CN103249409A - 用微小rna调节剂治疗皮肤的方法 - Google Patents
用微小rna调节剂治疗皮肤的方法 Download PDFInfo
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- CN103249409A CN103249409A CN2011800584943A CN201180058494A CN103249409A CN 103249409 A CN103249409 A CN 103249409A CN 2011800584943 A CN2011800584943 A CN 2011800584943A CN 201180058494 A CN201180058494 A CN 201180058494A CN 103249409 A CN103249409 A CN 103249409A
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Abstract
提供了用于预防、改善或减少老化的皮肤病学体征的方法,其采用抑制或下调真皮成纤维细胞中的微小RNA表达的活性剂,导致皮肤中的胶原、弹性蛋白和/或微纤维蛋白的增强生产。还提供的是用于筛选针对特定微小RNAs的活性的方法和使用通过皮肤治疗中的筛选方案鉴定的活性剂的方法。
Description
与相关申请的交叉参考
本申请根据35U.S.C.§119(e)要求于2010年12月28日提交的美国专利申请号12/979,695的优先权利益,所述申请的内容在此通过引用整体合并。
发明领域
本发明一般涉及改善人皮肤的美容外观和健康的方法,并且还涉及用于鉴定对于治疗皮肤有用的化合物的方法。特别地,本发明涉及减少特定微小RNAs的水平的化合物,所述特定微小RNAs抑制皮肤细胞中的胶原、弹性蛋白和/或微纤维蛋白表达。
发明背景
消费者对减轻或延迟老化的皮肤病学体征和由真皮表皮结合部和表皮中的细胞间凝聚的进行性降解引起的相关状况感兴趣,所述体征例如细纹、皱纹和下垂皮肤。年代老化、激素老化和光老化各自涉及降解皮肤的三个主要蛋白质组分的过程:胶原、弹性蛋白和微纤维蛋白。
胶原是身体的主要结构蛋白质,其支持组织和器官且使这些结构与骨连接。胶原在提供围绕细胞的结构支架中起关键作用,所述结构支架帮助支持细胞形状和分化。弹性蛋白是给予皮肤伸展和随后很快恢复至其原始状态的能力的蛋白质。微纤维蛋白是在结缔组织中发现的弹性纤维形成必需的糖蛋白。微纤维蛋白分泌到细胞外基质内且变得掺入不溶性微纤丝内,所述不溶性微纤丝看起来提供用于弹性蛋白沉积的支架。胶原、弹性蛋白和微纤维蛋白通过成纤维细胞产生,所述成纤维细胞是位于真皮中特化的皮肤细胞。胶原、弹性蛋白和微纤维蛋白的刺激可以改善皮肤的健康和外观,因为皮肤老化一般与这些蛋白质的丧失相关。本领域存在延缓皮肤老化且补救皮肤老化效应的组合物的需要。
微小RNAs(miRNAs)是短核糖核酸(RNA)分子,平均起来仅长约22个核苷酸且在所有真核细胞中发现。miRNAs被认为是与靶信使RNA转录物(mRNAs)上的互补序列结合的转录后调控物,通常导致翻译阻遏和基因沉默。如果在miRNA和靶mRNA序列之间存在完全互补,那么mRNA可以被切割,导致直接mRNA降解。然而,如果不存在完全互补,那么沉默通过阻止翻译来达到。已估计人基因组编码超过1000种miRNAs,其可以靶向约60%哺乳动物基因且在许多人细胞类型中丰富。然而,迄今为止,改善皮肤外观且对抗老化体征的努力仍未集中于微小RNAs的作用。
因此本发明的目的是提供用于治疗、改善、抑制和/或阻止老化的皮肤病学体征的组合物和方法。
本发明的另一个目的是提供通过调节微小RNAs水平用于治疗、改善、抑制和/或阻止老化的皮肤病学体征的组合物和方法,所述微小RNAs与皮肤细胞中的胶原、弹性蛋白和/或微纤维蛋白表达相关。
本发明的进一步目的是提供基于调节与皮肤细胞中的胶原、弹性蛋白和/或微纤维蛋白表达相关的微小RNAs水平的能力,用于鉴定对于治疗、改善、抑制和/或阻止老化的皮肤病学体征有用的化合物的方法。
前述讨论仅呈现为提供本领域面临问题的性质的更佳理解并且不应以任何方式解释为关于现有技术的承认。
发明概述
依照前述目的及其他,已惊讶地发现特定微小RNAs是皮肤细胞中的胶原、弹性蛋白和/或微纤维蛋白表达的负调控物。因此提供了用于改善人皮肤的美容外观的方法,其包括将在化妆品可接受的媒介物中的有效量的物质局部应用于有此需要的皮肤区域足以增强皮肤中的胶原、弹性蛋白和/或微纤维蛋白生产的时间,所述物质优选通过减少微小RNA-29a(miR-29a)和/或微小RNA-28b(miR-29b)的细胞水平来调节微小RNA-29a(miR-29a)和/或微小RNA-28b(miR-29b)。如下所示,miR-29a包含SEQ.ID.No.:1的核酸序列,并且miR-29b包含SEQ.ID.No.:2的序列。
UAGCACCAUCUGAAAUCGGUUA(SEQ.ID.No.:1)
UAGCACCAUUUGAAAUCAGUGUU(SEQ.ID.No.:2)
在各种实施方案中,该方法可以必须伴有抑制皮肤细胞中的miR-29a水平,抑制皮肤细胞中的miR-29b水平,或抑制皮肤细胞中的miR-29a和miR-29b水平。考虑皮肤细胞中miR-29a和miR-29b的抑制将提供增强皮肤中的胶原、弹性蛋白和/或微纤维蛋白表达中的协同利益。
在一个方面,适合于调节miR-29a和/或miR-29b水平的化合物可以具有式I的结构:
其中:
R1和R2独立地是氢、–R或–C(=O)R*,其中R1和R2可以连同它们与之附着的氮原子一起形成三至六元环;
