Arg Glu Gln Tyr Gly Gln Tyr Ala Leu Ala Val Arg Gly Ser
225 230 235 240
Asp Arg Asp Gly Gly Ala Asp Gly Met Ser Ala Glu Cys Glu Cys Asn
245 250 255
Ile Lys Ile Leu Asp Val Asn Asp Asn Ile Pro Tyr Met Glu Gln Ser
260 265 270
Ser Tyr Thr Ile Glu Ile Gln Glu Asn Thr Leu Asn Ser Asn Leu Leu
275 280 285
Glu Ile Arg Val Ile Asp Leu Asp Glu Glu Phe Ser Ala Asn Trp Met
290 295 300
Ala Val Ile Phe Phe Ile Ser Gly Asn Glu Gly Asn Trp Phe Glu Ile
305 310 315 320
Glu Met Asn Glu Arg Thr Asn Val Gly Ile Leu Lys Val Val Lys Pro
325 330 335
Leu Asp Tyr Glu Ala Met Gln Ser Leu Gln Leu Ser Ile Gly Val Arg
340 345 350
Asn Lys Ala Glu Phe His His Ser Ile Met Ser Gln Tyr Lys Leu Lys
355 360 365
Ala Ser Ala Ile Ser Val Thr Val Leu Asn Val Ile Glu Gly Pro Val
370 375 380
Phe Arg Pro Gly Ser Lys Thr Tyr Val Val Thr Gly Asn Met Gly Ser
385 390 395 400
Asn Asp Lys Val Gly Asp Phe Val Ala Thr Asp Leu Asp Thr Gly Arg
405 410 415
Pro Ser Thr Thr Val Arg Tyr Val Met Gly Asn Asn Pro Ala Asp Leu
420 425 430
Leu Ala Val Asp Ser Arg Thr Gly Lys Leu Thr Leu Lys Asn Lys Val
435 440 445
Thr Lys Glu Gln Tyr Asn Met Leu Gly Gly Lys Tyr Gln Gly ThrIle
450 455 460
Leu Ser Ile Asp Asp Asn Leu Gln Arg Thr Cys Thr Gly Thr Ile Asn
465 470 475 480
Ile Asn Ile Gln Ser Phe Gly Asn Asp Asp Arg Thr Asn Thr Glu Pro
485 490 495
Asn Thr Lys Ile Thr Thr Asn Thr Gly Arg Gln Glu Ser Thr Ser Ser
500 505 510
Thr Asn Tyr Asp Thr Ser Thr Thr Ser Thr Asp Ser Ser Gln Val Tyr
515 520 525
Ser Ser Glu Pro Gly Asn Gly Ala Lys Asp Leu Leu Ser Asp Asn Val
530 535 540
His Phe Gly Pro Ala Gly Ile Gly Leu Leu Ile Met Gly Phe Leu Val
545 550 555 560
Leu Gly Leu Val Pro Phe Leu Met Ile Cys Cys Asp Cys Gly Gly Ala
565 570 575
Pro Arg Ser Ala Ala Gly Phe Glu Pro Val Pro Glu Cys Ser Asp Gly
580 585 590
Ala Ile His Ser Trp Ala Val Glu Gly Pro Gln Pro Glu Pro Arg Asp
595 600 605
Ile Thr Thr Val Ile Pro Gln Ile Pro Pro Asp Asn Ala Asn Ile Ile
610 615 620
Glu Cys Ile Asp Asn Ser Gly Val Tyr Thr Asn Glu Tyr Gly Gly Arg
625 630 635 640
Glu Met Gln Asp Leu Gly Gly Gly Glu Arg Met Thr Gly Phe Glu Leu
645 650 655
Thr Glu Gly Val Lys Thr Ser Gly Met Pro Glu Ile Cys Gln Glu Tyr
660 665 670
Ser Gly Thr Leu Arg Arg Asn Ser Met Arg Glu Cys Arg Glu Gly Gly
675 680 685
Leu Asn Met Asn Phe Met Glu Ser Tyr Phe Cys Gln Lys Ala Tyr Ala
690 695 700
Tyr Ala Asp Glu Asp Glu Gly Arg Pro Ser Asn Asp Cys Leu Leu Ile
