CN103443291A - 用于促进皮肤细胞分化的物质的筛查方法 - Google Patents
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Abstract
本发明涉及用于促进皮肤细胞分化的物质的筛查方法,该方法包括:用测试物质处理皮肤细胞;和核实在前一步骤中用所述测试物质处理过的皮肤细胞内的DUOX1基因的相对表达水平。本发明也涉及用于促进皮肤细胞分化的物质的筛查试剂盒,该试剂盒包括用于核实皮肤细胞内的DUOX1基因的相对表达水平的装置。本发明又涉及一种组合物,该组合物包含作为活性成分的能够增加DUOX1基因表达的用于促进皮肤细胞分化、保湿皮肤、增强皮肤屏障功能以及降低或治疗特应性症状的物质。
Description
技术领域
本发明涉及用于促进皮肤细胞分化的物质的筛查方法及其试剂盒。
背景技术
表皮为皮肤的最外层,而角质层是表皮的最外层。当由角质形成细胞组成的角质层处于正常状态时,表皮才能充当身体的主要屏障,从而能够防御各种刺激并防止身体水分的发散。表皮形成细胞在皮肤最下层,即在基底层中进行增殖,然后通过棘层和颗粒层逐渐进行分化。通过这种角化过程,表皮形成细胞会产生天然保湿因子(NMFs)和脂质(神经酰胺、胆固醇或脂肪酸),进而形成角质层。通过这种角质层的正常形成,皮肤的屏障功能可以正常工作。
发明内容
技术问题
本发明在于提供用于促进皮肤细胞分化的物质的筛查方法及其试剂盒。进一步,本发明在于提供一种组合物,该组合物可以促进皮肤细胞的分化,滋润皮肤,增强皮肤屏障功能,或者降低或治疗特应性症状。
技术方案
在一方面,本发明提供用于促进皮肤细胞分化的物质的筛查方法,其包括:用测试物质处理皮肤细胞;以及核实在前一步骤中经测试物质处理过的皮肤细胞内的双氧化酶1(DUOX1)基因的相对表达水平。
在另一方面,本发明提供用于促进皮肤细胞分化的物质的筛查试剂盒,其包括可核实皮肤细胞内DUOX 1基因的相对表达水平的装置。
在又一方面,本发明提供用于促进皮肤细胞的分化、滋润皮肤、增强皮肤屏障功能或者降低或治疗特应新症状的组合物,该组合物包含作为活性成分的可增加DUOX1基因表达的物质。
有益效果
根据在此公开的用于促进皮肤细胞分化的物质的筛查方法,待用所述测试物质处理皮肤细胞后,该方法可通过检测DUOX1基因的相对表达水平来便捷且有效地核实用于促进皮肤细胞分化的物质。
附图说明
图1展示了根据正常人表皮角质形成细胞内钙浓度的DUOX1基因表达水平。
图2展示了当用DUOX1或DUOX2 siRNA处理皮肤表皮角质形成细胞时,与未用它们处理时相比,DUOX
1或DUOX 2的表达水平。
图3和图4展示了在用DUOX1或DUOX2 siRNA处理皮肤表皮角质形成细胞时,与未用它们处理时相比,纤聚蛋白(filaggrin)和兜甲蛋白(loricrin)(图3),以及角蛋白(keratin)1和角蛋白10(图4)的表达水平。
图5和图6展示了当用三百草或楝属(melia)的提取物处理皮肤表皮角质形成细胞时,与未用它们处理时相比,DUOX1和纤聚蛋白(图5),以及角蛋白1和角蛋白10(图6)的表达水平。
具体实施方式
双氧化酶也被称作Duox1或ThOX1(甲状腺氧化酶,Thyroid oxidase),是DUOX1基因编码而成的。它被首次发现于甲状腺中。人体内有两种同源物,即hDUOX 1和hDUOX 2, hDUOX1大量表达于气道上皮细胞内,而hDUOX2则大量表达于唾液腺和胃肠道中。DUOX1属于NADPH氧化酶(NOX),并且具有共7种同源物(Nox1、Nox2、Nox3、Nox4、Nox5、Duox1和Duox2)。其中,NOX在吞噬细胞的吞噬作用中作为产生活性氧簇(ROS)的蛋白质被人们做了大量研究,然而,最近在细胞组织内也发现了NOX并对其进行了研究,而不是在免疫细胞。已知,NOX/DUOX族将通过产生活性氧的生物作用参与高血压(NOX1)、免疫(NOX2/DUOX)、耳朵的形成(NOX)、甲状腺激素的产生(DUOX1和2)等当中。
构成皮肤屏障的最外层的角质层是由天然保湿因子、脂质等组成的。纤聚蛋白通过转录后修饰过程降解为多种亲水性氨基酸,而且已知由此形成的氨基酸池将构成天然保湿因子(NMFs),NMFs会帮助维持角质层的水分。进一步,亦知,纤聚蛋白基因的突变是重要的遗传危险因素,其通过减少皮肤保湿因子,破坏皮肤屏障功能,降低对过敏原或微生物的皮肤防御能力以及激活T细胞群来引发特应性湿疹,进而引发由自身免疫机制引起的慢性炎症。但是对其的治疗或预防方法还尚未出现。
