CN104771327B - 一种具有激活hsf‑1转录功能的组合物及其用途 - Google Patents
一种具有激活hsf‑1转录功能的组合物及其用途 Download PDFInfo
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Abstract
本发明提供了一种具有激活HSF‑1转录功能的组合物。本发明所述的具有激活HSF‑1转录功能的组合物可诱导体内HSF‑1活性增加，体内HSF‑1活性的增加，可以竞争协同转录增强子NF‑κB，从而特异增加腺苷酸环化酶、Sirt1和Sirt3活性，同时协同HSPs协助蛋白折叠和保护特性，激活抗衰老酶途径。本发明的重要之处是发现了HSF‑1及其转录的热激蛋白HSPs密切参与抗衰老酶表达及活性调节过程，该过程通过激活体内应激效应因子，特异激活抗氧化、抗凋亡途径，达到抗衰老的目的。因此，本发明为激活抗衰老酶途径提供了新的靶点，为细胞在基因水平上的衰老调控提供了有效的调节剂。
Description
技术领域
本发明涉及一种组合物，具体是一种具有激活HSF-1转录功能的组合物及其用途。
背景技术
应激(stress)是细胞应对生存环境中多种不利因素的反应,温度变化、蛋白质错误折叠、氧化性损伤及病毒入侵都可以引起细胞应激，它通过改变机体内稳态,启动相应信号传导途径,引起一系列分子事件，产生广泛而深刻的影响。应激反应的典型特征之一是激活细胞热应激因子(heat shock factor,HSF)，进而表达一种或数种热激蛋白(heat shockprotein,HSP)。热激转录因子是一类高度保守的蛋白，其在细胞生长、发育以及应激反应和疾病进程中都发挥重要作用。在人类基因组中，已发现4个热激转录因子基因，已知热激转录因子1(HSF1)在热激反应中起关键作用，热激转录因子2(HSF2)在发育和神经分化中起作用，热激转录因子4(HSF4)则对晶状体形成非常重要。体内的HSF1可被多条压力通路激活，包括热激、蛋白错误折叠、重金属、氧应激等。在应激条件下，HSF1发生磷酸化形成活性三聚体，入核与热激因子效应区(heat shock element,HSE)结合，激活/抑制相应基因表达。
HSF1调控了应激表达网络，约占人类全基因组3％的基因座在热激条件下被HSF1结合，其可与暂停的聚合酶Ⅱ结合，募集转录延伸因子P-TEFb、Cdk9-Cyclin T二聚体，以形成新的转录延伸复合物。Rawat和Mitra通过凝胶迁移实验(EMSA)也已证实HSF1可以激活绝大多数衰老相关基因，是衰老的重要调控因子。
由HSF1编码的热激蛋白(heat shock proteins，简称HSP)是生物体在高温、盐渍、干旱、渗透胁迫等环境条件下诱导合成的一类应激蛋白。其在细胞内起分子伴侣功能，参与新生肽链折叠、蛋白质组装与转运。同时，在细胞发生应激反应时，热激蛋白还可以与那些由于环境刺激而自身构象发生改变的蛋白相互作用，防止非特异性蛋白聚集，维持信号转导蛋白的活性。HSPs属于高度保守蛋白，约占细胞总蛋白的5-20％。其根据分子量大小分类为6类：HSP100、HSP90、HSP70、HSP60、HSP40和小分子HSPs。
HSP90家族成员即使在无胁迫的条件下，在真核生物体内也有一定量的表达，是真核生物必不可少的因子。从晶体结构来看，HSP90的N末端是一个二聚体，由含有一个配基“口袋”的αβ三明治结构组成，其一侧是一高度扭曲的，有8条链组成的β折叠，另一侧则被9条α螺旋所覆盖，在螺旋的中心有一个“口袋”，β折叠的表面透过这个“口袋”形成一个ATP/ADP结合域。现已明确这个25kD的N-末端具有格尔德霉素结合位点和根赤霉素结合位点。HSP90是一种钙结合蛋白，其N末端可使C末端二聚化，而C末端具有钙调蛋白结合位点，同时也是蛋白激酶、肌动蛋白、微管蛋白及类固醇激素受体等信号转到蛋白的结合位点。HSP90其主要功能为胞内信号传导。如它可与甾体受体结合并维持一种特定的构型，当受体与甾体激素结合后，HSP90从复合物中游离出来。
HSP70家族则是研究最多的一类热激蛋白，在生物体内分布最广，进化上最保守的一类蛋白质。HSP70具有两个主要的结构域，N端是高度保守的44kD结构域，且是ATP结合区，C端是25kD的肽链识别结合区。其中C末端又可分为一个保守的15kD多肽结合功能域和一个不保守的近C端10kD的可变功能域。DnaK(HSC70)的底物结合功能域和部分可变功能域重组片段的结构主要由两部分组成，N端折叠成一个紧密的β三明治结构；C端由5个α螺旋组成，形成一个松弛的α螺旋结构。N端部分的β三明治结构由底部和上部2个片层结构组成，每个片层结构都含有4条反向平行的β折叠链，其中三明治结构底部片层结构由4条链组成，而上部的片层结构由另外4条链组成。在生物体内，热激蛋白主要是充当分子伴侣的角色，参与新生肽的跨膜运输和折叠。在酵母体内，含有两种HSP70的成员SSa和SSc，分别在细胞浆和细胞核内表达。肽链刚产生时，依赖ATP酶的活性与SSa集合，当穿过线粒体膜时，进入线粒体内与体内合成的SSc结合，当ATP水解后，将结合的SSa释放，在依赖Mg-ATP酶的条件依赖HSP60、HSP10分子伴侣的帮助下完成折叠并释放到线粒体内。同时HSP70也参与胞内信号转导过程。
