CN103025339B - 时钟基因Period的表达调节剂 - Google Patents
时钟基因Period的表达调节剂 Download PDFInfo
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Abstract
本发明提供了能有效调节Period基因的表达的物质,其具有广泛的应用。所述Period基因的表达调节剂包含作为活性成分的一种或多种选自以下的物质:阿尼菊提取物、日本萍蓬草提取物、黑茶提取物、花椒提取物、刺柏油、雪松油、熏衣草油、丁香花蕾油、柏木油、玫瑰油、依兰油、格蓬油、卑柠油、胡椒油、百里香油、罗勒油和β-石竹烯。
Description
发明领域
本发明涉及时钟基因的表达调节剂,更具体涉及时钟基因Period的表达调节剂及包含所述表达调节剂的昼夜节律调节剂。
相关领域描述
地球上几乎所有的活的生物体都具有内在的“生物钟”,其在约24小时的周期内自主地波动。生物钟引起称为昼夜节律的生物学上的每日波动,其被认为控制多种生物学现象(活性)的昼间变化,所述生物学现象不仅包括生物的睡-醒周期,还包括体温、血压、激素分泌、新陈代谢、以及心理活动和身体活动、进食等。近年来已指出昼夜节律紊乱是多种心身症状(psychosomatic symptom)或疾病状况(包括睡眠障碍、皮肤疾病、与生活方式有关的疾病和神经精神障碍诸如抑郁等)的致病因素。
如图1中所阐明,生物钟由节律产生***控制,所述***包括一组称为“时钟基因”的基因。在哺乳动物中时钟的分子机制的核心是由编码四个蛋白质CLOCK、BMAL1、PERIOD和CRYPTOCHROME的基因的转录的促进/抑制所组成的反馈回路。昼夜节律由该反馈回路的波动产生,周期为约24小时。
虽然昼夜节律的控制中心(中枢时钟)位于下丘脑中的视交叉上核,但已经变得清楚的是时钟基因甚至在肝、肾、皮肤和其他的外周组织中表达,在其中通过相似的***产生昼夜节律。外周的时钟基因的表达通过来自视交叉上核的信号调节。已经进一步证实外周组织和细胞中的时钟基因的表达直接受信号刺激因子如糖皮质激素、儿茶酚胺、血管紧张素II和其它信号刺激因子控制以产生生理节律。近年来,通过在体外使用刺激因子如糖皮质激素、福斯高林、血清和其它刺激因子诱导时钟基因表达的昼夜节律,以同步表达节律,并通过使用它们的表达作为标准评价昼夜节律,对培养细胞诸如成纤维细胞的昼夜节律进行了研究(非专利文件1、2和3)。
时钟基因直接控制作为转录因子的其他基因的表达节律,并通过调节激素分泌等间接控制更多的基因的昼间表达。已经变得清楚的是生物中时钟基因的表达节律的破坏引起身体器官或内分泌***的问题,其导致多种疾病,包括与生活方式有关的疾病诸如高血压(非专利文件4)。例如,已报导患有肥胖症的人显示时钟基因的异常表达,还报道了与抑郁和癌症的关联性。另外,已经阐明时钟基因调节皮肤的多种生理功能的昼夜节律。在使用正常人皮肤成纤维细胞的试验中,报道了I型胶原基因以昼夜节律表达,其表达模式与时钟基因Period 2的表达模式相似(非专利文件5)。
通过调节时钟基因的表达,调整受时钟基因控制的活的生物体的多种行为节律和生理功能的昼夜节律是可能的。因此对开发能调节时钟基因的表达的活性剂有强烈的需求。
[非专利文件1]
H.Okamura,“细胞时钟中的时钟基因:作用、功能和奥秘(ClockGenes in Cell Clocks:Roles,Actions,and Mysteries)”,Journal ofBiological Rhythms,第19卷,第5期,第388-399页,2004。
[非专利文件2]
A.Balsalobre等人,“血清性休克诱导哺乳动物组织培养细胞中昼夜节律基因的表达(A Serum Shock Induces Circadian Gene Expression inMammalian Tissue Culture Cells)”,Cell,第93卷,第929-937页,1998。