705 710 715 720
Tyr Asp Ile Glu Gly Val Gly Ser Pro Ala Gly Ser Val Gly Cys Cys
725 730 735
Ser Phe Ile Gly Glu Asp Leu Asp Asp Ser Phe Leu Asp Thr Leu Gly
740 745 750
Pro Lys Phe Lys Lys Leu Ala Asp Ile Ser Leu Gly Lys Glu Ser Tyr
755 760 765
Pro Asp Leu Asp Pro Ser Trp Pro Pro Gln Ser Thr Glu Pro Val Cys
770 775 780
Leu Pro Gln Glu Thr Glu Pro Val Val Ser Gly His Pro Pro Ile Ser
785 790 795 800
Pro His Phe Gly Thr Thr Thr Val Ile Ser Glu Ser Thr Tyr Pro Ser
805 810 815
Gly Pro Gly Val Leu His Pro Lys Pro Ile Leu Asp Pro Leu Gly Tyr
820 825 830
Gly Asn Val Thr Val Thr Glu Ser Tyr Thr Thr Ser Asp Thr Leu Lys
835 840 845
Pro Ser Val His Val His Asp Asn Arg Pro Ala Ser Asn Val Val Val
850 855 860
Thr Glu Arg Val Val Gly Pro Ile Ser Gly Ala Asp Leu His Gly Met
865 870 875 880
Leu Glu Met Pro Asp Leu Arg Asp Gly Ser Asn Val Ile Val Thr Glu
885 890 895
Arg Val Ile Ala Pro Ser Ser Ser Leu Pro Thr Ser Leu Thr Ile His
900 905 910
His Pro Arg Glu Ser Ser Asn Val Val Val Thr Glu Arg Val Ile Gln
915 920 925
Pro Thr Ser Gly Met Ile Gly Ser Leu Ser Met His Pro Glu Leu Ala
930 935 940
Asn Ala His Asn Val Ile Val Thr Glu Arg Val Val Ser Gly Ala Gly
945 950 955 960
Val Thr Gly Ile Ser Gly Thr Thr Gly Ile Ser Gly Gly Ile Gly Ser
965 970 975
Ser Gly Leu Val Gly Thr Ser Met Gly Ala Gly Ser Gly Ala Leu Ser
980 985 990
Gly Ala Gly Ile Ser Gly Gly Gly Ile Gly Leu Ser Ser Leu Gly Gly
995 1000 1005
Thr Ala Ser Ile Gly His Met Arg Ser Ser Ser Asp His His Phe
1010 1015 1020
Asn Gln Thr Ile Gly Ser Ala Ser Pro Ser Thr Ala Arg Ser Arg
1025 1030 1035
Ile Thr Lys Tyr Ser Thr Val Gln Tyr Ser Lys
1040 1045
<210>3
<211>8
<212>PRT
<213>智人
<400>3
Ala Glu Phe His His Ser Ile Met
1 5
<210>4
<211>12
<212>PRT
<213>智人
<400>4
Ala Glu Phe His His Ser Ile Met Ser Gln Tyr Lys
1 5 10
<210>5
<211>13
<212>PRT
<213>智人
<400>5
Ala Gly Gln Ile Glu Glu Asn Ser Asn Ala Asn Thr Leu
1 5 10
<210>6
<211>14
<212>PRT
<213>智人
<400>6
Ala Gly Gln Ile Glu Glu Asn Ser Asn Ala Asn Thr Leu Val
1 5 10
<210>7
<211>16
<212>PRT
<213>智人
<400>7
Ala Leu Asn Ser Met Gly Gln Asp Leu Glu Arg Pro Leu Glu Leu Arg
1 5 10 15
<210>8
<211>18
<212>PRT
<213>智人
<400>8
Ala Ser Ala Ile Ser Val Thr Val Leu Asn Val Ile Glu Gly Pro Val
1 5 10 15
Phe Arg
<210>9
<211>22
<212>PRT
<213>智人
<400>9
Ala Ser Ala Ile Ser Val Thr Val Leu Asn Val Ile Glu Gly Pro Val
1 5 10 15
Phe Arg Pro Gly Ser Lys
20