R3选自氢、–R、–OR*、–SR*和–N(RN)(R*);
R4和R5在每种情况下独立地选自氢;–R;或X1;并且其中任何两个邻近基团,R5可以形成稠合至它们与之附着的苯环的五或六元环;
R6是氢、–R或–C(=O)R*;
R、R*和RN独立地是氢或C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1和/或选自氧、氮和硫的一至十二个杂原子取代;
X1选自–F;–Cl;–Br;–I;–OH;–C≡C–R*;–C≡N;–C(R)=N–RN;–C=N–N(RN)2;–C(=NRN)–N(RN)2;–CH2OH;–CHO;–(C=O)–R*;–CO2H;–CO2 –;–CO2R*;–CS2R*;–(C=O)–S–R*;–S–(C=O)–R*;–(C=O)–NH2;–(C=O)–NRNRN;–(C=O)–NHNH2;–O–(C=O)–NHNH2;–(C=S)–NH2;–(C=S)–N(RN)2;–O–(C=O)–H;–O–(C=O)–R*;–O–(C=O)–NH2;–O–(C=O)–NRNRN;–OR*;–SR*;–NH2;–NHRN;–NRN 2;–N(RN)3 +;–N(RN)–OH;–N(→O)(R*)2;–O–N(RN)2;–N(RN)–O–R*;–N(RN)–N(RN)2;–NRN–(C=O)–R*;–NRNC(=O)O–R*;–NRN–CHO;–NRN–(C=O)–R*;–NRNC(=O)NRN;–N(RN)–C(=O)–N(RN)2;–N(RN)–C(=S)–N(RN)2;–N=C(R*)2;–N=N–RN;–SCN;–NCS;–NSO;–SS–R*;–SO–R*;–SO2–R*;–O–S(=O)2–R*;–S(=O)2–OR*;–N(RN)–SO2–R*;–SO2–N(R*)2;–O–SO3 –;–O–S(=O)2–OR*;–O–S(=O)–OR*;–O–S(=O)–R*;–S(=O)–OR*;–S(=O)–R*;–NO;–NO2;–NO3;–O–NO;–O–NO2;–N3;–N2;–N(C2H4);–Si(R*)3;–CF3;–O–CF3;–(C=O)–R*;–P(R*)2;–O–P(=O)(OR*)2;和–P(=O)(OR*)2;
“n”是0–3的整数,并且在其中“n”是2或3的情况下,R5在每种情况下独立地选择;
及其化妆品可接受的酸加成盐。
在一些实施方案中,R1、R2、R3、R4和R6可以独立地是氢或基团–R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子取代。R1和R6通常但不一定是氢,并且R2,R3和R4可以独立地是基团-R,其中R是形式–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3的基团;其中a、b、c、x、y和z独立地是0–5的整数,并且X2代表键或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的二价基团或原子,并且X3代表氢、X1或R*。
在进一步实施方案中,R2是形式–(CH2)a–X2–(CH2)x–CH3的基团,和/或R3是形式–CH=CH–R*的基团,其中R*是芳基基团和/或R4是形式–(CH2)a–R*的基团,其中是R*是芳基基团。R5是在苯环上的一个或多个可用位置上的取代基,但通常在所有此类位置上是氢。
在一个实施中,miR-29a和/或miR-29b调节化合物具有下式:
或其化妆品可接受的酸加成盐。
调节miR-29a和/或miR-29b的另一类合适的化合物具有式II的结构:
其中,
R5选自氢;–R;或X1;其中“m”是0–5的整数,并且在其中“m”是2、3或4的情况下,R5在每种情况下独立地选择;和
R7和R8独立地是C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1和/或选自氧、氮和硫的一至六个杂原子取代;和
R、R*和RN独立地是氢或C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1(其中X1如上定义)和/或选自氧、氮和硫的一至十二个杂原子取代;及其化妆品可接受的盐。
在一些变体中,R7和R8独立地是基团-R,其中R是形式–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3的基团;其中a、b、c、x、y和z独立地是0–5的整数,并且X2代表键或二价基团或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的原子,并且X3代表氢、X1或R*;其中R*是任选由基团X1和/或选自氧、氮和硫的一至十二个杂原子取代的C1-20烃基团。RN、R7和R8可以例如独立地是基团-R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子取代。一种此类有用的化合物具有下式:
在本发明的一个方面,将miR-29a和/或miR-29b的调节剂局部应用于有此需要的皮肤,例如皱纹皮肤、过早变薄的皮肤或下垂皮肤,以因此改善美容外观。改善可以是例如:
(a)细纹或皱纹的治疗、减少和/或预防,
(b)皮肤毛孔大小的减少,
(c)皮肤厚度、丰满度和/或紧固度的改善;
(d)皮肤柔度和/或柔软性的改善;
(e)皮肤色调、光亮度和/或澄清度的改善;
(f)弹性蛋白的维持和重塑的改善;
(g)皮肤肌理的改善和/或重组构化的促进;
(h)皮肤屏障修复和/或功能的改善;
(i)皮肤轮廓外观的改善;
(j)皮肤光泽和/或亮度的恢复;
(k)通过绝经减少的皮肤外观的改善;
