CN107801402B - 用于诊断由微尘引起的皮肤损伤的组合物及包含高良姜素作为有效成分的组合物 - Google Patents
用于诊断由微尘引起的皮肤损伤的组合物及包含高良姜素作为有效成分的组合物 Download PDFInfo
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- CN107801402B CN107801402B CN201680021004.5A CN201680021004A CN107801402B CN 107801402 B CN107801402 B CN 107801402B CN 201680021004 A CN201680021004 A CN 201680021004A CN 107801402 B CN107801402 B CN 107801402B
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Abstract
本发明公开一种用于诊断由微尘引起的皮肤损伤的生物标记和一种使用该生物标记的试剂盒;以及一种包括高良姜素作为有效成分的组合物的新颖用途。具体地,通过测量和比较正常细胞与被微尘损伤细胞中的生物标记表达量,能轻易诊断由微尘引起的皮肤损伤。另外,包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物,作为有效成分的本发明的组合物使被微尘损伤的皮肤的基因表达正常化并能促进角质细胞分化,从而具有皮肤保湿效果或增强皮肤障壁效果。因此,由于所述组合物可用于防止、处理、或改善皮肤病,如:特异体质过敏症、银屑病等,该组合物是有用的。
Description
技术领域
本发明公开了一种可以用于诊断由微尘引起的皮肤损伤的生物标记、包含该生物标记的组合物、包含该生物标记的试剂盒;以及包含高良姜素作为有效成分的组合物的新颖用途。
【背景技术】
在皮肤中,表皮起着防止水分从人体蒸发出去的重要作用。皮肤表皮由从外侧起的角质层、颗粒层、棘层、及基底层组成。角质层的细胞或角质细胞如砖块般嵌入于脂质基体,其作用如同砂浆,藉此构成皮肤障壁(J.Invest.Dermatol.80(Suppl.)),44-49.1983)。在健康人的角质细胞中,天然保湿因子以高浓度存在,用以使皮肤保湿。例如,水溶性物质(如氨基酸)容易吸收水分并防止皮肤干燥(J.Invest.Dermatol.54,24-31,1970)。
然而,由于在环境或生活方式条件下的各种因素,包含通过加热/冷却进行的人为温度控制,因各种社会压力和环境污染、卸妆后的洗脸次数、长期皮肤老化等造成皮肤应力,由于角质层含水量降低而使得皮肤表面变得干燥、粗糙、松弛、无活力。由于这种原因,皮肤保湿霜的需求增加。同样的,来自外面的过度的物理及化学刺激以及紫外线(UV)、压力、营养不良等导致皮肤机能下降且加速皮肤老化现象(如,弹性下降、角质化、形成皱纹等)。尤其是,表皮/真皮界面因UV而严重损伤。最近,观察到居住在有严重黄色粉尘或微尘的住宅区的居民的皮肤增添了色素及法令纹。
现有技术的参考文献
非专利文件
(非专利文件1)J.Invest.Dermatol.80(Suppl.),44-49.1983.
发明内容
技术问题
在一方面中,本发明旨在提供一种用于诊断由微尘引起的皮肤损伤的方法。
在另一方面中,本发明旨在提供一种可用于诊断由微尘引起的皮肤损伤的生物标记及一种包含该生物标记的组合物。
在另一方面中,本发明旨在提供一种包含高良姜素作为有效成分的组合物。
在另一方面中,本发明旨在提供一种组合物,其在皮肤保湿、增强皮肤障壁机能、或诱导角质形成细胞分化中是有效的。
在另一方面中,本发明旨在防止或改善与皮肤干燥或皮肤障壁机能的异常相关的皮肤病。
在另一方面中,本发明旨在提供一种可以用于改善由微尘引起的皮肤损伤的组合物。
技术方案
在一方面中,本发明旨在提供一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的组合物,所述组合物包含用于测量一种或多种基因的mRNA或其蛋白质的表达水平的试剂,,其中,所述一种或多种基因选自:S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)gene和KRT13(NM_002274)基因。
在另一方面中,本发明提供一种试剂盒,用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤,其包含该组合物。
在另一方面中,本发明提供一种用于使皮肤保湿的组合物,所述组合物包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物,作为有效成分。
在另一方面中,本发明提供一种用于增强皮肤障壁机能的组合物,所述组合物包含:高良姜素,其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物,作为有效成分。
在另一方面中,本发明提供一种用于诱导角质形成细胞分化的组合物,,其包含:高良姜素,及其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物,作为有效成分。
在另一方面中,本发明提供一种用于改善由微尘引起的皮肤损伤的组合物,所述组合物包含:高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物,作为有效成分。
有利效果