<210>10
<211>16
<212>PRT
<213>智人
<400>10
Asp Gly Gly Ala Asp Gly Met Ser Ala Glu Cys Glu Cys Asn Ile Lys
1 5 10 15
<210>11
<211>17
<212>PRT
<213>智人
<400>11
Asp G1y Gly Ala Asp Gly Met Ser A1a G1u Cys Glu Cys Asn Ile Lys
1 5 10 15
Ile
<210>12
<211>18
<212>PRT
<213>智人
<400>12
Asp Gly Gly Ala Asp Gly Met Ser Ala Glu Cys Glu Cys Asn Ile Lys
1 5 10 15
Ile Leu
<210>13
<211>13
<212>PRT
<213>智人
<400>13
Asp Ile Asn Asp Asn Pro Pro Val Phe Ser Met Ala Thr
1 5 10
<210>14
<211>12
<212>PRT
<213>智人
<400>14
Asp Leu Asp Thr Gly Arg Pro Ser Thr Thr Val Arg
1 5 10
<210>15
<211>9
<212>PRT
<213>智人
<400>15
Asp Ser Pro Met Phe Ile Ile Asn Arg
1 5
<210>16
<211>11
<212>PRT
<213>智人
<400>16
Glu Ile Arg Val Ile Asp Leu Asp Glu Glu Phe
1 5 10
<210>17
<211>14
<212>PRT
<213>智人
<400>17
Glu Ile Arg Val Ile Asp Leu Asp Glu Glu Phe Ser Ala Asn
1 5 10
<210>18
<211>11
<212>PRT
<213>智人
<400>18
Glu Gln Tyr Gly Gln Tyr Ala Leu Ala Val Arg
1 5 10
<210>19
<211>9
<212>PRT
<213>智人
<400>19
Glu Gln Tyr Asn Met Leu Gly Gly Lys
1 5
<210>20
<211>10
<212>PRT
<213>智人
<400>20
Glu Ser Ser Asn Val Val Val Thr Glu Arg
1 5 10
<210>21
<211>11
<212>PRT
<213>智人
<400>21
Glu Val Thr Pro Phe Phe Ile Ile Tyr Cys Arg
1 5 10
<210>22
<211>13
<212>PRT
<213>智人
<400>22
Phe Ile Ser Gly Asn Glu Gly Asn Trp Phe Glu Ile Glu
1 5 10
<210>23
<211>16
<212>PRT
<213>智人
<400>23
Phe Leu Val Leu Gly Leu Val Pro Phe Leu Met Ile Cys Cys Asp Cys
1 5 10 15
<210>24
<211>17
<212>PRT
<213>智人
<400>24
Phe Leu Val Leu Gly Leu Val Pro Phe Leu Met Ile Cys Cys Asp Cys
1 5 10 15
Gly
<210>25
<211>18
<212>PRT
<213>智人
<400>25
Phe Leu Val Leu Gly Leu Val Pro Phe Leu Met Ile Cys Cys Asp Cys
1 5 10 15
Gly Gly
<210>26
<211>17
<212>PRT
<213>智人
<400>26
Gly Val Gly Ile Asp Gln Pro Pro Tyr Gly Ile Phe Val Ile Asn Gln
1 5 10 15
Lys
<210>27
<211>14
<212>PRT
<213>智人
<400>27
Ile His Ser Asp Cys Ala Ala Asn Gln Gln Val Thr Tyr Arg
1 5 10
<210>28
<211>16
<212>PRT
<213>智人
<400>28
Ile Ile Arg Gln Glu Pro Ser Asp Ser Pro Met Phe Ile Ile Asn Arg
1 5 10 15
<210>29
<211>10
<212>PRT
<213>智人
<400>29
Ile Leu Asp Val Asn Asp Asn Ile Pro Tyr
1 5 10
<210>30
<211>10
<212>PRT
<213>智人
<400>30
Ile Leu Ser Ile Asp Asp Asn Leu Gln Arg
1 5 10
<210>31
<211>19
<212>PRT
<213>智人
<400>31
Ile Ser Gly Val Gly Ile Asp Gln Pro Pro Tyr Gly Ile Phe Val Ile
1 5 10 15
Asn Gln Lys
<210>32
<211>16
<212>PRT
<213>智人
<400>32