(l)皮肤保湿的改善;
(m)皮肤弹力和/或弹性的增加;
(n)皮肤下垂的治疗、减少和/或预防;或
(o)色素斑点的减少。
在本发明的另一个方面,提供了用于鉴定对于改善皮肤的美容外观有用的活性剂的方法,其包括就抑制或下调细胞中的miR-29a和/或miR-29b的能力测定候选物质。测定步骤可以包括使人真皮成纤维细胞与候选化合物一起温育,且随后例如通过qRT-PCR测量miR-29a和/或miR-29b的水平。减少miR-29a和/或miR-29b但优选两者的水平的活性剂预期在增强皮肤中的胶原、弹性蛋白和/或微纤维蛋白水平中是有用的。
在本发明的另外一个方面,提供了通过增加皮肤中的胶原、弹性蛋白和/或微纤维蛋白生产用于改善皮肤的美容外观的方法,该方法包括将有效量的抑制miR-29a和/或miR-29b的化合物局部应用于有此需要的皮肤区域,其中化合物通过测定物质抑制细胞中的miR-29a和/或miR-29b表达的能力的检测进行鉴定。在一个变体中,该方法用于治疗、减少或改善皱纹和细纹,并且包括抑制miR-29a和miR-29b的物质的局部应用,其中化合物通过测定物质抑制细胞中的miR-29a和/或miR-29b水平的能力的检测进行鉴定。
本发明的进一步方面、特点和优点在阅读本发明的详述后得到更佳理解。
发明详述
除非另有提供,本文使用的所有术语预期具有其通常含义。“化妆品可接受的”意指特定组分在采用的水平一般视为安全和无毒的。如本文使用的,术语“预防”包括减少皮肤老化的特定体征的严重性,或延迟皮肤老化的特定体征的发作或进展。术语“薄皮肤”包括随着年代老化变得更薄的皮肤以及可以例如通过光老化引起的过早变薄的皮肤。短语“有此需要的个体”指可以获益于改善的真皮外观或健康的人,包括男性或女性。术语“皮肤”包括但不限于唇、面部皮肤、手、臂、颈和胸。如本文使用的,术语“基本上由……组成”意欲使本发明限制于指定材料或步骤和实质上不影响本发明的基本和新型特征的那些,如由阅读本说明书理解的。
本发明提供了用于预防、改善或减少老化的皮肤病学体征的活性剂。术语“活性剂”包含任何物质,包括但不限于有机分子;生物分子(例如肽、蛋白质、抗体、核酸寡聚物等);及物质组合例如植物提取物。活性剂调节特定微小RNAs的细胞水平。优选地,调节必须伴有抑制、阻遏或下调微小RNAs,从而使得微小RNA的水平由于活性剂的存在而降低。活性剂以有效量局部应用于皮肤,所述有效量意指足以达到皮肤中的胶原、弹性蛋白或微纤维蛋白生产的可测量增加的量。
活性剂一般应用于皮肤足以提供皮肤老化的一种或多种皮肤病学体征的改善的时间。皮肤老化的此类体征包括但不限于下述:
(a)细纹或皱纹的治疗、减少和/或预防,
(b)皮肤毛孔大小的减少,
(c)皮肤厚度、丰满度和/或紧固度的改善;
(d)皮肤柔度和/或柔软性的改善;
(e)皮肤色调、光亮度和/或澄清度的改善;
(f)前胶原和/或胶原生产的改善;
(g)弹性蛋白的维持和重塑的改善;
(h)皮肤肌理的改善和/或重组构化的促进;
(i)皮肤屏障修复和/或功能的改善;
(j)皮肤轮廓外观的改善;
(k)皮肤光泽和/或亮度的恢复;
(l)皮肤中的必需营养素和/或组成成分的补充;
(m)通过老化和/或绝经减少的;
(n)皮肤保湿的改善;
(o)皮肤弹力和/或弹性的增加;
(p)皮肤下垂的治疗、减少和/或预防,和/或
(q)色素斑点的减少。
在实践中,本发明的组合物应用于需要治疗的皮肤。即,患有前述属性的任何的缺失或丧失或另外获益于前述皮肤属性的任何的改善的皮肤。皮肤一般每天治疗一次或两次。治疗可以继续一周、两周、四周、八周、六个月或更久。
在一个实施方案中,活性剂在化妆品可接受的媒介物中局部应用于患有细纹和/或皱纹的皮肤,以预防、治疗和/或改善皮肤中的细纹和/或皱纹外观。在这种情况下,组合物应用于需要治疗的皮肤,这意指已具有皱纹和/或细纹的皮肤或处于发展皱纹和/或细纹的危险中的皮肤。优选地,组合物直接应用于面部、颈、胸和/或手皮肤上的皱纹和/或细纹。
本发明的前提为真皮细胞中的蛋白质调节的新型机制涉及细胞微小RNAs的调节的发现。本发明基于miR-29a和miR-29b作为细胞外基质蛋白质特别是皮肤细胞中的胶原、弹性蛋白和微纤维蛋白的负调控物的鉴定。本文描述的实验法证实miR-29a和miR-29b的水平随着年龄增加,并且miR-29a和miR-29b的抑制增加胶原、弹性蛋白和微纤维蛋白的产生。
本发明的活性剂已显示减少miR-29a和miR-29b的水平。智人(Homo sapiens)miR-29a包含SEQ.ID.No.:1的核酸序列,并且智人miR-29b包含SEQ.ID.No.:2的序列,如下所示。
UAGCACCAUCUGAAAUCGGUUA(SEQ.ID.No.:1)
UAGCACCAUUUGAAAUCAGUGUU(SEQ.ID.No.:2)
活性剂可以是减少这些微小RNAs的水平的任何物质。例如,与序列互补的核酸寡聚物(抗miRs)可以是有用的。抗miR优选与SEQ.ID.No.:1或SEQ.ID No.:2的至少八个相邻核苷酸互补。在其他实施方案中,抗miR与SEQ.ID.No.:1或SEQ.ID No.:2的至少10、至少12、至少14、至少16、至少18、或至少20个相邻核苷酸互补。
在这些微小RNAs和重要皮肤蛋白质生产之间的关联的发现致使能够筛选对于治疗皮肤有用的活性剂。相应地,本发明的一个实施方案是用于鉴定此类活性剂的筛选方法。筛选方法一般必须伴有使皮肤细胞特别是真皮成纤维细胞与待测试的候选物质接触,且将细胞培养足以提供微小RNA水平的可测量减少的时间段,所述时间段一般是至少一小时,且更一般为约12小时–约72小时。miR-29a和miR-29b的水平随后通过本领域已知用于定量测定细胞核酸聚合物的任何技术进行测量。特别有用的方法是定量RT-PCR(qRT-PCR)。通过比较用候选物质处理的细胞中的微小RNA水平与未处理的对照,可以测定微小RNA水平中的减少量级。