在一方面中,使用用以诊断由微尘引起的皮肤细胞损伤的生物标记,及包含该生物标记的组合物能够通过检查因由微尘引起的皮肤细胞损伤而使表达增加或减少的基因的表达水平来轻易且快速诊断皮肤细胞的损伤,且通过调查由该基因编码的蛋白质的活性是否被抑制或增加能轻易筛选由微尘引起的皮肤细胞损伤的抑制剂。
此外,包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物作为有效成分的本发明的组合物能用于防止、处理或改善皮肤病(如:特异体质过敏症、银屑病等)。由于其有效地使皮肤保湿或通过促进丝聚合蛋白和角蛋白的合成来增强皮肤障壁,且促进角质形成细胞分化。另外,所述组合物能用于改善由微尘引起的皮肤损伤。
附图说明
图1显示以微尘提取物处理后的细胞存活率。ADSP是指亚洲尘暴颗粒;或黄色粉尘PM10(颗粒物质10)是指颗粒尺寸为10μm的微尘;黄色粉尘PM2.5(颗粒物质2.5)是指颗粒尺寸为2.5μm的微尘。
图2a~2k显示被微尘刺激的皮肤细胞中表达增加的基因在用高良姜素处理后,表达下降。
图3a~3d,3g~3k显示被微尘刺激的皮肤细胞中表达下降的基因在用高良姜素处理后,表达增加,并且3e~3f显示微尘刺激的皮肤细胞中表达增加的基因在用高良姜素处理后,表达下降。
图4a~4d显示依据高良姜素浓度,正常人角质形成细胞中的丝聚合蛋白、角蛋白10、角蛋白1、角蛋白13、及角蛋白15的相对mRNA表达水平。
图5显示依据高良姜素浓度,未用微尘处理的角质形成细胞的分化程度。
图6显示依据高良姜素浓度,在正常人角质形成细胞中未用微尘处理的丝聚合蛋白质的合成程度。
具体实施方式
本发明详述如下:
本发明所使用的“微尘”是指人眼看不见的,且长时间悬浮或飘扬于大气层中的颗粒物质。微尘可以指的是粒径为10μm或更小的颗粒物质。特别地,粒径为10μm或更小的颗粒物质称为“超细粉尘”。在本发明中,“微尘”包含「超细粉尘」。
本发明涉及一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的生物标记,所述生物标记包含一种或多种特定基因、或由该基因编码的蛋白质。
该特定基因可为选自以下基因中的一种或多种基因:S100A7(NM_002963)、S100A8(NM_002964)、S100A9(NM_002965)、CYP1A1(NM_000499)、CYP1B1(NM_000104)、PI3(NM_002638)、IL36G(NM_019618)、IL1B(NM_000576)、CCL27(NM_006664)、IL8(NM_000584)、PTGS2(NM_000963)、NOX5(NM_001184779)、XDH(NM_000379)、CXCL14(NM_004887)、SOD3(NM_003102)、KRT1(NM_006121)、H19(NR_002196)、CASP14(NM_012114)、KRT10(NM_000421)、CASP8(NM_001080125)、KRT15(NM_002275)、及KRT13(NM_002274)。
一种或多种,具体地,两种或多种、三种或多种、四种或多种、五种或多种、六种或多种、七种或多种、八种或多种、九种或多种、十种或多种、十一种或多种、十二种或多种、十三种或多种、十四种或多种、十五种或多种、十六种或多种、十七种或多种、十八种或多种、十九种或多种、二十种或多种、二十一种或多种、或是二十二种或多种基因、或是所有基因可用作一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的生物标记。
在另一方面中,本发明涉及一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的组合物,所述组合物包含一种用于测量选自上述基因的一种或多种基因的mRNA或蛋白质的表达水平的试剂。
在另一方面中,本发明涉及使用一种用于测量一种或多种基因的mRNA或蛋白质的表达水平的试剂,该一种或多种基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、及KRT13(NM_002274)基因,并用该试剂制备一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的组合物。
在另一方面中,本发明涉及使用一种用于测量一种或多种基因的mRNA或由用于诊断由微尘引起的皮肤细胞皮肤障壁损伤的基因编码的蛋白质的表达水平的试剂的用途,该一种或多种基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、及KRT13(NM_002274)。
在另一方面中,本发明涉及一种使用用于测量一种或多种基因的mRNA或由该基因编码的蛋白质的表达水平的试剂来诊断由微尘引起的皮肤细胞损伤或皮肤障壁损伤的方法,该一种或多种基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、及KRT13(NM_002274)。
该试剂可以为与该基因的mRNA互补的多核苷酸或其片段,探针或能扩增基因或抗体(例如:单克隆抗体或多克隆抗体),具体地识别蛋白质,的引物。
在另一方面中,本发明涉及一种包含用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的组合物的试剂盒(kit)。通过使用依据本发明的试剂盒,能快速且轻易诊断由微尘引起的皮肤细胞损伤或皮肤障壁损伤。