Lys Ile Ile Arg Gln Glu Pro Ser Asp Ser Pro Met Phe Ile Ile Asn
1 5 10 15
<210>33
<211>17
<212>PRT
<213>智人
<400>33
Lys Ile Ile Arg Gln Glu Pro Ser Asp Ser Pro Met Phe Ile Ile Asn
1 5 10 15
Arg
<210>34
<211>11
<212>PRT
<213>智人
<400>34
Lys Leu Lys Ala Ser Ala Ile Ser Val Thr Val
1 5 10
<210>35
<211>12
<212>PRT
<213>智人
<400>35
Lys Leu Lys Ala Ser Ala Ile Ser Val Thr Val Leu
1 5 10
<210>36
<211>8
<212>PRT
<213>智人
<400>36
Leu Ala Asp Ile Ser Leu Gly Lys
1 5
<210>37
<211>9
<212>PRT
<213>智人
<400>37
Leu Asp Arg Glu Gln Tyr Gly Gln Tyr
1 5
<210>38
<211>11
<212>PRT
<213>智人
<400>38
Asn Met Leu Gly Gly Lys Tyr Gln Gly Thr Ile
1 5 10
<210>39
<211>12
<212>PRT
<213>智人
<400>39
Asn Met Leu Gly Gly Lys Tyr Gln Gly Thr Ile Leu
1 5 10
<210>40
<211>9
<212>PRT
<213>智人
<400>40
Asn Asn Phe Leu Asp Arg Glu Gln Tyr
1 5
<210>41
<211>10
<212>PRT
<213>智人
<400>41
Asn AsnPhe Leu Asp Arg Glu Gln Tyr Gly
1 5 10
<210>42
<211>11
<212>PRT
<213>智人
<400>42
Asn Asn Phe Leu Asp Arg Glu Gln Tyr Gly Gln
1 5 10
<210>43
<211>12
<212>PRT
<213>智人
<400>43
Ash Asn Phe Leu Asp Arg Glu Gln Tyr Gly Gln Tyr
1 5 10
<210>44
<211>8
<212>PRT
<213>智人
<400>44
Asn Ser Asn Leu Leu Glu Ile Arg
1 5
<210>45
<211>9
<212>PRT
<213>智人
<400>45
Asn Val Ile Glu Gly Pro Val Phe Arg
1 5
<210>46
<211>12
<212>PRT
<213>智人
<400>46
Asn Val Ile Glu Gly Pro Val Phe Arg Pro Gly Ser
1 5 10
<210>47
<211>13
<212>PRT
<213>智人
<400>47
Asn Val Ile Glu Gly Pro Val Phe Arg Pro Gly Ser Lys
1 5 10
<210>48
<211>14
<212>PRT
<213>智人
<400>48
Asn Val Ile Glu Gly Pro Val Phe Arg Pro Gly Ser Lys Thr
1 5 10
<210>49
<211>15
<212>PRT
<213>智人
<400>49
Asn Val Ile Glu Gly Pro Val Phe Arg Pro Gly Ser Lys Thr Tyr
1 5 10 15
<210>50
<211>11
<212>PRT
<213>智人
<400>50
Pro Pro Tyr Gly Ile Phe Val Ile Asn Gln Lys
1 5 10
<210>51
<211>13
<212>PRT
<213>智人
<400>51
Gln Glu Pro Ser Asp Ser Pro Met Phe Ile Ile Asn Arg
1 5 10
<210>52
<211>11
<212>PRT
<213>智人
<400>52
Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro
1 5 10
<210>53
<211>12
<212>PRT
<213>智人
<400>53
Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro Tyr
1 5 10
<210>54
<211>13
<212>PRT
<213>智人
<400>54
Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro Tyr Gly
1 5 10
<210>55
<211>14
<212>PRT
<213>智人
<400>55
Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro Tyr Gly Ile
1 5 10
<210>56
<211>15
<212>PRT
<213>智人
<400>56
Arg Ile Ser Gly Val Gly Ile Asp Gln Pro Pro Tyr Gly Ile Phe