下面,将详细地描述本发明。
本发明人已检测了DUOX1的表达在正常人皮肤的表皮角质形成细胞内相对会多,而且其表达水平在分化过程中会增加。进一步,通过删除DUOX1
(siRNA)来证实各种分化基因的标记如兜甲蛋白、角蛋白1和角蛋白10的表达水平能与纤聚蛋白基因的表达水平一同增加,从而确认了DUOX1的表达与参与皮肤细胞分化的纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10基因的表达相关。基于此,可以判断出,能增加皮肤细胞内DUOX1基因的表达水平的物质也就是用于促进皮肤细胞分化的物质。亦即,通过用某一物质处理皮肤细胞后检查DUOX1基因的相对表达水平,可简单地证实所述某一物质是否为用于促进皮肤细胞分化的物质。
本发明的一个实施例提供用于促进皮肤细胞分化的物质的筛查方法,该方法包括:用测试物质处理皮肤细胞的步骤;和检测在用前一步骤中的测试物质处理过的皮肤细胞内的双氧化酶1(DUOX1)基因(基因库登记号:NM_017434)的相对表达水平的步骤。
在本说明书中,术语“皮肤”指覆盖动物身体表面的组织,而且是最广义的概念,其包括头皮和头发,以及覆盖脸和身体的表面的组织。
在本发明的一个实施例中,所述皮肤细胞包括表皮角质形成细胞。在本发明的另一个实施例中,所述皮肤细胞包括人的皮肤表皮角质形成细胞。在本发明的又一个实施例中,所述皮肤细胞包括人的正常的皮肤表皮角质形成细胞。
在本说明书中,术语“相对表达水平”可以为与在未经测试物质处理的皮肤细胞内的DUOX1基因表达的表达水平相比时的表达水平。所述表达水平包括表达量和表达质量。
待检测完本发明一个实施例的DUOX 1基因的相对表达水平后,可以进一步包括将增加DUOX1基因表达水平的物质判断为用于促进皮肤细胞分化的物质的步骤。具体地,当DUOX1基因在经所述测试物质处理的皮肤细胞内的表达水平高于在未经所述测试物质处理的皮肤细胞内的表达水平时,可判断出用来处理的测试物质能够增加DUOX1基因的表达水平。反之,当DUOX1基因在经所述测试物质处理的皮肤细胞内的表达水平低于在未经所述测试物质处理的皮肤细胞内的表达水平时,可判断出用来处理的测试物质不能增加DUOX1基因的表达水平。综上所述,可将所述能够增加DUOX1基因的表达水平的用来处理的测试物质判断为用于促进皮肤细胞分化的物质。
根据本发明一个实施例,在经所述测试物质处理的细胞内检测DUOX 1基因的相对表达水平的步骤中,所述相对表达水平可以用RT-PCR、ELISA或western印迹(免疫印迹)法来检测。
除了检测DUOX 1基因的相对表达水平外,本发明一个实施例的用于促进皮肤细胞分化的物质的筛查方法可进一步包括,在用所述测试物质处理的皮肤细胞内检测选自纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10中至少一种基因的相对表达水平的步骤。通过对参与皮肤细胞表达中的基因标记的相对表达水平,可明确地判断出所述目标测试物质是否为用于促进皮肤细胞分化的物质。
根据本发明一个实施例,待检测完选自纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10中至少一种基因的相对表达水平后,可进一步包括将增加所选取的至少一种基因的表达水平的物质判断为用于促进皮肤细胞的分化的物质的步骤。具体地,当在经所述测试物质处理的皮肤细胞中选取的至少一种基因的表达水平高于在未经所述测试物质处理的皮肤细胞中选取的至少一种基因的表达水平时,就可判断出所述用来处理的测试物质可增加所选取的至少一种基因的表达水平。综上所述,可将所述能够增加所选取的至少一种基因的表达水平的用来处理的测试物质判断为用于促进皮肤细胞分化的物质。
如果皮肤细胞分化不当,皮肤的角质层就会无法正常工作。因此,皮肤的保湿能力会下降,且皮肤的屏障功能可能会退化。进一步,由于各种因素而无法维持正常皮肤角质层的功能时,将引起皮肤疾病如特应性,其主要症状是皮肤炎症和皮肤干燥。因此,用于促进皮肤细胞分化的物质可表现出保湿皮肤、增强皮肤屏障功能以及降低或治疗特应性症状的效果。亦即,根据本发明一个实施例,可通过使用用于促进皮肤细胞分化的物质的筛查方法来检测用于保湿皮肤、增强皮肤屏障功能以及降低或治疗特应性症状的物质。