[非专利文件3]
K.Yagita等人,“在培养的成纤维细胞中的生物钟的分子机制(Molecular Mechanisms of the Biological Clock in Cultured Fibroblasts)”,Science,第292卷,第278-281页,2001。
[非专利文件4]
M.Hastings等人,“昼夜节律钟:内分泌和代谢节律的调节剂(Circadian clocks:regulators of endocrine and metabolic rhythms)”,Journal of Endocrinology,第195卷,第187-198页,2007。
[非专利文件5]
K.Izumi等人,“具有昼夜节律表达的皮肤生理基因的分析(Gaijitsurizumu wo motsu hifuseiriidennshi no tansaku)”,日本分子生物学会,第32届年会,摘要2P-0009,2009。
发明内容
鉴于上述情况,本发明的目的是提供能调节作为生物钟核心基因的Period基因的表达的活性剂。
由于本发明人已经发现某些植物提取物或精油具有诱导时钟基因Period的表达节律以及促进其表达的特性,所以发明人完成了本发明。
本发明的Period基因的表达调节剂包含作为活性成分的一种或多种选自以下的物质:阿尼菊提取物(arnica extract)、日本萍蓬草提取物(nupharextract)、黑茶提取物、花椒提取物(Zanthoxylum extract)、刺柏油(juniperoil)、雪松油(cedar oil)、熏衣草油、丁香花蕾油(clove bud oil)、柏木油、玫瑰油、依兰油、格蓬油(galbanum oil)、卑柠油、胡椒油、百里香油、罗勒油和β-石竹烯。上文提及的特定的植物提取物或精油能调节时钟基因的表达迄今为止尚未为人所知。
在本发明中基因表达的调节不仅包括基因表达的促进而且包括基因表达的节律(相或周期)的调节。
本发明的昼夜节律调节剂包含上文提及的Period基因的表达调节剂。如上所述,时钟基因直接或间接控制参与身体器官的功能和内分泌***的多种基因的昼间表达。通过调节作为生物钟核心基因的Period基因的表达,调节受所述基因控制的活的生物体的多种行为节律和生理功能的昼夜节律是可能的。
本发明所有的Period基因的表达调节剂为草药(herbal medicine)或香料。它们可通过多种施用模式诸如透皮、经口和吸入施用而应用,且可用于包括药物、医药部外品(quasi-drug)、化妆品、食品、杂货、衣物等的多种实施方案中。通过有效地调节Period基因的表达,改善多种由昼夜节律功能障碍导致的心身或皮肤症状或疾病是可能的。
而且,在本发明的Period基因的表达调节剂中,调节透明质酸合成酶(Has)基因的表达节律的那些调节剂能促进其表达,因此被认为通过调节皮肤中透明质酸产生的昼夜节律以及通过增加其产量而改善皮肤功能。
附图简述
图1是仅显示时钟基因参与的昼夜节律产生***的核心回路的示意图。
图2是显示在培养的人皮肤成纤维细胞中使用氢化可的松和福斯高林诱导时钟基因表达的昼夜节律的图。
图3是显示在培养的人皮肤成纤维细胞中受测试物质调节的时钟基因Period1的表达的图。
实施本发明的最佳模式
本发明的Period基因的表达调节剂包含作为活性成分的特定的植物提取物或精油。
能调节Period基因的表达的植物提取物包括选自阿尼菊(arnica)、日本萍蓬草(nuphar)、黑茶和花椒(Zanthoxylum)的草药提取物。关于这些草药的详细内容请参考日本化妆品成分词典(Nihon Hann-you KeshouhinGenryou Shu)第四版(YAKUJI NIPPO LIMITED)。