在示例性实施例中,该试剂盒可以根据下面的情况来确定皮肤细胞被微尘损伤,1)当自受试对象皮肤细胞测量到的一种或多种基因的mRNA或蛋白质的表达水平低于自未被微尘损伤的皮肤细胞样本所测量到的表达水平时,其中,该一种或多种基因选自CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、KRT13(NM_002274)基因、及丝聚合蛋白基因,或2)当自受试对象的皮肤细胞测量到的一种或多种基因的mRNA或由其编码的蛋白质的表达水平高于自未被微尘损伤的皮肤细胞样本所测量到的表达水平时,其中,该一种或多种基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、及XDH(NM_000379)基因。
在一示例性实施例中,该试剂盒包含一种或多种抗体,该一种或多种抗体用于识别由一种或多种、两种或多种、三种或多种、四种或多种、五种或多种、六种或多种、七种或多种、八种或多种、九种或多种、十种或多种、十一种或多种、十二种或多种、十三种或多种、十四种或多种、十五种或多种、十六种或多种、十七种或多种、十八种或多种、十九种或多种、二十种或多种、二十一种或多种、或是二十二种或多种选自S100A7、S100A8、S100A9、CYP1A1、CYP1B1、PI3、IL36G、IL1B、CCL27、IL8、PTGS2、NOX5、XDH、CXCL14、SOD3、KRT1、H19、CASP14、KRT10、CASP8、KRT15、及KRT13的基因或所有所述基因编码的蛋白质。测量受试对象的皮肤细胞中连结到抗体之抗原量,藉此能诊断由微尘引起的皮肤损伤。
在另一方面中,本发明涉及一种用于诊断由微尘引起的皮肤细胞或皮肤障壁的损伤的方法。具体地,该方法可以包括:a)测量来自受试对象的细胞样本的一种或多种基因的mRNA或由其编码的蛋白质的表达水平的步骤,该一种或多种基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、及KRT13(NM_002274)基因;及b)与未被微尘损伤的皮肤细胞样本的基因的mRNA或由其编码的蛋白质的表达水平进行比较的步骤。
在本发明方面中,该方法进一步包含:在如下情况下诊断皮肤细胞或皮肤障壁被微尘损伤的步骤,1)当自受试对象的皮肤细胞测量到的一种或多种基因的mRNA或由其编码的蛋白质的表达水平低于自未被微尘损伤的皮肤细胞样本所测量到的表达水平时,其中,该基因选自CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、KRT13(NM_002274)基因、及丝聚合蛋白基因;或2)当自受试对象的皮肤细胞测量到的一种或多种基因的mRNA或由其编码的蛋白质的表达水平高于自未被微尘损伤的皮肤细胞样本所测量到的表达水平时,其中,该基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、及XDH(NM_000379)基因。
在本发明的该方面中,通过选自以下方法中的一种或多种方法来测量所述mRNA或蛋白质的表达水平:微阵列、PCR、NGS(二代测序法)、蛋白质印迹法(western blot)、Northern印迹法(northern blot)、ELISA、放射免疫测定法、放射性免疫扩散法、组织学免疫染色法及免疫沉淀分析法。
本发明中使用的基因表达的“正常水平”等是指未被微尘刺激的正常皮肤细胞的基因表达水平。在本发明中,通过测量受试对象的皮肤细胞中的基因的mRNA或其蛋白质的数量,且将其与未被微尘刺激的正常皮肤细胞的基因的mRNA或其蛋白质的表达水平进行比较来诊断皮肤细胞损伤。
本发明中使用的术语“多”或“少”是指与参考量之差为1.5倍或更多、2倍或更多,具体地,2.2倍或更多。
表1和表2描述了表达因微尘而增加或降低的本发明中使用的基因。表1显示表达因微尘而增加的基因,且表2显示表达因微尘而减少的基因。在该表中,名称是指NCBIGenBank登录ID,基因符号是指基因的官方符号,且基因标题是指基因名称。
【表1】
【表2】
用作本发明的试剂盒的探针的多核苷酸作包含因微尘刺激而增加或减少表达的全长标记基因或其片段。具体地,该片段可能为10个核苷酸或更长。假如探针为10bps或更短,则其可能非特异结合键。
具体地,用作本发明的试剂盒中的引物的多核苷酸长度可以为18~22bps,但并非特定地受限于此。
针对由本发明的试剂盒中包含的标记基因编码的多核苷酸的该单克隆抗体可通过一般的单克隆抗体制备方法制备。
本发明还涉及一种通过将被微尘损伤的皮肤细胞中的特定基因的表达水平调节至正常水平来抑制或改善皮肤细胞损伤的组合物。
在本发明中,表达受微尘影响的皮肤细胞的基因包含:S100A7、S100A8、S100A9、CYP1A1、CYP1B1、PI3、IL36G、IL1B、CCL27、IL8、PTGS2、NOX5、XDH、CXCL14、SOD3、KRT1、H19、CASP14、KRT10、CASP8、KRT15、KRT13等。由于S100A7、S100A8、S100A9、CYP1A1、CYP1B1、PI3、IL36G、IL1B、CCL27、IL8、PTGS2、NOX5、及XDH为表达因微尘而增加的基因,因而通过将基因表达水平降低至正常水平,能抑制皮肤细胞损伤。并且,由于CXCL14、SOD3、KRT1、H19、CASP14、KRT10、CASP8、KRT15、及KRT13为表达因微尘而减少的基因,因而通过将基因表达水平增加至正常水平,能抑制皮肤细胞损伤。