1 5 10 15
<210>57
<211>8
<212>PRT
<213>智人
<400>57
Ser Ile Asp Asp Asn Leu Gln Arg
1 5
<210>58
<211>10
<212>PRT
<213>智人
<400>58
Ser Ile Val Asp Arg Glu Val Thr Pro Phe
1 5 10
<210>59
<211>12
<212>PRT
<213>智人
<400>59
Thr Ser lle Val Asp Arg Glu Val Thr Pro Phe Phe
1 5 10
<210>60
<211>17
<212>PRT
<213>智人
<400>60
Thr Ile Glu Ile Gln Glu Asn Thr Leu Asn Ser Asn Leu Leu Glu Ile
1 5 10 15
Arg
<210>61
<211>10
<212>PRT
<213>智人
<400>61
Thr Leu Ash Ser Asn Leu Leu Glu Ile Arg
1 5 10
<210>62
<211>8
<212>PRT
<213>智人
<400>62
Thr Met Asn Asn Phe Leu Asp Arg
1 5
<210>63
<211>13
<212>PRT
<213>智人
<400>63
Thr Tyr Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys
1 5 10
<210>64
<211>12
<212>PRT
<213>智人
<400>64
Val Ala Thr Asp Leu Asp Thr Gly Arg Pro Ser Thr
1 5 10
<210>65
<211>14
<212>PRT
<213>智人
<400>65
Val Ala Thr Asp Leu Asp Thr Gly Arg Pro Ser Thr Thr Val
1 5 10
<210>66
<211>15
<212>PRT
<213>智人
<400>66
Val Ala Thr Asp Leu Asp Thr Gly Arg Pro Ser Thr Thr Val Arg
1 5 10 15
<210>67
<211>19
<212>PRT
<213>智人
<400>67
Val Gly Asp Phe Val Ala Thr Asp Leu Asp Thr Gly Arg Pro Ser Thr
1 5 10 15
Thr Val Arg
<210>68
<211>11
<212>PRT
<213>智人
<400>68
Val Ile Asp Leu Asp Glu Glu Phe Ser Ala Asn
1 5 10
<210>69
<211>29
<212>PRT
<213>智人
<400>69
Val Ile Gln Pro Thr Ser Gly Met Ile Gly Ser Leu Ser Met His Pro
1 5 10 15
Glu Leu Ala Asn Ala His Asn Val Ile Val Thr Glu Arg
20 25
<210>70
<211>10
<212>PRT
<213>智人
<400>70
Val Leu Asp Ile Asn Asp Asn Pro Pro Val
1 5 10
<210>71
<211>13
<212>PRT
<213>智人
<400>71
Val Leu Asp Ile Asn Asp Asn Pro Pro Val Phe Ser Met
1 5 10
<210>72
<211>14
<212>PRT
<213>智人
<400>72
Val Leu Asp Ile Asn Asp Asn Pro Pro Val Phe Ser Met Ala
1 5 10
<210>73
<211>11
<212>PRr
<213>智人
<400>73
Val Leu Asn Val Ile Glu Gly Pro Val Phe Arg
1 5 10
<210>74
<211>10
<212>PRr
<213>智人
<400>74
Val Met Gly Asn Asn Pro Ala Asp Leu Leu
1 5 10
<210>75
<211>15
<212>PRT
<213>智人
<400>75
Val Met Gly Asn Asn Pro Ala Asp Leu Leu Ala Val Asp Ser Arg
1 5 10 15
<210>76
<211>18
<212>PRT
<213>智人
<400>76
Val Met Gly Asn Asn Pro Ala Asp Leu Leu Ala Val Asp Ser Arg Thr
1 5 10 15
Gly Lys
<210>77
<211>20
<212>PRT
<213>智人
<400>77
Val Met Gly Asn Asn Pro Ala Asp Leu Leu Ala Val Asp Ser Arg Thr
1 5 10 15
Gly Lys Leu Thr
20
<210>78
<211>20
<212>PRT
<213>智人
<400>78
Val Val Lys Pro Leu Asp Tyr Glu Ala Met Gln Ser Leu Gln Leu Ser
1 5 10 15
Ile Gly Val Arg
20
<210>79
<211>11