以上提及的草药提取物可通过通常已知的技术获得,例如,通过使用提取溶剂将植物材料(各提取物来自其中)浸渍或加热至回流、随后过滤并浓缩。通常用于提取的任何溶剂可用作提取溶剂,所述溶剂包括水、甲醇、乙醇、丙二醇、1,3-丁二醇、甘油和其他的醇类、含水醇类溶剂、氯仿、二氯乙烷、四氯化碳、丙酮、乙酸乙酯、己烷和其他的有机溶剂,这些溶剂可以单独或组合使用。使用上文提及的溶剂获得的提取物可原样使用,或者可使用吸附技术(例如经离子交换树脂或多孔聚合物(例如AmberliteXAD-2)柱)、随后用甲醇或乙醇洗脱、然后浓缩除去杂质后使用。也可使用例如,使用水/乙酸乙酯等得到的提取物。
所有的这些草药提取物可商购获得,且下文对它们中的每一个进行简述。
阿尼菊提取物(arnica extract)由菊科阿尼菊(山生阿尼菊(Arnica montana))获得,优选从阿尼菊的花用50%乙醇或类似溶剂提取得到。
日本萍蓬草提取物(nuphar extract)由日本萍蓬草根茎(日本萍蓬草(Nuphar japonicum)获得,优选从日本萍蓬草根茎用50%乙醇或类似溶剂提取得到。
黑茶提取物由茶科(Theaceae)的黑茶(普洱茶(Thea sinensis L.var.assamica))获得,优选从黑茶或茶(Thea sinensis)的叶用30%乙醇或类似溶剂提取得到。
花椒提取物(Zanthoxylum extract)由花椒果实(川陕花椒(Zanthoxylum piperitum))获得,优选从花椒果实的果皮用70%乙醇或类似溶剂提取得到。
能调节Period基因表达的植物精油(香料)包括刺柏油、雪松油、熏衣草油、丁香花蕾油、柏木油、玫瑰油、依兰油、格蓬油、卑柠油、胡椒油、百里香油、罗勒油和β-石竹烯。这些香料均是商购可得的,将其简述如下。
刺柏油是通过水蒸气蒸馏刺柏(欧洲刺柏(Juniperus communis L),该植物是柏科(Cupressacea)的常绿树)的枝和叶而获得的精油。
雪松油是通过水蒸气蒸馏雪松属(Cedrus)喜马拉雅雪松树(Himalayancedar tree)的木材而获得的精油。
熏衣草油是通过水蒸气蒸馏药用薰衣草(Lavandula officinalis)的精选的花而获得的精油,该植物为唇形科(Lamiaceae)的矮灌木。
丁香花蕾油是通过水蒸气蒸馏在开花前干燥的桃金娘科丁香(Eugenia caryophyllata)的丁香花蕾而获得的精油。
柏木油是通过水蒸气蒸馏柏木(地中海柏木(Cupressus sempervirene))的枝和叶而获得的精油。
玫瑰油是通过水蒸气蒸馏洋蔷薇(百叶蔷薇(Rosa centifoliaL))、大马士革蔷薇(突厥蔷薇(Rosa damascena Mill.))和其他蔷薇花而获得的精油。
依兰油是通过直接水蒸气蒸馏番荔枝科(Anonaceae)的植物依兰(Canning odorata)的花或者用石油醚或其他溶剂提取新鲜的花而获得的精油。
格蓬油是通过水蒸气蒸馏从格蓬(Ferula galbaniflua)的叶和芽和伞形科(Umbelliferae)相关的种的叶和芽渗出的橡胶状物质而获得的精油。
卑柠油是通过水蒸气蒸馏芸香科(Rutaceae)苦橙(bitter orange)(酸橙(Citrus aurantium))的叶和其他部分的而获得的精油。
胡椒油是通过水蒸气蒸馏胡椒(胡椒(Piper nigrum L.))的浆果而获得的精油,该植物属于胡椒科的多年生植物。
百里香油是通过水蒸气蒸馏百里香(麝香草(Thymus vulgaris L.))全植物而获得的精油,该植物是唇形科的多年生草本植物。
罗勒油是通过水蒸气蒸馏零陵香(basil)(罗勒(Ocimum basilicum L.))的全部地上部分而获得的精油,该植物是唇形科的一年生草本植物。
β-石竹烯是主要存在于桃金娘科植物诸如丁香和存在于精油诸如熏衣草油中的天然倍半萜.