在另一方面中,本发明涉及一种用于筛选改善由微尘引起的皮肤损伤的物质的方法,所述方法包含:用微尘处理皮肤细胞的步骤;用测试物质处理经微尘处理过的皮肤细胞的步骤;以及在用所述测试物质处理前和处理后,检查用该测试物质处理的皮肤细胞中的一种或多种基因的mRNA或由该基因编码的蛋白质的表达水平的步骤,其中,该基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、XDH(NM_000379)基因、CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、及KRT13(NM_002274)基因。
在本发明该方面中,该方法可以进一步包含这样的步骤:与用测试物质处理前相比,用测试物质处理后出现如下情况下则确定该测试物质为改善由微尘引起的皮肤损伤的物质:1)当一种或多种基因的mRNA或由该基因编码的蛋白质的表达水平增加时,其中,该基因选自CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、KRT13(NM_002274)基因、及丝聚合蛋白基因;或2)当一种或多种基因的mRNA或由该基因编码的蛋白质的表达水平减少时,其中,该基因选自S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、及XDH(NM_000379)基因、及丝聚合蛋白基因。
在示例性实施例中,该皮肤细胞可以为角质形成细胞。
由上述方法筛选的、用于抑制或改善由微尘引起的皮肤细胞损伤或皮肤障壁损伤的所述物质包含高良姜素,但并不受限于此。
在另一方面中,本发明涉及一种用于使皮肤保湿的组合物,该组合物包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物作为有效成分。
在另一方面中,本发明涉及一种用于使皮肤保湿的方法,该方法包含对有需要的受试对象施用高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物的步骤。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在使皮肤保湿上的用途。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在制备用于使皮肤保湿的组合物上的用途。
在本发明中,“高良姜素”是指一黄酮类,其为针形黄色结晶。其化学式为C15H10O5,分子量为270,熔点为214~215℃。高良姜素能从蜂胶、蜡菊属(Helichrysumaureonitens)、良姜(Alpinia officinarum)、良姜根茎(galangal rhizome)等获得。已知高良姜素具有抗菌及抗病毒活性,且能抑制乳房肿瘤细胞的成长。高良姜素的结构如化学式1所示。
[化学式1]
高良姜素可以具有衍生物,如:三乙酰高良姜素(C15H7O2(OCOCH3)3)或三甲基高良姜素(C15H7O2(OCH3)3),但并非受限于此。
在本发明中使用的“异构体”不仅包含:光学异构体(例如:基本上纯的对映异构体、基本上纯的非对映异构体或其混合物),而且还包括构象异构体(即仅在一个或多个化学键的角度上不同的异构体)、位置异构体(特别地,互变异构体)或几何异构体(例如顺式-反式异构体)。
在本发明中,“基本上纯的”是指,例如,当与对映异构体或非对映异构体结合使用时,作为对映异构体或非对映异构体的例子的具体化合物以约90%(w/w)或以上,具体地约95%或以上,更具体地约97%或以上,或约98%以上,进一步更具体地约99%或以上,甚至更具体地约99.5%以上的量存在。。
在本发明中,“药学上可接受的”是指因以常用药物剂量使用时可以避免明显毒性影响而被经政府管制机构或国际组织认可或罗列于药典或其它普遍公认的药典中用于动物,更具体地用于人类。
在本发明中,“药学上可接受的盐”是指药学上可接受的且具有其亲体化合物的所需药理学作用的根据本发明一方面的盐。该盐包含由无机酸、有机酸、无机碱或有机碱形成的食盐、及季铵离子的酸加成盐。该盐可以包含:(1)由无机酸(如:盐酸、氢溴酸、硫酸、硝酸、磷酸等)或有机酸(如:乙酸、丙酸、己酸、环戊丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸()、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟苯甲酰基)苯甲酸、桂皮酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-奈磺酸、4-甲苯磺酸、樟脑磺酸、4-甲双环[2,2,2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡萄糖酸、谷氨酸、羟基奈酸、水杨酸、硬脂酸或己二烯二酸形成的酸加成盐;或(2)当亲体化合物中存在的酸性质子被取代时形成的盐。
在本发明中,“前药”是指物理与化学性能已改变,因此其不会呈现生理活性,但在体内经由化学或酵促作用而转变成原药后发挥药效的药物。
在本发明中,“水合物”」是指一种与水结合的化合物。该术语以广泛概念使用,包含在水与化合物间缺乏化学键的包合物。
在本发明中,“溶剂化物”是指一种形成于溶质分子或离子与溶剂分子或离子之间的高级化合物(higher-order compound)。