选择证实使人真皮成纤维细胞中的miR-29a和/或miR-29b水平减少至少约5%、优选至少约10%、更优选至少约20%且更优选至少约30%的能力的物质用于进一步估计使用。在一些实施方案中,所选物质是使人真皮成纤维细胞中的miR-29a和/或miR-29b水平减少至少约40%、至少约50%、或至少约60%的那些。
在一个实施方案中,本发明涉及通过增加皮肤中的胶原、弹性蛋白和/或微纤维蛋白生产来改善皮肤的美容外观的方法,该方法包括将有效量的抑制miR-29a和/或miR-29b的活性剂局部应用于有此需要的皮肤区域,其中所述活性剂是已通过测定鉴定用于使用的那种,所述测定确定物质抑制细胞中的miR-29a和/或miR-29b表达的能力,包括本文描述的测定。
在一个实施方案中,活性剂包含能够调节miR-29a和/或miR-29b水平的化合物,其具有式I的结构:
其中:
R1和R2独立地是氢、–R或–C(=O)R*;并且R1和R2可以连同它们与之附着的氮原子一起形成三至六元环;
R3选自氢、–R、–OR*、–SR*和–N(RN)(R*);
R4和R5在每种情况下独立地选自氢;–R;或X1;并且其中任何两个邻近基团,R5可以形成稠合至它们与之附着的苯环的五或六元环;
R6是氢、–R或–C(=O)R*;
R、R*和RN独立地是氢或C1-20烃基团;或C1-16烃基团、或C1-12烃基团、或C1-10烃基团,其中所述烃基团可以任选由基团X1和/或选自氧、氮和硫的一至十二个、或一至八个、或一至六个、或一至四个杂原子取代;
X1选自–F;–Cl;–Br;–I;–OH;–C≡C–R*;–C≡N;–C(R)=N–RN;–C=N–N(RN)2;–C(=NRN)–N(RN)2;–CH2OH;–CHO;–(C=O)–R*;–CO2H;–CO2 –;–CO2R*;–CS2R*;–(C=O)–S–R*;–S–(C=O)–R*;–(C=O)–NH2;–(C=O)–NRNRN;–(C=O)–NHNH2;–O–(C=O)–NHNH2;–(C=S)–NH2;–(C=S)–N(RN)2;–O–(C=O)–H;–O–(C=O)–R*;–O–(C=O)–NH2;–O–(C=O)–NRNRN;–OR*;–SR*;–NH2;–NHRN;–NRN 2;–N(RN)3 +;–N(RN)–OH;–N(→O)(R*)2;–O–N(RN)2;–N(RN)–O–R*;–N(RN)–N(RN)2;–NRN–(C=O)–R*;–NRNC(=O)O–R*;–NRN–CHO;–NRN–(C=O)–R*;–NRNC(=O)NRN;–N(RN)–C(=O)–N(RN)2;–N(RN)–C(=S)–N(RN)2;–N=C(R*)2;–N=N–RN;–SCN;–NCS;–NSO;–SS–R*;–SO–R*;–SO2–R*;–O–S(=O)2–R*;–S(=O)2–OR*;–N(RN)–SO2–R*;–SO2–N(R*)2;–O–SO3 –;–O–S(=O)2–OR*;–O–S(=O)–OR*;–O–S(=O)–R*;–S(=O)–OR*;–S(=O)–R*;–NO;–NO2;–NO3;–O–NO;–O–NO2;–N3;–N2;–N(C2H4);–Si(R*)3;–CF3;–O–CF3;–(C=O)–R*;–P(R*)2;–O–P(=O)(OR*)2;和–P(=O)(OR*)2;
“n”是0–3的整数(即0、1、2或3),并且在其中“n”是2或3的情况下,R5在每种情况下独立地选择;
及其化妆品盐,包括酸加成盐。
在一些实施方案中,R1、R2、R3、R4和/或R6可以独立地是氢或基团–R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子、或一至八个、或一至六个、或一至四个杂原子取代,尽管R1和R6优选不都是氢。
在一些实施方案中,R1和/或R6将是氢,和/或R2,R3和R4独立地是基团-R,其中R具有如下形式:–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3;其中a、b、c、x、y和z独立地是0–5的整数(即0、1、2、3、4和5),包括其中a、b、c、x、y和z各自是0的情况;并且X2代表键或二价基团或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的原子,并且X3代表氢、X1或R*。
在进一步实施方案中,R2是形式–(CH2)a–X2–(CH2)x–CH3的基团,和/或R3是形式–CH=CH–R*的基团,其中R*是芳基基团和/或R4是形式–(CH2)a–R*的基团,其中是R*是芳基基团。R5是在苯环上的一个或多个可用位置上的取代基,但通常在所有此类位置上是氢。
在一个实施中,miR-29a和/或miR-29b调节化合物是2-(4-苄基哌啶-1-基)-N-(3-乙氧基丙基)-5-[(2E)-3-苯基丙-2烯酰胺基]苯甲酰胺,具有下式:
或其化妆品可接受的酸加成盐。
在另一个实施方案中,调节miR-29a和/或miR-29b的试剂包含具有式II的结构的化合物:
其中,
R5选自氢;–R;或X1;其中“m”是0–5的整数(即0、1、2、3、4或5),并且在其中“m”是2、3或4的情况下,R5在每种情况下独立地选择;和
R7和R8独立地是C1-20烃基团;或C1-16烃基团、或C1-12烃基团、或C1-10烃基团,其中所述烃基团可以任选由基团X1和/或选自氧、氮和硫的一至十二个、或一至六个、或一至四个杂原子取代;和