本发明的Period基因的表达调节剂可包含一种或多种的上文提及的植物的提取物(草药)或精油(香料)。例如,所述表达调节剂可包含一种或多种的上文提及的草药与一种或多种的上文提及的香料的组合。
本发明的昼夜节律的调节剂包含一种或多种的作为Period基因的表达调节剂的上文提及的植物提取物或精油。
Period基因的表达调节剂可单独使用或与具有调节其它的时钟基因表达的作用的活性剂组合使用。
其它的时钟基因的实例包括Bmal基因(Bmal1、Bmal2)、Clock基因、Cryptochrome基因、白蛋白D位点结合蛋白(Dbp)基因、E4BP4基因、Npas2基因和Rev-erb基因。然而,Period基因的表达调节剂优选与Bmal、Clock和/或Cryptochrome基因、生物钟的其它核心基因的表达调节剂组合使用,尤其优选与一种或多种Bmal基因的表达调节剂组合施用。
在如图1中所示的昼夜节律的节律-产生***中,BMAL1(Bmal基因的表达产物)与CLOCK形成异源二聚体以促进Period基因的转录,而表达的PERIOD(PER)与CRYPTOCHROME(CRY)形成异源二聚体以抑制BMAL和CLOCK活性,由此形成在24小时期间波动的反馈回路。在哺乳动物中,Bmal和Period基因的昼夜节律波动的相转换时间约12小时。Bmal表达在夜间增加,而Period表达在白天增加。因此认为经由Period和Bmal基因二者的表达的调节可调节生物钟的核心回路,从而可更有效地调节昼夜节律。
Bmal基因的表达调节剂包括但不限于草药诸如,日本扁柏(hinokicypress)、小球藻(chlorella)、酒花(hop)、花椒(Zanthoxylum)和其它的提取物;和香料诸如,刺柏油、熏衣草油、桉树油、乳香、柏木油、玫瑰草油、松针油、玫瑰油、依兰油、榄香油、卑柠油(petitgrain oil)、胡椒油(pepperoil)、百里香油和春黄菊油和其它的精油。已确认这些草药或香料能在培养的皮肤成纤维细胞中诱导Bmal基因的表达节律或促进其表达。
此外,Period基因的表达调节剂和本发明的昼夜节律调节剂可单独使用或可包含在各种不同的物体中。根据物体的种类,所述物体可补充地包含任何成分以及上文提及的必需成分。
例如,当所述物体为应用于皮肤的外用制剂,根据其剂型(例如液体制剂、粉末制剂、颗粒剂、气雾剂、固体制剂、凝胶剂、贴剂、栓剂等)或其产品形式(例如化妆品、药物、医药部外品等)可包含通常存在于这样的外用制剂中的任何成分以及上文提及的Period基因的表达调节剂。应用于皮肤的外用制剂包括通常应用于皮肤(包括头部皮肤、头发和指甲)的组合物,且包括化妆品诸如护肤品、美容品、护发产品、洗面产品、洗发产品等,以及各种药物和医药部外品诸如软膏剂、贴剂、栓剂、牙膏等。所述剂型包括但不限于基于水的***、增溶***、乳剂、基于油的***、凝胶剂、糊剂、软膏剂、气雾剂、水-油两相***、水-油-粉末三相***等。当应用于皮肤的外用制剂为化妆品时,其包括香水、淡香水(eaux de toilet)、古龙香水(eaux de cologne)、霜、乳状液、化妆水、粉底化妆品、擦脸粉、唇膏、肥皂、洗发剂和护发素、沐浴露(body shampoo)、沐浴乳(body rinse)、爽身粉、浴皂等。
本发明的Period基因的表达调节剂可包含在空气清新剂、除臭剂、芳香蜡烛、香(incense)、文具、钱包、包、鞋和任何其它的杂货;内衣、全套服装(outfit)、帽子、长袜、短袜和任何其它衣物中;或在粉末、颗粒剂、胶囊剂和多种其他制剂中作为食物补充剂;和在零食、饮料和任何其它食品中。此外,当本发明的Period基因的表达调节剂包含上文提及的精油(香料)时,其可用于吸入剂诸如药物吸入产品和雾化剂中,只要本发明产生其作用即可。
在本说明书中举例阐述了本发明的Period基因的表达调节剂的实施方案。然而本发明不仅限于说明书中描述的实施方案,而且可采用于任何应用模式,条件是产生本发明的作用。根据具体的应用模式,可将具有调节昼夜节律作用的其它活性剂与本发明的Period基因的表达调节剂组合,条件是不妨碍本发明的作用。