在另一方面中,本发明涉及一种用于增强皮肤障壁机能的组合物,其包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物作为有效成分。
在另一方面中,本发明涉及一种用于增强皮肤障壁机能的方法,其包含向有需要的受试对象施用高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物的步骤。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在增强皮肤障壁机能上的用途。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在制备用于增强皮肤障壁机能的组合物上的用途。
在另一方面中,本发明涉及一种用于诱导角质形成细胞分化的组合物,所述组合物包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物作为有效成分。
在另一方面中,本发明涉及一种用于诱导角质形成细胞分化的方法,该方法包含向有需要的受试对象施用高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物的步骤。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在诱导角质形成细胞分化上的用途。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在制备用于诱导角质形成细胞分化的组合物上的用途。
在另一方面中,本发明涉及一种用于改善由微尘引起的皮肤损伤的组合物,该组合物包含高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物作为有效成分。
在本发明中,术语皮肤损伤以广泛概念使用,包含降低或削弱皮肤机能。例如,其可能包含降低皮肤障壁机能、降低皮肤保湿能力、降低皮肤弹性等。
在另一方面中,本发明涉及一种用于改善被微尘损伤的皮肤状态的方法,该方法包含一种向有需要的受试对象施用高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在改善由微尘引起的皮肤损伤上的用途。
在另一方面中,本发明涉及高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物在制备用于改善由微尘引起的皮肤损伤的组合物上的用途。
根据本发明的一方面的组合物可以含有占所述组合物总重量0.00001~30wt%的高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物。当含量为0.00001~30wt%时,可以实现优异的皮肤保湿效果,增进皮肤障壁机能,且诱导角质形成细胞分化等。
具体地,该含量可以为0.0000001wt%或更多、0.0000005wt%或更多、0.0000007wt%或更多、0.0000009wt%或更多、0.000001wt%或更多、0.000002wt%或更多、0.000004wt%或更多、0.000006wt%或更多、0.000008wt%或更多、0.00001wt%或更多、0.00003wt%或更多、0.00005wt%或更多、0.00007wt%或更多、0.00009wt%或更多、0.0001wt%或更多、0.0003wt%或更多、0.0005wt%或更多、0.0007wt%或更多、0.0009wt%或更多、0.001wt%或更多、0.01wt%或更多、0.1wt%或更多、1wt%或更多、3wt%或更多、5wt%或更多、7wt%或更多、9wt%或更多、10wt%或更多、13wt%或更多、15wt%或更多、17wt%或更多、19wt%或更多、21wt%或更多、23wt%或更多、25wt%或更多、27wt%或更多、29wt%或更多、30wt%或更多、31wt%或更多、且可以为32wt%或更少、31wt%或更少、30wt%或更少、29wt%或更少、28wt%或更少、26wt%或更少、24wt%或更少、22wt%或更少、20wt%或更少、18wt%或更少、16wt%或更少、14wt%或更少、12wt%或更少、10wt%或更少、9wt%或更少、8wt%或更少、6wt%或更少、4wt%或更少、2wt%或更少、1wt%或更少、0.1wt%或更少、0.09wt%或更少、0.04wt%或更少、0.01wt%或更少、0.006wt%或更少、0.001wt%或更少、0.0009wt%或更少、0.0007wt%或更少、0.00005wt%或更少、0.00003wt%或更少、0.00001wt%或更少、0.000009wt%或更少、0.000007wt%或更少、0.000005wt%或更少、0.000003wt%或更少、0.000001wt%或更少、0.0000009wt%或更少、0.0000007wt%或更少、0.0000005wt%或更少、0.0000003wt%或更少、0.0000002wt%或更少、0.0000001wt%或更少、0.00000009wt%或更少,但并非受限于此。