本发明的一个实施例提供用于促进皮肤细胞分化的物质的筛查试剂盒,该试剂盒包括能检测在皮肤细胞内DUOX 1基因的相对表达水平的装置。通过使用所述检测试剂盒可检测皮肤细胞内DUOX 1基因的相对表达水平,从而可便捷并有效地检测出用于促进皮肤细胞分化的物质。
如上述可知,能够增加DUOX 1基因表达的物质表现出了促进皮肤细胞分化、保湿皮肤、增强皮肤屏障功能以及降低或治疗特应性症状的效果。因此,本发明的一个实施例提供用于促进皮肤细胞分化的组合物、用于保湿皮肤的组合物、用于增强皮肤屏障功能的组合物以及用于降低或治疗特应性症状的组合物,这些组合物包含作为活性成分的能够增加DUOX 1基因表达的物质。本发明的另一个实施例提供用于促进皮肤细胞分化的组合物、用于保湿皮肤的组合物、用于增强皮肤屏障功能的组合物以及用于降低或治疗特应性的症状的组合物,这些组合物包含作为活性成分的能够增加所检测到的DUOX1基因表达的物质。
在一个实施例中,所述组合物可以为化妆品组合物。在另一个实施例中,所述组合物可以为药物组合物。在又一个实施例中,所述组合物可以为保健食品组合物。
现在起描述所述实施例。以下实施例仅作说明为目的,不用于限制本发明的范围。
【实施例1】对根据钙浓度的DUOX1基因表达变化的评估
通常,已知当细胞内钙浓度高时能够促进皮肤细胞的分化。本实验在于,通过用不同浓度的钙处理细胞来改变皮肤细胞的分化程度后评估DUOX1基因的表达水平。
从龙沙公司(Lonza, Inc.,美国马里兰州沃克斯维尔)购买正常人的表皮角质形成细胞(人表皮新生角质形成细胞)并进行继代培养(subculture),然后在37°C和5%CO2的CO2培养箱内进行培养。根据龙沙公司(美国马里兰州沃克斯维尔)的说明书,准备细胞培养。在KBM-2(Clonetics CC-3103)培养基(500ml)中加入KGM-2 子弹套件【牛垂体提取物(BPE,2ml)、人表皮成长因子(hEGF, 0.5ml)、胰岛素(0.5ml)、氢化可的松(0.5ml)、转铁蛋白(transferrin,0.5ml)、肾上腺素(0.5ml),硫酸庆大霉素+ amphofericin B(GA-1000,0.5ml)】。
在所述人表皮角质形成细胞的培养基中分别加入120μM和1.2mM的钙并培养24小时。将它们用作低钙组(对照组)和高钙组(测试组)。待用白细胞间介素处理完24小时后,用10ml的磷酸盐缓冲液(PBS)清洗所述细胞2次,然后用Trizol试剂(Invitrogen,美国加利福尼亚洲卡尔斯巴德)从所述细胞中分离出细胞内所有的RNA。用RNA试剂盒(Qiagen RNeasy试剂盒, Qiagen, 加利福尼亚洲瓦伦西亚)再次提纯所述分离出的RNA,然后用安捷伦2100生物分析仪(Agilent 2100
BioAnalyzer,Agilent Technologies,美国加利福尼亚州圣克拉拉)检测RNA质量。用反转录试剂盒(Superscript
Reverse Transcriptase (RT) II kit,Invitrogen,
加利福尼亚洲卡尔斯巴德)从分离出的RNA中合成cDNA,而后通过实时定量逆转录聚合酶链式反应方法(real
time-reverse transcription polymerase chain reaction,Q-RT-PCR)对各种NOX基因的表达进行定量分析。使用TaqMan®基因表达检测试剂盒(Applied
Biosystems公司,加利福尼亚洲福斯特市)评估NOX1(Hs00246589_m1)、NOX2(Hs00166163_m1)、NOX3(Hs00210462_m1)、NOX4(Hs00276431_m1)、NOX5(Hs00225846_m1)、
DUOX1(Hs00213694_m1)和DUOX2(Hs00204187_m1)的表达模式的变化。其结果在图1中展示。
如图1所示,在正常人表皮角质形成细胞中,DUOX1基因的表达水平基本上会高,而且当利用钙增加皮肤细胞分化时,更能显著地增加DUOX 1基因的表达。亦即,可以确认的是,DUOX1基因与皮肤细胞分化有关,更为具体地,DUOX1基因表达的增加与皮肤细胞分化有关。