在物体中的本发明的Period基因的表达调节剂的含量不被特别限制,且可根据所用的草药或香料的种类和形式、该物体等适当地进行选择,例如为该物体的总质量的0.00001质量%至100质量%、优选0.0001质量%至50质量%、且更优选0.0001质量%至20质量%。
本发明的Period基因的表达调节剂或昼夜节律的调节剂以及包含所述调节剂的物体的具体应用不被特别限制,只要与昼夜节律的调节相关即可。例如,其可应用于飞行时差反应综合征、轮班制工作综合征(shift worksyndrome)、睡眠时相延迟综合征、非24小时型睡眠-觉醒障碍、与昼夜节律睡眠障碍有关的抑郁等、以及失眠、身体状况不佳(poor physicalconditions)、注意力缺陷、情感淡漠(apathy)、皮肤粗糙(rough skin)和各种其它的与昼夜节律失调相关的症状的预防、改善、治疗等。
[实施例]
下文将使用实施例详细叙述本发明,但本发明不限于这些实施例。皮肤成纤维细胞、上皮细胞、内皮细胞、色素细胞、脂肪细胞、神经细胞和各种其它类型的细胞可用作培养细胞。然而在实施例中使用人皮肤成纤维细胞进行评价。因为时钟基因的核心***是所有物种的生物和所有类型的细胞所共有的,所以认为由人皮肤成纤维细胞得到的评价结果应当可适用于其它物种的生物和其它类型的细胞。在人类中,三种基因被称为Period基因:Period1、Period2和Period3。由于它们属于同一基因家族,所以认为它们的表现相似。在以下的实施例中,以Period1表达作为代表进行测定。
对于使用培养的人皮肤成纤维细胞的时钟基因表达节律的评价***的
研究
已证实能在使用培养的人皮肤成纤维细胞的***中评价时钟基因表达节律。
购买了来自正常人皮肤的成纤维细胞作为培养的人成纤维细胞(CellApplication,Inc.)并将其用于试验中。将它们接种于DMEM培养基(补充有10%FBS、20mM HEPES、Glutamax和抗菌剂)中,并在37°C、5%CO2条件下培养。在培养的第6天,将50ng/mL氢化可的松或10μM福斯高林添加至各孔中,并在0时间后的多个时间点收获各样品,所述0时间定义为一经添加氢化可的松或福斯高林后的时间。使用商购可得的RNA提取试剂盒从细胞提取RNA,并使用商购可得的PCR引物(Perfect RealTime Primer,Takara Bio)通过RT-PCR技术测定目标基因的表达的量。对于时钟基因,测定Period1和Bmal1(它们包括在所述核心***中)的表达的量。相似地,定量测定管家基因RPLP0的表达的量,并用作内标准以计算目标基因相对于RPLP0的表达。
在活的生物体中,糖皮质激素诸如氢化可的松与在外周组织等中调节生物钟相关,而且认为当在早上觉醒时,氢化可的松的血液浓度升高以重置生物钟。在培养的细胞中,单独的细胞通常独立地保持它们的节律。通过使用信号刺激因子诸如氢化可的松或福斯高林进行刺激能同步时钟基因的表达节律以诱导昼夜节律。
结果在图2中显示。证实了Period1和Bmal1表达分别在刺激后约2小时和约16小时出现高峰,且这两种基因均以约24小时周期的昼夜节律循环表达。
测试物质对Period基因的表达调节作用的评价
使用培养的人皮肤成纤维细胞的评价***的以上提及的结果证明Period1显示了在使用试剂刺激后约2小时具有基因表达的高峰的昼夜节律。基于在刺激后2小时的基因表达的量评价测试物质对Period基因的表达调节作用。为证实对Period基因的表达节律的诱导,还测定了Period1基因在刺激后16小时的表达的量。
根据与上文所使用的相似的方法接种来自正常人皮肤的成纤维细胞(Cell Application,Inc.)。在培养的第6天加入各个测试物质,最终浓度100ppm,并在刺激后2和16小时收获细胞。使用商购可得的RNA提取试剂盒从细胞提取RNA。使用商购可得的PCR引物(Perfect Real Time Primer,Takara Bio)通过RT-PCR技术测定Period1基因的表达的量。
此外,还针对透明质酸合成酶(HAS)类似地测定了基因表达,透明质酸合成酶与透明质酸的生成相关,透明质酸在保持皮肤水分方面起重要作用。HAS1、HAS2和HAS3被称为HAS,且将HAS2作为透代表性的明质酸合成酶进行了测定。
定量测定管家基因RPLP0的基因表达的量,并将其用作内标准以计算目标基因相对于RPLP0的相对表达。对得到的各测定结果进行Dunnett的多重比较检验,与对照相比具有单向的5%的显著性水平的测定结果被认定为是显著有效的。