高良姜素、其异构体、其药学上可接受的盐、其前药、其水合物或其溶剂化物的浓度可以为占所述组合物总体积的0.1~5μM。具体地,所述浓度可以为0.1μM或更高、0.1μM或更高、0.2μM或更高、0.3μM或更高、0.4μM或更高、0.45μM或更高、0.47μM或更高、0.49μM或更高、0.5μM或更高、0.51μM或更高、0.53μM或更高、0.55μM或更高、0.6μM或更高、0.7μM或更高、0.8μM或更高、0.9μM或更高、1.0μM或更高、1.1μM或更高、1.2μM或更高、1.3μM或更高、1.5μM或更高、1.7μM或更高、1.9μM或更高、2.0μM或更高、2.1μM或更高、μM或更高、2.5μM或更高、2.7μM或更高、2.9μM或更高、3.0μM或更高、4.0μM或更高、4.5μM或更高、5.0μM或更高、5.1μM或更高、且可以为5.1μM或更低、4.6μM或更低、4.1μM或更低、3.6μM或更低、3.1μM或更低、2.6μM或更低、2.3μM或更低、2.2μM或更低、2.1μM或更低、2.0μM或更低、1.9μM或更低、1.8μM或更低、1.6μM或更低、1.4μM或更低、1.2μM或更低、1.1μM或更低、1.0μM或更低、0.9μM或更低、0.8μM或更低、0.6μM或更低、0.5μM或更低、0.4μM或更低、0.3μM或更低、0.2μM或更低,但并非受限于此。当浓度为0.2μM或更高时,所述组合物的效果可能更好。
在该方面中,所述组合物可以促进选自如下的一种或多种基因的表达:CXCL14(NM_004887)基因、SOD3(NM_003102)基因、KRT1(NM_006121)基因、H19(NR_002196)基因、CASP14(NM_012114)基因、KRT10(NM_000421)基因、CASP8(NM_001080125)基因、KRT15(NM_002275)基因、KRT13(NM_002274)基因、及丝聚合蛋白基因。此外,所述组合物可促进丝聚合蛋白或角蛋白的合成。
并且,所述组合物可减少选自如下的一种或多种基因的表达:S100A7(NM_002963)基因、S100A8(NM_002964)基因、S100A9(NM_002965)基因、CYP1A1(NM_000499)基因、CYP1B1(NM_000104)基因、PI3(NM_002638)基因、IL36G(NM_019618)基因、IL1B(NM_000576)基因、CCL27(NM_006664)基因、IL8(NM_000584)基因、PTGS2(NM_000963)基因、NOX5(NM_001184779)基因、及XDH(NM_000379)基因。
因此,根据本发明的一方面的所述组合物在防止、改善、或处理异位性皮肤炎、银屑病、干燥性皮肤炎等上显现优异的效果。
在本发明的一方面中,所述组合物可以为化妆品组合物、药物组合物或保健食品组合物。
所述化妆品组合物可以为,例如:乳霜、洗液等,清洁剂、洗面奶、肥皂、化妆液等。
加入本发明的含高良姜素的组合物的化妆品可以为溶液、乳液、黏性混合物等的形式。
本发明的化妆品并不特别限定于制剂方面。例如,其可以配制为乳液、乳霜、化妆水、精华液、面膜、凝胶、粉末、妆前底霜、粉底、洗液、软膏、修补液、化妆液、洁肤泡沫、洁肤霜、洁肤水、润肤洗液、润肤霜、润肤油、润肤精油、洗发精、润发液、沐浴乳、肥皂、染发液、喷雾剂等。
所述化妆组合物的每种制剂可包含高良姜素外的成分,本领域技术人员可以根据特定的制剂或使用的目的来选择该成分而无困难。
所述制剂可以包含皮肤吸收-促进材料以增加皮肤保湿效果,增强皮肤障壁机能并诱导角质形成细胞的分化。
同样的,本发明的化妆品制剂可包含选自如下物质中的一种或多种物质:水溶性维生素、油溶性维生素、多肽、多醣、鞘脂、及海藻提取物。
此外,本发明的化妆品制剂可包含基本成分之外的化妆品中常用的其它成分。
进一步添加的成分的实施例可以包含:油、脂、保湿剂、润滑剂、表面活化剂、有机或无机颜料、有机粉末、UV吸收剂、防腐剂、杀菌剂、抗氧化剂、植物提取物、pH控制剂、醇、着色剂、芳香剂、血液循环兴奋剂、冷却剂、止汗剂、纯净水等。
然而,可添加的成分并不限于此。并且,可以确定在不对本发明的目的和效果产生负面影响的范围内的进一步添加的成分的量。
包括本发明的高良姜素的药物组合物还可以包含常用于制备药物组合物的适当的载体、赋形剂、稀释剂。
包括本发明的高良姜素的药物组合物可以根据常用的方法配制成任何药学上合适的制剂,包含软膏、凝胶、霜剂、修补液、喷雾剂等。
制剂的施用量可能为1.0~3.0mL/天,但该施用量依据受试对象的年龄、性别、体重、症状、及施用方法而变化。具体地,可以1天施用1~5次,持续一个月或更长时间。
保健食品可以指的是使用日常饮食可能缺乏的养分或功能性成分制备的食品,该保健食品能通过维持人体正常机能或激活生理活动维持并改善健康之,但并非限定于此。根据相关法律,所述保健食品可制备并加工成片剂、胶囊、粉末、颗粒、液体、丸剂等,但并非限定于此。
在本发明的一方面中,除了作为基本成分的上述化合物外,保健饮料组合物还可以包含其它成分,如常用于饮料中的各种调味料、天然碳水化合物等,而无特殊限定。所述天然碳水化合物的实例包含常见的糖,如:单醣、多醣、环糊精,以及糖醇,如:木糖醇、山梨醇、赤藓糖醇等。此外,天然调味料(索马甜或甜菊提取物(例如:莱苞迪甙A、甘草酸等))或合成调味料(糖精、阿斯巴甜等)可用作调味料。
通常,包含在保健食品组合物中的有效成分的施用量可以为约0.0001~1000mg/kg/天。更具体地,施用量可以为约0.02~6mg/kg/天。一天可以施用一次或数次。
以下,通过实施例对本发明进行详细说明。然而,以下实施例仅用于说明目的,对于本领域普通技术人员显而易见的是,本发明的范围不受实施例的限制。
[实施例1]微尘的采集及提取。