【实施例2】对根据删除DUOX1时纤聚蛋白基因和各种分化标记的表达的变化的评估
从Dharmacone购买能够抑制DUOX1或DUOX2基因的表达的siRNA(SMARTPOOL)。
如同实施例1,培养正常人表皮角质形成细胞,而后在6孔板上以2×104cells/cm2标准进行培养。待24小时后,用RNAi MAX试剂(Invitrogen)将50nM的DUOX1或DUOX2的siRNA分别进行转染。6小时后更换细胞培养基。转染完24小时后,用10ml的磷酸盐缓冲液(PBS)清洗所述细胞2次,然后用Trizol试剂(Invitrogen,美国加利福尼亚洲卡尔斯巴德)从所述细胞中分离出细胞内所有的RNA。用RNA试剂盒(Qiagen RNeasy试剂盒,
Qiagen, 加利福尼亚洲瓦伦西亚)再次提纯所述分离出的RNA,然后用安捷伦2100生物分析仪(Agilent 2100
BioAnalyzer,Agilent Technologies,美国加利福尼亚州圣克拉拉)检测RNA质量。用反转录试剂盒(Superscript
Reverse Transcriptase (RT) II kit,Invitrogen公司, 加利福尼亚洲卡尔斯巴德)从分离出的RNA中合成cDNA,而后用实时定量逆转录聚合酶链式反应方法(real
time-reverse transcription polymerase chain reaction,Q-RT-PCR)进行定量分析。使用TaqMan®基因表达检测试剂盒(Applied Biosystems公司,加利福尼亚洲福斯特市)评估DUOX1(Hs00213694_m1)和作为人表皮角质形成细胞分化的标记基因的纤聚蛋白(基因库登记号:NM_002016)(Hs00856927_g1)、兜甲蛋白(基因库登记号:NM_000427)(Hs01894962_s1)、角蛋白1(基因库登记号:NM_006121)(Hs00196158_m1)、角蛋白10(基因库登记号:NM_000421)(Hs00166289_m1)的表达模式的变化。其结果在图2-4中展示。
图2为展示了DUOX1或DUOX2的表达水平在用DUOX1或DUOX2 siRNA处理时相比未经处理的对照组时的图表。图3为展示了纤聚蛋白和兜甲蛋白基因的表达水平在用DUOX 1或DUOX
2 siRNA处理时相比未经处理的对照组时的图表,图4为以相同方法展示角蛋白1和角蛋白10基因的表达水平的图表。
如上述结果所示,当用DUOX1或DUOX2
siRNA处理时DUOX1或DUOX2基因的表达水平会下降。进一步,与未用DUOX1或DUOX2的siRNA处理时相比,纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10基因的表达水平都会下降。亦即,可以确定的是,当删除DUOX1时参与皮肤细胞分化的基因的表达水平会下降。
【实施例3】对测试物质的如DUOX1和纤聚蛋白的基因的表达水平的评估
已知,三百草或楝属(melia)的提取物能够促进皮肤细胞分化,通过使用三百草和楝属的提取物检测DUOX1、纤聚蛋白、角蛋白1和角蛋白10的表达水平。
从龙沙公司(Lonza, Inc.,美国马里兰州沃克斯维尔)购买正常人表皮角质形成细胞,在37°C和5%CO2的CO2培养箱内的KBM-2(Clonetics CC-3103)培养基中进行培养。
将未经处理的人表皮角质形成细胞培养组(对照组)和用10μM的三百草或楝属的提取物处理的人表皮角质形成细胞培养组分别培养24小时。所述三百草和楝属的提取物是从韩国Plank提取库购买的。待用三百草或楝属的提取物处理完24小时后,用10ml的磷酸盐缓冲液(PBS)清洗所述细胞,然后用Trizol试剂(Invitrogen,美国加利福尼亚洲卡尔斯巴德)从此细胞中分离出细胞内的所有RNA。用RNA试剂盒(Qiagen RNeasy试剂盒, Qiagen, 加利福尼亚洲瓦伦西亚)再次提纯所述分离出的RNA,然后用安捷伦2100生物分析仪(Agilent 2100
BioAnalyzer,Agilent Technologies,美国加利福尼亚州圣克拉拉)检测RNA质量和浓度。用反转录试剂盒(Superscript