R、R*和RN独立地是氢或C1-20烃基团;或C1-16烃基团、或C1-12烃基团、或C1-10烃基团,其中所述烃基团可以任选由基团X1(其中X1如上定义)和/或选自氧、氮和硫的一至十二个、或一至六个、或一至四个杂原子取代;及其化妆品可接受的盐。
在一些变体中,R7和R8独立地是基团-R,其中R是形式–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3的基团;其中a、b、c、x、y和z独立地是0–5的整数,并且X2代表键或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的二价基团或原子,并且X3代表氢、X1或R*;其中R*是C1-20烃基团、或C1-16烃基团、或C1-12烃基团、或C1-10烃基团、或C1-8烃基团、或C1-6烃基团,任选由基团X1和/或一至十二个杂原子、或一至六个杂原子、或一至四个杂原子取代,所述杂原子选自氧、氮和硫。
RN、R7和R8可以例如独立地是基团-R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子取代。RN、R7和R8可以例如独立地是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、环戊基、己基、环己基(cyclohexeyl)、苯基或苄基。
一种此类有用的化合物是N-(2-甲基丙基)-N-[[4-[(甲磺酰)氧基]苯基]甲基]-苯磺酰胺,其具有结构:
根据本发明的化妆品组合物可以以用于局部应用的多种形式配制,并且包含按重量计约0.00001%-约90%的根据式(I)或式(II)的一种或多种化合物,并且优选包含按重量计约0.001%-约25%,和更优选按重量计约0.001%-约1%。组合物包含有效量的式(I)或式(II)的化合物,所述有效量意指当局部应用于皮肤时,足以下调微小RNAs且反过来又增强特定皮肤区域中的胶原、弹性蛋白和/或微纤维蛋白生产的量。
组合物可以包括化妆品可接受的媒介物。此类媒介物可以采用本领域已知适合于应用于皮肤的任何形式,并且可以包括但不限于水;植物油;矿物油;酯例如棕榈酸辛酯、肉豆蔻酸异丙酯和棕榈酸异丙酯;醚例如二癸醚和二甲基异山梨醇酯;醇例如乙醇和异丙醇;脂肪醇例如鲸蜡醇、cetearyl alcohol、硬脂醇和联苯醇;异链烷烃例如异辛烷、异十二烷且是十六烷;硅油例如环甲硅油,烃油例如矿物油、矿脂、异二十烷和聚异丁烯;多元醇例如丙二醇、丙三醇、丁二醇、戊二醇和己二醇;脂质体;蜡;或前述的任何组合或混合物。
媒介物可以包含水相、油相、醇、硅酮相或其混合物,并且可以以乳状液的形式。合适的乳状液的非限制性例子包括油包水乳状液、水包油乳状液、水包硅酮乳状液、硅酮包水乳状液、油包丙三醇乳状液、水包蜡乳状液、水-油-水三重乳状液等。乳状液可以包括乳化剂例如非离子型、阴离子型或两性表面活性剂,或胶凝剂。
在本发明的一个实施方案中,组合物可以包括另外的皮肤活性物,包括但不限于植物性药材、角质溶解剂、脱屑剂、角化细胞增殖增强剂、胶原酶抑制剂、弹性蛋白酶抑制剂、脱色剂、抗炎剂、类固醇、抗粉刺剂、抗氧化剂和晚期糖化终末产物(AGE)抑制剂。
组合物可以包含具有抗老化利益的另外活性成分,因为考虑协同改善可以用此类组合获得。示例性抗老化组分包括但不限于植物性药材(例如甄叔迦树(Butea Frondosa)提取物);叶绿醇;硫代二丙酸(TDPA)及其酯;维甲酸类(例如9-顺式维甲酸;13-顺式维甲酸、全反式维甲酸及其衍生物、植烷酸、视黄醇(维生素A)及其酯,例如视黄醇棕榈酸酯、视黄醇乙酸酯和视黄醇丙酸酯及其盐和其他);羟酸(包括α-羟酸和β-羟酸)、水杨酸和烷基水杨酸酯;剥落剂(例如羟乙酸、3,6,9-三氧杂十一烷二酸等)、雌激素合成酶刺激化合物(例如咖啡因和衍生物);能够抑制5α-还原酶活性的化合物(例如亚麻酸、亚油酸、非那雄胺及其混合物);和屏障功能增强试剂(例如神经酰胺、甘油酯、胆固醇及其酯、α-羟基和ω-羟基脂肪酸及其酯等),仅举几个例子。示例性维甲酸类包括但不限于维甲酸(例如全反式或13-顺式)及其衍生物、视黄醇(维生素A)及其酯例如视黄醇棕榈酸酯、视黄醇乙酸酯和视黄醇丙酸酯及其盐。
在另一个实施方案中,本发明的局部组合物还可以包括下述中的一种或多种:皮肤穿透增强剂、润肤剂例如肉豆蔻酸异丙酯、矿脂、硅酮(例如甲基硅酮、二甲硅油)、油、矿物油及脂肪酸酯;保湿剂例如丙三醇或辛二醇、皮肤鼓颊器(plumper)例如棕榈酰寡肽、胶原或胶原和/或糖胺聚糖(GAG)增强试剂、防晒霜例如阿伏苯宗、剥落剂和抗氧化剂。
合适的剥落剂包括例如α-羟酸、β-羟酸、噁酸、噁二酸及其衍生物例如其酯、酐和盐。合适的羟酸包括例如羟乙酸、乳酸、苹果酸、酒石酸、柠檬酸、2-羟基链烷酸、扁桃酸、水杨酸及其衍生物。优选的剥落剂是羟乙酸。当存在时,剥落剂可以包含约0.1重量%-约80重量%的组合物。
可以在呈现的组合物中使用的抗氧化剂的例子包括具有酚羟基官能团的化合物,例如抗坏血酸及其衍生物/酯;β-胡萝卜素;儿茶素;姜黄素;阿魏酸衍生物(例如阿魏酸乙酯、阿魏酸钠);没食子酸衍生物(例如没食子酸丙酯);番茄红素;还原酸;迷迭香酸;鞣酸;四氢姜黄素;生育酚及其衍生物;尿酸;或其任何混合物。其他合适的抗氧化剂是具有以还原或非还原形式的一个或多个硫醇官能团(-SH)的那些,例如谷胱甘肽、硫辛酸、巯基乙酸及其他巯基化合物。抗氧化剂可以是无机的,例如亚硫酸氢盐、偏亚硫酸氢盐、亚硫酸盐或其他含硫的无机盐和酸。本发明的组合物可以包含优选组合物总重量约0.001重量%-约10重量%、且更优选约0.01重量%-约5重量%的抗氧化剂。