<212>PRT
<213>智人
<400>79
Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys
1 5 10
<210>80
<211>15
<212>PRT
<213>智人
<400>80
Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys Val Gly Asp Phe
1 5 10 15
<210>81
<211>18
<212>PRT
<213>智人
<400>81
Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys Val Gly Asp Phe Val
1 5 10 15
Ala Thr
<210>82
<211>20
<212>PRT
<213>智人
<400>82
Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys Val Gly Asp Phe Val
1 5 10 15
Ala Thr Asp Leu
20
<210>83
<211>30
<212>PRT
<213>智人
<400>83
Val Val Thr Gly Asn Met Gly Ser Asn Asp Lys Val Gly Asp Phe Val
1 5 10 15
Ala Thr Asp Leu Asp Thr Gly Arg Pro Ser Thr Thr Val Arg
20 25 30
<210>84
<211>14
<212>PRT
<213>智人
<400>84
Tyr Gln Gly Thr Ile Leu Ser Ile Asp Asp Asn Leu Gln Arg
1 5 10
<210>85
<211>16
<212>PRT
<213>智人
<400>85
Tyr Val Met Gly Asn Asn Pro Ala Asp Leu Leu Ala Val Asp Ser Arg
1 5 10 15
Claims (9)
1.至少一种可溶性肽复合物或非复合物用作预防和/或治疗皮肤衰老的活性剂的筛选工具的用途,所述肽衍生于具有SEQ ID No.2表示的氨基酸序列的多肽的蛋白水解,其中通过使用定向抗桥粒芯糖蛋白I细胞外结构域的抗体检测所述至少一种可溶性肽,所述可溶性肽有能力在没有蛋白变性物质的水或水介质中溶解,并且其中检测到所述肽的存在或其含量增加表示活性剂具有用作预防和/或治疗皮肤衰老的性能。
2.如权利要求1的用途,所述可溶性肽是非复合型。
3.如权利要求1的用途,其特征在于所述可溶性复合物衍生于桥粒芯糖蛋白I与另一种桥粒芯糖蛋白I蛋白或其片段、或靶蛋白的结合,靶蛋白选自:桥粒芯胶蛋白2a(Dsc 2),斑珠蛋白1、2和3,盘状球蛋白,激肽释放酶5,生长激素1(GH1),SSSCA1(27kD的着丝粒自身抗原),RuvB样蛋白1,C3orfl0蛋白及VRK3(痘苗相关激酶3)。
4.抗衰老活性剂的筛选方法,包括至少以下步骤:
a)在适于可溶性肽释放的条件下,将至少一种细胞类型与至少一种待试抗衰老活性剂相接触,该细胞类型能释放至少一种肽,所述肽衍生于具有SEQ ID No.2表示的氨基酸序列的多肽的蛋白水解,
b)测定所述可溶性肽的含量,以及
c)将步骤b)所测得的含量,与无待试化学化合物或生物化合物存在条件下测得的可溶性肽的含量比较,
其中,通过使用定向抗桥粒芯糖蛋白I细胞外结构域的抗体进行步骤b),其中所述可溶性肽有能力在没有蛋白变性物质的水或水介质中溶解,并且其中检测到所述肽的存在或其含量增加表示活性剂具有用作抗衰老活性剂的性能。
5.对美容处置的效果进行表征的方法,所述美容处置用于预防和/或处置个体中与自然老化相关的皮肤衰老征兆,所述方法至少包括对至少一种复合的或非复合的可溶性肽进行定性或定量地表征,所述肽衍生于具有SEQ ID No.2表示的氨基酸序列的多肽的蛋白水解,其中,通过使用定向抗桥粒芯糖蛋白I细胞外结构域的抗体进行该表征,其中所述可溶性肽有能力在没有蛋白变性物质的水或水介质中溶解,并且其中检测到 或表征所述可溶性肽的存在或其含量增加表示所述活性剂或所述处置具有的效果。
6.对处置的效果进行表征的非治疗方法,所述处置用于预防和/或处置个体皮肤衰老征兆,该方法包括至少以下步骤:
i.提供至少第一个代表上述个体的皮肤表面样品,
ii.在上述样品中,对所述的至少一种可溶性肽定量,所述肽衍生于具有SEQ ID No.2表示的氨基酸序列的多肽的蛋白水解,
iii.对代表上述个体的第二个皮肤表面样品重复进行步骤i和ii,以及
iv.比较步骤ii和iii所得的结果,所述第一和第二皮肤表面样品对应于不同处置阶段,其中,通过使用定向抗桥粒芯糖蛋白I细胞外结构域的抗体进行步骤ii,其中所述可溶性肽有能力在没有蛋白变性物质的水或水介质中溶解,以及在步骤iv中,检测到所述可溶性肽的存在或其含量增加是所述处置有效的指标。
7.如权利要求6所述方法,其特征在于其中第一个样品代表预处置的状态,第二个样品代表处置期间或处置后的状态。
8.如权利要求6的方法,其特征在于进一步包括对个体施用美容护理组合物的调节步骤,用以调节所述处置,所述组合物是通过步骤iv所获的相关信息而构建或选择的。
9.如权利要求6的方法,其特征在于步骤ii中的定量是通过ELISA分析技术进行的。
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