Reverse Transcriptase (RT) II kit,Invitrogen公司, 加利福尼亚洲卡尔斯巴德)从分离出的RNA中合成cDNA,通过实时定量逆转录聚合酶链式反应(real
time-reverse transcription polymerase chain reaction,Q-RT-PCR)对基因表达的变化进行定量分析。使用TaqMan®基因表达检测试剂盒(Applied Biosystems公司,加利福尼亚洲福斯特市)评估DUOX1(Hs00213694_m1)和作为人表皮角质形成细胞分化的标记基因的纤聚蛋白(Hs00856927_g1)、角蛋白1(Hs00196158_m1)、角蛋白10(Hs00166289_m1)的基因表达模式的变化。其结果在图5和图6中展示。
图5为展示了DUOX 1和纤聚蛋白的表达水平在用三百草或楝属的提取物处理皮肤表皮角质形成细胞时相比未经处理时的图表,而图6为以相同方法展示角蛋白1和角蛋白10基因的表达水平的图表。
如上述结果所示,三百草或楝属的提取物能显著地增加人表皮角质形成细胞内的DUOX1基因、纤聚蛋白、角蛋白1和角蛋白10基因的表达水平。亦即,可以确定的是,具有皮肤细胞分化促进效果的物质,进一步具有皮肤保湿、增强皮肤屏障功能以及降低或治疗特应性症状的效果的物质可以增加所述基因的表达水平。
Claims (13)
1.用于促进皮肤细胞分化的物质的筛查方法,包括:
用测试物质处理皮肤细胞;和
核实用所述测试物质处理过的皮肤细胞内双氧化酶1(DUOX1)基因(基因库登记号:NM_017434)的相对表达水平。
2.根据权利要求1所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,还包括:在核实DUOX1基因的相对表达水平后,将使DUOX1基因的表达水平上升的物质判断为用于促进皮肤细胞分化的物质。
3.根据权利要求1所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,该方法除了核实DUOX1基因的相对表达水平外,还包括核实用所述测试物质处理过的皮肤细胞内的选自纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10的至少一种基因的相对表达水平。
4.根据权利要求3所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,还包括:在核实选自纤聚蛋白、兜甲蛋白、角蛋白1和角蛋白10的至少一种基因的相对表达水平后,将使至少一种选定基因的表达水平上升的物质判断为用于促进皮肤细胞分化的物质。
5.根据权利要求1所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,所述皮肤细胞为角质形成细胞。
6.根据权利要求1~5中的任何一项所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,该方法为用于通过促进皮肤细胞分化来保湿皮肤的物质的筛查方法。
7.根据权利要求1~5中任何一项所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,该方法为用于通过促进皮肤细胞分化来增强皮肤屏障功能的物质的筛查方法。
8.根据权利要求1~5中任何一项所述的用于促进皮肤细胞分化的物质的筛查方法,其特征在于,该方法为用于通过促进皮肤细胞分化来降低或治疗特应性症状的物质的筛查方法。
9.用于促进皮肤细胞分化的物质的筛查试剂盒,其特征在于,该试剂盒包括用于核实皮肤细胞内的DUOX1基因的相对表达水平的装置。
10.用于促进皮肤细胞分化的组合物,其特征在于,该组合物包含作为活性成分的能够增加DUOX1基因的表达的物质。
11.用于保湿皮肤的组合物,其特征在于,该组合物包含作为活性成分的能够增加DUOX1基因的表达的物质。
12.用于增强皮肤屏障功能的组合物,其特征在于,该组合物包含作为活性成分的能够增加DUOX1基因的表达的物质。
13.用于降低或治疗特应性症状的组合物,其特征在于,该组合物包含作为活性成分的能够增加DUOX1基因的表达的物质。
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