其他常规添加剂包括:维生素例如生育酚和抗坏血酸;维生素衍生物例如单棕榈酸抗坏血酸酯;增稠剂例如羟烷基纤维素;胶凝剂;组构剂、金属螯合剂例如EDTA;色素;着色剂和pH调整剂。组合物可以任选包含本领域技术人员已知的其他组分,包括但不限于成膜物、增湿剂、矿物质、粘度和/或流变学改性剂、抗粉刺剂、驱虫剂、皮肤冷却化合物、护肤剂、润滑剂、芳香剂、防腐剂、稳定剂及其混合物。除了前述外,本发明的化妆品组合物可以含有用于治疗皮肤病症的任何其他化合物。
组合物可以以特别是用于局部施用的多种产品形式配制,例如乳状液、洗剂、乳膏、浆液、喷雾剂、气溶胶、饼状物、软膏、香精、凝胶、糊剂、贴剂、笔剂、小毛巾、面膜、棒、泡沫、酏剂、浓缩剂等。优选地,组合物配制为乳状液、洗剂、乳膏、软膏、浆液或凝胶。
本发明提供了通过将包含调节微小RNAs的活性剂的组合物局部应用于受累区域上足以减少、改善、逆转或预防老化的皮肤病学体征的时间段用于治疗老化皮肤的方法,所述微小RNAs调控胶原、弹性蛋白和/或微纤维蛋白生产,所述活性剂包括但不限于式I或式II的化合物,优选在化妆品可接受的媒介物中。
一般地,状况和/或美容外观中的改善选自:减少年代老化、光老化、激素老化和/或光化性老化的皮肤病学体征;预防和/或减少线和/或皱纹的外观;减少面线和皱纹、颊上的面部皱纹、前额、眼间的垂直皱纹、在眼上方和口周围的水平皱纹、木偶纹且特别是深皱纹或皱褶的显著性;改善眶下纹和/或眶周纹的外观;减少鸟足印(crow’s feet)的外观;使皮肤特别是老化皮肤恢复精神和/或恢复生气,减少皮肤脆性;预防和/或逆转糖胺聚糖和/或胶原的丧失;改善雌激素失调的效应;预防皮肤萎缩;预防、减少和/或治疗色素沉着过多;使皮肤脱色降到最低;改善皮肤色调、光亮度、澄清度和/或紧固度;预防、减少和/或改善皮肤下垂;改善皮肤硬度、丰满度、柔度和/或柔软性;改善前胶原和/或胶原生产;改善皮肤肌理和/或促进再组构化;改善皮肤屏障修复和/或功能;改善皮肤轮廓外观;恢复皮肤光泽和/或亮度;使疲劳和/或应激的皮肤病学体征降到最低;抵抗环境应激;补充通过老化和/或绝经减少的皮肤中的成分;改善皮肤细胞中的通讯;增加细胞增殖和/或繁殖;增加通过老化和/或绝经减少的皮肤细胞代谢;延缓细胞老化;改善皮肤保湿;增强皮肤厚度;减慢或暂停皮肤变薄;增加皮肤弹力和/或弹性;增强剥落;改善微循环;减少和/或预防脂肪团形成;及其任何组合。
组合物一般每天应用于皮肤一、二或三次,只要是达到所需结果需要的。治疗方案可以包含每天应用至少一周、至少两周、至少四周、至少八周或至少十二周或更多。还考虑了慢性治疗方案。组合物对细纹和皱纹的形成或外观的作用可以例如通过目视检查定性或例如通过皱纹形态(例如皱纹数目、深度、长度、面积、体积和/或宽度/皮肤的单位面积)的显微镜或计算机辅助测量定量估计。
还考虑本发明的组合物通过将组合物局部应用于有此需要的个体的薄皮肤对于治疗薄皮肤将是有用的。“薄皮肤”预期包括由于年代老化、绝经或光损害变薄的皮肤和过早变薄的皮肤。在一些实施方案中,治疗用于男性的薄皮肤,而其他实施方案治疗绝经前或绝经后的女性的薄皮肤,因为认为皮肤在男性和女性中,并且特别是在处于不同生命阶段的女性中随着年龄不同变薄。
本发明的方法可以预防用于阻止老化,包括在未显示皮肤老化体征的个体中,最通常在25岁以下的个体中。该方法还可以逆转或治疗如在超过25岁的个体中常见的已显示的老化体征,或减慢此类个体中皮肤病学老化的进展。
实施例
下述实施例描述了本发明的特定方面以举例说明本发明,但不应解释为限制本发明,因为实施例仅提供在本发明及其多个方面的理解和实践中有用的特定方法学。
实施例1
皮肤成纤维细胞中的miR-29a和miR-29b水平的年龄相关表达。
年轻与年老皮肤成纤维细胞中的miR-29a和miR-29b表达通过qRT-PCR进行检查。实验使用三组供体细胞(即,三个年轻供体(年龄22-28岁)和三个年老供体(年龄55-66岁)进行。HDFa细胞生长至约80%汇合。细胞使用Taqman MicroRNA Cells-to-Ct Kit进行裂解。cDNA使用miR特异性引物和TaqMan MicroRNA ReverseTranscription Kit进行制备。qPCR使用预先设计的TaqManMicroRNA Assays对于hsa-miR-29a和hsa-miR-29b以及购自AppliedBiosystems的对照RNU6B和GAPDH进行。下表1中概括的数据证实与更年轻的皮肤成纤维细胞相比较,在更年老的人中存在显著更高水平的miR-29a和miR-29b。
表1
微小RNA | 年轻(%) | 年老(%) |
miR-29a | 100 | 350 |
miR-29b | 100 | 390 |
在表1中,数据代表3个供体/年龄组的平均值。所有值在p<0.05都是统计上显著的。可见在这些同类者之间的这些微小RNAs水平中存在三至四倍差异,其中与更年轻的供体相比较,来自更年老供体的细胞具有急剧增加的水平。
实施例2
经由抑制miR-29a和miR-29b的ECM蛋白质调节。
使用来自55岁供体的人真皮成纤维细胞检查特定微小RNAs,miR-29a和miR-29b调节真皮基质蛋白质例如胶原、微纤维蛋白和弹性蛋白的表达的能力。使用siSPORT NeoFX转染试剂(Ambion),用60nm抗miR-29a或miR-29b(商购可得的试剂)转染细胞。转染后72小时收获细胞,并且通过qRT-PCR测定胶原和微纤维蛋白的mRNA水平,并且通过ELISA测定弹性蛋白的蛋白质水平。这些实验指出通过抑制miR-29a或miR-29b,胶原蛋白、微纤维蛋白和弹性蛋白的净表达水平可以是增加的(表3)。所有值在p<0.05都是统计上显著的。
表2.