采用低容量的采样器(Sensidyne,Gillian,Low Volume Air Sampler,FL,USA)采集微尘。持续取样约24小时,同时在进行取样的当天约上午10时更换过滤器及过滤组的扩散管。从2014年2月1日到2014年2月28日,在韩国首尔(龙仁市,在六层建筑的屋顶)的下风区,每天采集微尘。通过使用定时器检测真空泵运作的时间记录取样时间。在开始及完成取样时,使用流量计(Model 4143,TSI Inc.)测量设定为16.7L/分钟的取样率。在取样前及取样后,将装载于过滤组内的铁氟龙过滤器(Teflon filter)称重。在对铁氟龙过滤器称重前,其被设置在一种相对湿度为40%的干燥器(Nikko,日本)中。使用电子天平(DVG215CD,Ohaus)测量重量二次,取小数点后5位数,然后加以平均。另外,取样后,在放置于干燥器24小时后,再次将过滤器称重两次。根据取样前所测得的重量计算质量浓度。根据如下步骤提取微尘:将铁氟龙过滤器浸泡于1mL乙醇中。在添加14mL的DW,以便水平面达到过滤器的气溶胶取样表面,并封盖后;通过超声处理进行萃取30分钟。置于干燥器中48小时将过滤器的水完全移除以使误差最小化后,用能够测量高达0.1mg的高精度天平(Mettler ToledoCompany)测量过滤器的重量。
[实施例2]培养人正常角质形成细胞
将从Lonza,Inc.(Walkersville,MD,USA)购得的人正常角质形成细胞(表皮新生角质形成细胞)在37℃及5%CO2条件下,在CO2培养器内培养。根据Lonza,Inc的操作指南培养细胞。使用KGMTM-2Bullet Kit CC-3107(成分:BPE(牛垂体提取物)、人表皮生长因子(hEGF)、胰岛素、氢化可的松、转铁蛋白、肾上腺素和GA-1000(硫酸庆大霉素+两性霉素B)),其中KGM-2Bullet试剂盒CC-4152加入至500m的KBM-2(KBMTM-2,CC-3103)培养基中。
[实施例3]用微尘处理人正常角质形成细胞及细胞毒性的测量
为了调查微尘的细胞毒性,依据Mossman等人的方法(J.Immunol.Methods,65,55-63,1983),使用人正常角质形成细胞进行MTT分析法。
具体地,使用24孔板,且将由例1获得的粒径为10μm的微尘及粒径为2.5μm的微尘分别分散于纯净水中。将在实施例2的条件下培养的2.5x105个人正常角质形成细胞的每个细胞用制备好的微尘分散系处理后,培养24小时,并在添加5mg/mL MTT(3-4,5-二甲基噻唑-2,5-二苯四唑溴盐后,将该细胞进一步在37℃培养3小时。然后,移除培养基,将所形成的甲瓒结晶溶解于500μL的DMSO中。所溶解的甲瓒结晶转移至96孔培养盘,且通过测量540nm的吸光率来确定OD值。其结果如图1所示。
由图1可见,对于粒径为10μm的微尘及粒径为2.5μm的微尘的两种分散系(以下称为水性微尘提取物),细胞存活率为80%(IC20)时,浓度为12.5μg/mL。
[实施例4]采用二代测序法,分析以微尘处理的细胞中基因的变化。
为了进行RNA-seq数据处理及分析,使用Trapnell等人(2012)所开发的一般分析法。使用FastQC(http://www.bioinformatics.babraham.ac.uk/projects/fastqc/)对RNA-seq数据进行质量控制,且使用FASTX(http://hannonlab.cshl.edu/fastx_toolkit/)来移除低精确度的碱基及接头序列。然后,使用Tophat(Trapnell et al.,2009)及人类基因组(hg19)进行比对,并使用更名为RSeQC的EVER-seq确认每种样本的数据量(Wang etal.,2012)。另外,用Cufflink将转录本的表达水平量化,并在以两种微尘分散系处理的样本与正常样本之间进行比较(Trapnell et al.,2012)。通过应用FDR校正p值<0.05且≧2.0倍数变化的严格分界,确定以粒径为2.5μm的微尘分散系及以粒径为10μm的微尘的分散系处理后,表达明显变化的基因。结果如表3及表4所示。
【表3】
【表4】
[实施例5]实时RT-PCR
实施例2中培养的人正常角质形成细胞用在1mL细胞培养基中提取的12.5μg的粒径为2.5μm的微尘处理且使用表5与表6(primers,Applied Biosystems)所述引物来测量mRNA相对表达水平。
【表5】
【表6】
微尘处理过的人正常角质形成细胞、或实施例2中培养的未经微尘处理的人正常角质形成细胞皆以不同浓度(0.25μM、0.5μM、1μM、及2μM)的高良姜素进行处理。24小时后,将培养基移除,并以2mL磷酸缓冲盐溶液(PBS)清洗细胞。然后,使用TRIzol试剂(Invitrogen,Carlsbad,CA,USA)将RNA自细胞中分离出来。以0.25μM高良姜素处理后,对S100A8、S100A9、CYP1A1、CYP1B1、PI3、IL36G、IL1B、CCL27、IL8、NOX6、XDH、CXCL14、H19、CASP14及CASP8测量表达水平。该高良姜素从南京康满林化工有限公司(Nanjing ChemlinChemical,CAS号548-83-4)商业购得。分离的RNA再以Qiagen RNA试剂盒(Qiagen,Valencia、CA)再纯化一次。使用Agilent 2100BioAnalyzer(Agilent Technologies,SantaClara,CA,USA)确定RNA的质量。使用SuperScript逆转录酶(RT)试剂盒(Invitrogen、Carlsbad、CA)从RNA合成的cDNA使用表5和表6所述引物,通过实时逆转录-聚合酶链反应(Q-RT-PCR)来进行量化分析。使用TaqMan基因表达分析试剂盒(Applied Biosystems,Foster City,CA)实时评估基因表达模式的变化。结果如图2和图3所示。皆根据LifeTechnologies的标准协议进行Q-RT-PCR和实时PCR,具体地,95℃持续20秒,接着95℃持续3秒及60℃持续30秒,40个循环。