上述HSP分子在不同的环境和信号通路中参与了细胞衰老、凋亡的调控过程。例如HSP90与IKKα结合，曾强了IKK活性，降解胞内IκB，激活NF-κB，抑制了细胞凋亡。而HSP70通过激活HSF1参与了抗衰老基因激活的过程。除此以外，HSP还广泛参与机体免疫以及能量代谢过程，通过调控相关因子减少细胞损伤，减缓细胞衰老。
总体而言，HSF1及其编码的HSPs以直接激活抗衰老酶通路或者间接调控抗衰老、抗凋亡信号通路激活的方式参与了细胞衰老进程。这类因子尚未开发但有广阔前景的靶点，但目前，国内外都未见有调控HSF1及其编码的HSPs阻止或延缓细胞衰老与死亡的应用。
发明内容
为了获得一种高效且具有获得方便，易于通过皮下渗透吸收优势的HSF1调控组合物，本发明人对HSF1的转录调控及修饰激活进行了深入研究，最终设计出了能够高效激活HSF1转录的组合物，实现了HSF1的人工调控。
为实现上述目的，所采取的技术方案：一种具有激活HSF-1转录功能的组合物，所述组合物包括白藜芦醇，且还包括β-羟基甲基丁酸酯、3,4-二氯异香豆素、聚肌苷酸胞嘧啶核苷酸、肉桂酸、褐藻素、葡萄籽提取物和亮氨酸中的至少三种。
优选地，所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.035至0.500重量份，所述β-羟基甲基丁酸酯的用量为0.200至3.000重量份，3,4-二氯异香豆素的用量为0.010至0.200重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.020至0.050重量份。在本发明中将这里所述组合物称为组合物A。
优选地，所述组合物为白藜芦醇、褐藻素、鸢尾素和亮氨酸的混合物，所述白藜芦醇的用量为0.035至0.500重量份，所述褐藻素的用量为0.150至4.000重量份，所述鸢尾素的用量为0.010至0.050重量份，所述亮氨酸的用量为0.750至3.000重量份。在本发明中将这里所述组合物称为组合物B。
优选地，所述组合物还包括烟酸、维生素B6、维生素B12、泛酸和鸢尾素中的至少一种。
优选地，所述组合物还包括赖氨酸、谷氨酸、脯氨酸、精氨酸、缬氨酸、异亮氨酸、天冬氨酸、天冬酰胺、甘氨酸、苏氨酸、丝氨酸、苯丙氨酸、酪氨酸、组氨酸、丙氨酸、色氨酸、甲硫氨酸、谷氨酰胺、牛磺酸、肉碱、胱氨酸和半胱氨酸中的至少一种。
本发明提供了一种抗衰老的药物组合物，所述药物组合物包含药用有效量的上述所述的组合物和药学上可接受载体。
本发明提供了一种抗衰老的保健品组合物，所述保健品组合物包含保健有效量的上述所述的组合物和保健品可用的载体。
本发明所述药物组合物或保健品组合物内含有的载体，其通常用在制药或保健品配方中，但不限于此，包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉等。根据本发明所述的药物组合物或保健品组合物可以另外包含润滑剂、湿润剂、增甜剂、增香剂、乳化剂、悬浮剂和防腐剂等物质。根据本领域技术人员已知的常规技术，可以与如上所述的载体和/或赋形剂一起配制，根据本发明所述的药物组合物或保健品组合物，最终提供几种形式的单剂量型和多剂量型。
本发明提供了一种抗衰老的化妆品组合物，所述化妆品组合物包含美容有效量的上述所述的组合物和化妆品可用的载体。本发明所述化妆品组合物可以制成很多种形式，例如，包括溶液、混悬液、乳状液、膏、油膏、凝胶、霜、洗剂、粉、肥皂、含表面活性剂的清洁剂、油、粉底、乳状液粉底、蜡状粉底和喷雾剂。优选地，可以将本发明的化妆品组合物制成以下形式：营养液、营养霜、按摩霜、精华素、眼霜等。
本发明还提供了上述所述的组合物在制备抗衰老的药物、保健品或化妆品中的用途。本发明提供的具有激活HSF-1转录功能的组合物在治疗抗衰老中的作用机理：本发明的具有激活HSF-1转录功能的组合物能够激活HSF1及其编码的HSPs，通过直接激活抗衰老酶通路或者间接调控抗衰老、抗凋亡信号通路激活的方式减缓肌体衰老。