如表2中所示,miR-29a和miR-29b通过其各自抗miRs被显著抑制(58%和65%)。抑制细胞中的miR-29a和miR-29b导致胶原、微纤维蛋白和弹性蛋白表达中的增加。胶原1a、微纤维蛋白和弹性蛋白测量为超过不含抗miR的对照的百分比改变。
实施例3
通过特定化合物抑制miR-29a或miR-29b。
人真皮成纤维细胞在不存在血清的情况下生长过夜,随后在不存在血清的情况下用0.0005%测试化合物处理48小时。如实施例1和2中所述,通过qRT-PCR就miR-29a和miR-29b的表达水平分析细胞。相对于媒介物处理的细胞,用0.0005%N-(2-甲基丙基)-N-[[4-[(甲磺酰)氧基]苯基]甲基]-苯磺酰胺(1)或2-(4-苄基哌啶-1-基)-N-(3-乙氧基丙基)-5-[(2E)-3-苯基丙-2-烯酰胺基]苯甲酰胺(2)处理的细胞证实miR-29a和miR-29b的显著抑制(表3)。如通过ELISA测量的,用这些化合物处理的细胞还显示增加的胶原蛋白质水平。所有值在p<0.05都是统计上显著的。
表3.
化合物 | 浓度 | miR-29a(%) | miR-29b(%) | 胶原(%) |
1 | 0.0005% | -61.57 | -85.00 | 102% |
2 | 0.0005% | -33.67 | -61.53 | 30% |
在本文中引用的所有参考文献包括专利申请和出版物整体且为了所有目的通过引用合并入本文,其程度与每个个别出版物或专利或专利申请特别且个别指出为了所有目的通过引用整体合并相同。如对于本领域技术人员显而易见的,可以作出本发明的许多修饰和变动,而不背离其精神和范围。本文描述的特定实施方案仅提供作为例子,并且本发明仅受连同此类权利要求赋予权力的等价物的完全范围一起的附加权利要求条款限制。
Claims (25)
1.一种用于改善人皮肤的美容外观的方法,其包括将在化妆品可接受的媒介物中的有效量的活性剂局部应用于有此需要的皮肤区域足以增强所述皮肤中的胶原、弹性蛋白和/或微纤维蛋白生产的时间,所述活性剂抑制miR-29a,具有序列UAGCACCAUCUGAAAUCGGUUA(SEQ.ID.No.:1),和/或miR-29b,具有序列UAGCACCAUUUGAAAUCAGUGUU(SEQ.IDNo.:2)。
2.根据权利要求1的方法,其中所述活性剂抑制miR-29a。
3.根据权利要求1的方法,其中所述活性剂抑制miR-29b。
4.根据权利要求1的方法,其中所述活性剂抑制miR-29a和miR-29b。
5.根据权利要求4的方法,其中所述活性剂是具有式I的结构的化合物:
其中:
R1和R2独立地是氢、–R或–C(=O)R*,其中R1和R2可以连同它们与之附着的氮原子一起形成三至六元环;
R3选自氢、–R、–OR*、–SR*和–N(RN)(R*);
R4和R5在每种情况下独立地选自氢;–R;或X1;并且其中任何两个邻近基团,R5可以形成稠合至它们与之附着的苯环的五或六元环;
R6是氢、–R或–C(=O)R*;
R、R*和RN独立地是氢或C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1和/或选自氧、氮和硫的一至十二个杂原子取代;
X1选自–F;–Cl;–Br;–I;–OH;–C≡C–R*;–C≡N;–C(R)=N–RN;–C=N–N(RN)2;–C(=NRN)–N(RN)2;–CH2OH;–CHO;–(C=O)–R*;–CO2H;–CO2 –;–CO2R*;–CS2R*;–(C=O)–S–R*;–S–(C=O)–R*;–(C=O)–NH2;–(C=O)–NRNRN;–(C=O)–NHNH2;–O–(C=O)–NHNH2;–(C=S)–NH2;–(C=S)–N(RN)2;–O–(C=O)–H;–O–(C=O)–R*;–O–(C=O)–NH2;–O–(C=O)–NRNRN;–OR*;–SR*;–NH2;–NHRN;–NRN 2;–N(RN)3 +;–N(RN)–OH;–N(→O)(R*)2;–O–N(RN)2;–N(RN)–O–R*;–N(RN)–N(RN)2;–NRN–(C=O)–R*;–NRNC(=O)O–R*;–NRN–CHO;–NRN–(C=O)–R*;–NRNC(=O)NRN;–N(RN)–C(=O)–N(RN)2;–N(RN)–C(=S)–N(RN)2;–N=C(R*)2;–N=N–RN;–SCN;–NCS;–NSO;–SS–R*;–SO–R*;–SO2–R*;–O–S(=O)2–R*;–S(=O)2–OR*;–N(RN)–SO2–R*;–SO2–N(R*)2;–O–SO3 –;–O–S(=O)2–OR*;–O–S(=O)–OR*;–O–S(=O)–R*;–S(=O)–OR*;–S(=O)–R*;–NO;–NO2;–NO3;–O–NO;–O–NO2;–N3;–N2;–N(C2H4);–Si(R*)3;–CF3;–O–CF3;–(C=O)–R*;–P(R*)2;–O–P(=O)(OR*)2;和–P(=O)(OR*)2;
“n”是0–3的整数,并且在其中“n”是2或3的情况下,R5在每种情况下独立地选择;
及其化妆品可接受的酸加成盐。
6.根据权利要求5的方法,其中R1、R2、R3、R4和R6独立地是氢或基团–R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子取代。
7.根据权利要求6的方法,其中R2,R3和R4独立地是基团-R,其中R是形式–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3的基团;其中a、b、c、x、y和z独立地是0–5的整数,并且X2代表键或二价基团或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的原子,并且X3代表氢、X1或R*。
8.根据权利要求7的方法,其中R1和R6是氢。
9.根据权利要求8的方法,其中R2是形式–(CH2)a–X2–(CH2)x–CH3的基团。
10.根据权利要求8的方法,其中R3是形式–CH=CH–R*的基团,其中R*是芳基基团。
11.根据权利要求8的方法,其中R4是形式–(CH2)a–R*的基团,其中R*是芳基基团。
12.根据权利要求7的方法,其中R5是氢。
14.根据权利要求1的方法,其中所述化合物具有式II的结构:
其中,
R5选自氢;–R;或X1;其中“m”是0–5的整数,并且在其中“m”是2、3或4的情况下,R5在每种情况下独立地选择;和
R7和R8独立地是C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1和/或选自氧、氮和硫的一至六个杂原子取代;