从图2和图3可见,被微尘刺激的皮肤细胞中表达增加或减少且以高良姜素处理后表达恢复正常水平的基因。
[实施例6]以高良姜素处理正常角质形成细胞后基因表达的变化的测量。
用不同浓度(0μM、0.5μM、1μM、及2μM)的高良姜素,处理实施例2中培养的人正常角质形成细胞后,测量丝聚合蛋白、角蛋白10、角蛋白1、角蛋白13、及角蛋白15的mRNA相对表达水平。
以高良姜素处理24小时后,移除培养基,并用2mL磷酸缓冲盐溶液(PBS)清洗细胞。然后,使用TRIzol试剂(Invitrogen,Carlsbad,CA,USA)将RNA从细胞中分离。
从图4可见,即使在未用微尘处理的细胞中,丝聚合蛋白、角蛋白10、角蛋白1、角蛋白13、角蛋白15的表达随高良姜素浓度的增加而增加。
[实施例7]用高良姜素处理后角质形成细胞增加分化。
用不同浓度(0μM、1μM、及2μM)的高良姜素处理实施例2中培养的人正常角质形成细胞。经过24小时后,将培养基移除,在光学显微镜(Olympus IX71;×40及×200)下观察角质形成细胞分化程度。如图5所示,未用微尘处理的人正常角质形成细胞随着高良姜素浓度增加而显示活化分化作用。
[实施例8]用高良姜素处理增加丝聚合蛋白的表达。
,用不同浓度(0μM、0.5μM、1μM、及2μM)的高良姜素处理实施例2中培养的人正常角质形成蛋白。24小时后,将培养基移除,并用2mL磷酸缓冲盐溶液(PBS)清洗细胞。添加细胞裂解缓冲液并搅拌后,从所获得的上清液,定量蛋白质。将从正常皮肤和干燥皮肤表皮获得的蛋白质加载于SDS凝胶上,然后使用丝聚合蛋白抗体(Covance,France)进行印迹。量化结果用β-肌动蛋白(Sigma,USA)进行标准化。从图6可见,丝聚合蛋白的表达随着高良姜素浓度的增加而增加。
下文将通过制剂实施例详细描述本发明。然而,以下制剂实施例仅用于说明目的,本发明的范围不受其限制。
[制剂实施例1]肥皂
【表7】
[制剂实施例2]洗剂
【表8】
成分 | 含量(%) |
高良姜素 | 5.00 |
L-抗坏血酸2-磷酸镁盐 | 1.00 |
水溶性胶原蛋白(1%水溶液) | 1.00 |
柠檬酸钠 | 0.10 |
柠檬酸 | 0.05 |
甘草提取物 | 0.20 |
1,3-丁二醇 | 3.00 |
纯净水 | 余量 |
[制剂实施例3]乳霜
【表9】
[制剂实施例4]软膏
【表10】
[制剂实施例5]化妆液
【表11】
成分 | 含量(%) |
高良姜素 | 3.00 |
羟乙基纤维素(2%水溶液) | 12.00 |
黄原胶(2%水溶液) | 2.00 |
1,3-丁二醇 | 6.00 |
稠甘油 | 4.00 |
透明质酸钠(1%水溶液) | 2.00 |
纯净水 | 余量 |
[制剂实施例6]保健食品
【表12】
[制剂实施例7]保健饮料
【表13】
成分 | 含量 |
高良姜素 | 50mg |
柠檬酸 | 1000mg |
寡糖 | 100g |
牛磺酸 | 1g |
纯净水 | 余量 |
Claims (7)
1.高良姜素或其药学上可接受的盐在制备用于改善由微尘引起的皮肤损伤的组合物上的用途。
2.如权利要求1所述的用途,其特征在于,所述组合物包含占所述组合物总重量0.000001~30wt%的高良姜素或其药学上可接受的盐。
3.如权利要求1所述的用途,其特征在于,高良姜素或其药学上可接受的盐的浓度占所述组合物总体积为0.1~5μM。
4.如权利要求1所述的用途,其特征在于,所述组合物促进选自以下的一种或多种基因的表达:如NM_004887所示的CXCL14基因、如NM_003102所示的SOD3基因、如NM_006121所示的KRT1基因、如NR_002196所示的H19基因、如NM_012114所示的CASP14基因、如NM_000421所示的KRT10基因、如NM_001080125所示的CASP8基因、如NM_002275所示的KRT15基因、如NM_002274所示的KRT13基因、及丝聚合蛋白基因。
5.如权利要求1所述的用途,其特征在于,所述组合物降低选自以下的一种或多种基因的表达:如NM_002963所示的S100A7基因、如NM_002964所示的S100A8基因、如NM_002965所示的S100A9基因、如NM_000499所示的CYP1A1基因、如NM_000104所示的CYP1B1基因、如NM_002638所示的PI3基因、如NM_019618所示的IL36G基因、如NM_000576所示的IL1B基因、如NM_006664所示的CCL27基因、如NM_000584所示的IL8基因、如NM_000963所示的PTGS2基因、如NM_001184779所示的NOX5基因、及如NM_000379所示的XDH基因。
6.如权利要求1所述的用途,其特征在于,所述组合物促进丝聚合蛋白或角蛋白的合成。
7.如权利要求1所述的用途,其特征在于,所述组合物为化妆品组合物、药物组合物、或保健食品组合物。
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