本发明的有益效果在于：本发明提供了一种具有激活HSF-1转录功能的组合物。本发明所述的具有激活HSF-1转录功能的组合物可诱导体内HSF-1活性增加，体内HSF-1活性的增加，可以竞争协同转录增强子NF-κB，从而特异增加腺苷酸环化酶、Sirt1和Sirt3活性，同时协同HSPs协助蛋白折叠和保护特性，激活抗衰老酶途径。本发明的重要之处是通过我方研究发现了HSF-1及其转录的热激蛋白HSPs密切参与抗衰老酶表达及活性调节过程，该过程通过激活体内应激效应因子，特异激活抗氧化、抗凋亡途径，达到抗衰老的目的。因此，本发明为激活抗衰老酶和在基因水平上调控衰老过程提供了有效的调节剂。
附图说明
图1为本发明所述的具有激活HSF-1转录功能的组合物激活HSF-1、HSP70及HSP90mRNA转录水平的检测结果示意图，图中横坐标上的浓度为本发明所述的组合物的浓度；
图2为本发明所述的具有激活HSF-1转录功能的组合物的激活抗衰老酶通路检测结果示意图；
图3为本发明所述的具有激活HSF-1转录功能的组合物的激活抗衰老酶通路检测结果示意图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
实施例1：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.035重量份，所述β-羟基甲基丁酸酯的用量为0.200重量份，3,4-二氯异香豆素的用量为0.010重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.020重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物A。
实施例2：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.500重量份，所述β-羟基甲基丁酸酯的用量为3.000重量份，3,4-二氯异香豆素的用量为0.200重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.050重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物A。
实施例3：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.20重量份，所述β-羟基甲基丁酸酯的用量为1.00重量份，3,4-二氯异香豆素的用量为0.10重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.03重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物A。
实施例4：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.035重量份，所述β-羟基甲基丁酸酯的用量为3.000重量份，3,4-二氯异香豆素的用量为0.010重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.050重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物A。
实施例5：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物B为白藜芦醇、褐藻素、鸢尾素和亮氨酸的混合物，所述白藜芦醇的用量为0.035重量份，所述褐藻素的用量为0.150重量份，所述鸢尾素的用量为0.010重量份，所述亮氨酸的用量为0.750重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物B。
实施例6：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物B为白藜芦醇、褐藻素、鸢尾素和亮氨酸的混合物，所述白藜芦醇的用量为0.500重量份，所述褐藻素的用量为4.000重量份，所述鸢尾素的用量为0.050重量份，所述亮氨酸的用量为3.000重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物B。
实施例7：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物B为白藜芦醇、褐藻素、鸢尾素和亮氨酸的混合物，所述白藜芦醇的用量为0.20重量份，所述褐藻素的用量为2.00重量份，所述鸢尾素的用量为0.03重量份，所述亮氨酸的用量为2.00重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物B。
实施例8：本发明所述的具有激活HSF-1转录功能的组合物的一种实施例