R、R*和RN独立地是氢或C1-20烃基团;其中所述C1-20烃基团可以任选由基团X1和/或选自氧、氮和硫的一至十二个杂原子取代;和
X1选自–F;–Cl;–Br;–I;–OH;–C≡C–R*;–C≡N;–C(R)=N–RN;–C=N–N(RN)2;–C(=NRN)–N(RN)2;–CH2OH;–CHO;–(C=O)–R*;–CO2H;–CO2 –;–CO2R*;–CS2R*;–(C=O)–S–R*;–S–(C=O)–R*;–(C=O)–NH2;–(C=O)–NRNRN;–(C=O)–NHNH2;–O–(C=O)–NHNH2;–(C=S)–NH2;–(C=S)–N(RN)2;–O–(C=O)–H;–O–(C=O)–R*;–O–(C=O)–NH2;–O–(C=O)–NRNRN;–OR*;–SR*;–NH2;–NHRN;–NRN 2;–N(RN)3 +;–N(RN)–OH;–N(→O)(R*)2;–O–N(RN)2;–N(RN)–O–R*;–N(RN)–N(RN)2;–NRN–(C=O)–R*;–NRNC(=O)O–R*;–NRN–CHO;–NRN–(C=O)–R*;–NRNC(=O)NRN;–N(RN)–C(=O)–N(RN)2;–N(RN)–C(=S)–N(RN)2;–N=C(R*)2;–N=N–RN;–SCN;–NCS;–NSO;–SS–R*;–SO–R*;–SO2–R*;–O–S(=O)2–R*;–S(=O)2–OR*;–N(RN)–SO2–R*;–SO2–N(R*)2;–O–SO3 –;–O–S(=O)2–OR*;–O–S(=O)–OR*;–O–S(=O)–R*;–S(=O)–OR*;–S(=O)–R*;–NO;–NO2;–NO3;–O–NO;–O–NO2;–N3;–N2;–N(C2H4);–Si(R*)3;–CF3;–O–CF3;–(C=O)–R*;–P(R*)2;–O–P(=O)(OR*)2;和–P(=O)(OR*)2;
及其化妆品可接受的盐。
15.根据权利要求14的方法,其中R7和R8独立地是基团-R,其中R是形式–(CH2)a–(CR*=CR*)b–(CH2)c–X2–(CH2)x–(CR*=CR*)y–(CH2)z–X3的基团;其中a、b、c、x、y和z独立地是0–5的整数,并且X2代表键或二价基团或选自–O–、–S–、–C(=O)–、–N(RN)–、–C(=O)O–、–OC(=O)–、–C(=O)–N(RN)–、–N(RN)–C(=O)–的原子,并且X3代表氢、X1或R*;其中R*是任选由基团X1和/或选自氧、氮和硫的一至十二个杂原子取代的C1-20烃基团。
16.根据权利要求15的方法,其中RN、R7和R8独立地是基团-R,其中R选自烷基、烯基、炔基、芳基、芳烷基和烷芳基,各自任选由选自卤素、O、N和S的1-12个杂原子取代。
18.根据权利要求1的方法,其中所述皮肤的所述美容改善选自:
(a)细纹或皱纹的治疗、减少和/或预防,
(b)皮肤毛孔大小的减少,
(c)皮肤厚度、丰满度和/或紧固度的改善;
(d)皮肤柔度和/或柔软性的改善;
(e)皮肤色调、光亮度和/或澄清度的改善;
(f)弹性蛋白的维持和重塑的改善;
(g)皮肤肌理的改善和/或重组构化的促进;
(h)皮肤屏障修复和/或功能的改善;
(i)皮肤轮廓外观的改善;
(j)皮肤光泽和/或亮度的恢复;
(k)通过绝经减少的皮肤外观的改善;
(l)皮肤保湿的改善;
(m)皮肤弹力和/或弹性的增加;
(n)皮肤下垂的治疗、减少和/或预防;或
(o)色素斑点的减少。
19.一种用于鉴定对于改善皮肤的美容外观有用的活性剂的方法,其包括就抑制或下调细胞中的miR-29a和/或miR-29b的能力测定候选物质。
20.根据权利要求19的方法,其中所述测定步骤包括使人真皮成纤维细胞与所述候选物质一起温育,且随后测量miR-29a和/或miR-29b的水平。
21.根据权利要求20的方法,其中所述测量步骤通过qRT-PCR进行。
22.一种通过增加皮肤中的胶原、弹性蛋白和/或微纤维蛋白生产用于改善皮肤的美容外观的方法,所述方法包括将有效量的抑制miR-29a和/或miR-29b的活性剂局部应用于有此需要的皮肤区域,其中所述活性剂通过测定物质抑制细胞中的miR-29a和/或miR-29b表达的能力的测定进行鉴定。
23.一种通过刺激选自胶原、弹性蛋白、微纤维蛋白及其组合的细胞外基质蛋白质来改善老化皮肤的外观的方法,其包括将在局部可接受的媒介物中的有效量的抑制miR-29a和/或miR-29b的活性剂局部应用于需要此类刺激的皮肤。
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BR112012032082B1 (pt) | 2010-06-30 | 2019-11-26 | Avon Products, Inc. | Composição e método cosmético para melhorar a aparência estética da pele humana |
US8632827B2 (en) | 2011-12-13 | 2014-01-21 | Avon Products, Inc | Modulation of thymosin beta-4 in skin |
JP6120398B2 (ja) * | 2012-11-02 | 2017-04-26 | 国立大学法人三重大学 | 水溶性フィブリリン組成物による弾性線維増強法 |
TW201422246A (zh) | 2012-12-11 | 2014-06-16 | Avon Prod Inc | 藉由調節wipi-1改善皮膚老化外觀之方法 |
US9186316B2 (en) | 2012-12-11 | 2015-11-17 | Avon Products, Inc. | Stephanotis jasminoides extracts and methods of use |
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US9445981B2 (en) | 2012-12-20 | 2016-09-20 | Avon Products, Inc | PLOD-2 stimulators and their use in the treatment of skin |
CN110205366B (zh) * | 2018-02-28 | 2022-06-21 | 伽蓝(集团)股份有限公司 | 一种皮肤内源性老化靶标的筛选方法及改善皮肤内源性老化的活性物及其筛选方法 |
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