所述组合物B为白藜芦醇、褐藻素、鸢尾素和亮氨酸的混合物，所述白藜芦醇的用量为0.035重量份，所述褐藻素的用量为4.000重量份，所述鸢尾素的用量为0.010重量份，所述亮氨酸的用量为3.000重量份。按上述重量份将上述物质混合即可得到所述组合物，将这里的组合物称为组合物B。
实施例9：本发明所述的具有激活HSF-1转录功能的组合物激活HSF-1mRNA转录水平的检测
实验方法：
提取经本发明实施例1-8所述的具有激活HSF-1转录功能的组合物处理的HeLa细胞系不同时间点的总RNA。利用反转录酶合成相关基因的cDNA第一链。在适当的温度参数下扩增28-32个循环。为了保证实验结果的可靠与准确，可在PCR扩增目的基因时，加入一对内参(如β-actin)的特异性引物，同时扩增内参DNA，作为对照。扩增结果通过琼脂糖凝胶电泳进行鉴定。
其中内参基因为β-actin，上游引物：5’-TCGTGCGTGACATTAAGGAG-3’,下游引物5’-AGGAAGGAAGGCTGGAAGAG-3’,HSF-1上游引物5’-GCCTTCCTGACCAAGCTGT-3’,下游引物：5’-AAGTACTTGGGCAGCACCTC-3’,PCR实验方法参照Sambrook,Molecular Cloning:ALaboratory Manual.Cold Spring Harbor Laboratory Pr；3rd edition.标准操作进行，采用ABI 7300实时荧光定量PCR仪进行检测。
实验结果：
实验结果见图1。图1显示在本发明实施例1-8所述的具有激活HSF-1转录功能的组合物加入的条件下，热激蛋白HSF-1的转录水平随着抗衰老酶通路激活水平的提高而逐渐升高。
实施例10：本发明所述的具有激活HSF-1转录功能的组合物激活抗衰老酶通路的检测
实验方法：
将本发明实施例1-4所述的组合物A与溶媒DMSO按一定比例混匀溶解后，梯度稀释加入CHO细胞培养液中，选择细胞致死浓度以下的组合物A浓度为培养浓度，继续培养24小时，分离细胞，提取mRNA，与未加组合物A的对照组同期进行抗衰老酶通路关键基因mRNA表达水平检测。
实验结果：
实验结果见图2。在本发明所述的组合物A存在条件下，中国仓鼠细胞中抗衰老酶通路关键基因Bdnf、lgf1、Arc和cFOS的表达量都出现明显上调，表明本发明所述的组合物A能够有效激活抗衰老酶通路。
实施例11：本发明所述的具有激活HSF-1转录功能的组合物激活抗衰老酶通路的检测
实验方法：
将本发明实施例5-8所述的组合物B与溶媒DMSO按一定比例混匀溶解后，梯度稀释加入CHO细胞培养液中，选择细胞致死浓度以下的组合物B浓度为培养浓度，继续培养24小时，分离细胞，提取mRNA，与未加组合物B的对照组同期进行抗衰老酶通路关键基因mRNA表达水平检测。
实验结果：
实验结果见图3。在本发明所述的组合物B存在条件下，中国仓鼠细胞中抗衰老酶通路关键基因Bdnf、lgf1、Arc和cFOS的表达量都出现明显上调，表明本发明所述的组合物B能够有效激活抗衰老酶通路。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (7)
1.一种具有激活HSF-1转录功能的组合物，其特征在于，所述组合物为白藜芦醇、β-羟基甲基丁酸酯、3,4-二氯异香豆素和聚肌苷酸胞嘧啶核苷酸的混合物，所述白藜芦醇的用量为0.035至0.500重量份，所述β-羟基甲基丁酸酯的用量为0.200至3.000重量份，3,4-二氯异香豆素的用量为0.010至0.200重量份，聚肌苷酸胞嘧啶核苷酸的用量为0.020至0.050重量份。
2.根据权利要求1所述的组合物，其特征在于，所述组合物还包括烟酸、维生素B6、维生素B12、泛酸中的至少一种。
3.根据权利要求1所述的组合物，其特征在于，所述组合物还包括赖氨酸、谷氨酸、脯氨酸、精氨酸、缬氨酸、异亮氨酸、天冬氨酸、天冬酰胺、甘氨酸、苏氨酸、丝氨酸、苯丙氨酸、酪氨酸、组氨酸、丙氨酸、色氨酸、甲硫氨酸、谷氨酰胺、牛磺酸、胱氨酸和半胱氨酸中的至少一种。
4.一种抗衰老的药物组合物，其特征在于，所述药物组合物包含药用有效量的如权利要求1-3任一所述的组合物和药学上可接受载体。
5.一种抗衰老的保健品组合物，其特征在于，所述保健品组合物包含保健有效量的如权利要求1-3任一所述的组合物和保健品可用的载体。
6.一种抗衰老的化妆品组合物，其特征在于，所述化妆品组合物包含美容有效量的如权利要求1-3任一所述的组合物和化妆品可用的载体。
7.一种如权利要求1-3任一所述的组合物在制备抗衰老的药物、保健品或化妆品中的用途。
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