图3显示在添加各种测试物质和作为阳性对照的氢化可的松或福斯高林2和16小时后Period1基因的基因表达的相对量。
以下表1显示在刺激后2小时Period1基因的基因表达的相对量。对于一些测试物质,在刺激后16小时Has2基因的基因表达的相对量也显示表1中。
[表1]
*:p<0.05,**:p<0.01
已证实阿尼菊提取物、日本萍蓬草提取物、黑茶提取物、花椒提取物、刺柏油、雪松油、熏衣草油、丁香花蕾油、柏木油、玫瑰油、依兰油、格蓬油、卑柠油、胡椒油、百里香油、罗勒油和β-石竹烯、以及阳性对照氢化可的松和福斯高林能够诱导在刺激后2小时具有高峰的表达节律,并显著地增加Period1基因表达的量,因此这些草药或香料能够调节Period基因的表达。
另外,还提示了刺柏油、依兰油和胡椒油能够通过增加透明质酸生成而改善或增进皮肤功能,原因是它们被证明在刺激后16小时促进Has2基因表达。
本发明的Period基因的表达调节剂可与Bmal基因的表达调节剂组合使用,所述Bmal基因的表达调节剂包括但不限于草药诸如日本扁柏(hinokicypress)、小球藻(chlorella)、酒花(hop)、花椒(Zanthoxylum)和其它的提取物;和香料,诸如刺柏油、熏衣草油、桉树油、乳香、柏木油、玫瑰草油、松针油、玫瑰油、依兰油、榄香油、卑柠油、胡椒油、百里香油、春黄菊油和其它精油。通过在培养的皮肤成纤维细胞中使用Bmal1作为代表检测Bmal基因的表达节律,已证实这些草药或香料能够诱导Bmal基因的表达节律或促进其表达。下表2显示在刺激后16小时Bmal1基因的基因表达的相对量。
[表2]
*:p<0.05,**:p<0.01
(组合物实施例)
下文给出本发明的Period基因的表达调节剂的组合物实施例,但本发明不限于以下所述内容。在下文的组合物实施例中,将百里香油用作本发明的Period基因的表达调节剂。可包含上文所述的能调节Period基因的表达的草药和/或香料中的一种或超过一种的混合物。组合量均以相对于各产品的总量的质量百分比表示。
[香料]
(1)酒精 75.0
(2)净化水 剩余部分
(3)双丙二醇 5.0
(4)本发明的Period基因的表达调节剂(百里香油) 10.0
(5)抗氧化剂 8.0
(6)色素 适量
(7)紫外线吸收剂 适量
[房间清新剂]
(1)酒精 80.0
(2)净化水 剩余部分
(3)抗氧化剂 5.0
(4)本发明的Period基因的表达调节剂(百里香油) 3.0
(5)3-甲基-3-甲氧基丁醇 5.0
(6)二亚苄基山梨醇 5.0
[香]
(1)Makko粉 75.5
(2)苯甲酸钠 15.5
(3)本发明的Period基因的表达调节剂(百里香油) 5.0
(4)桉树油 1.0
(5)净化水 剩余部分
[浴盐]
(1)硫酸钠 45.0
(2)碳酸氢钠 45.0
(3)熏衣草油 9.0
(4)本发明的Period基因的表达调节剂(百里香油) 1.0
[按摩凝胶]
(1)赤藓糖醇 2.0
(2)咖啡因 5.0
(3)黄柏(Phellodendron amurense)树皮提取物 3.0
(4)甘油 50.0
(5)聚羧乙烯 0.4
(6)聚乙二醇400 30.0
(7)依地酸三钠 0.1
(8)聚氧乙烯(10)甲基聚硅氧烷共聚物 2.0
(9)角鲨烷 1.0
(10)氢氧化钾 0.15
(11)本发明的Period基因的表达调节剂(百里香油) 1.0
[按摩霜]
(1)固体石蜡 5.0
(2)蜂蜡 10.0
(3)凡士林 15.0
(4)液体石蜡 41.0
(5)1,3-丁二醇 4.0
(6)单硬脂酸甘油酯 2.0
(7)POE(20)脱水山梨醇单月桂酸酯 2.0
(8)硼砂 0.2
(9)咖啡因 2.0
(10)防腐剂 适量
(11)抗氧化剂 适量
(12)本发明的Period基因的表达调节剂(百里香油) 1.0
(13)净化水剩 余部分
[芳香型纤维]
将含本发明的Period基因的表达调节剂的微囊剂(颗粒直径:不大于50μm(微米);微囊剂中精油的百分比:50重量%)以纤维素重量的0.1重量%至20重量%添加至铜铵纤维素(cuproammonium cellulose)溶液(纤维素浓度:10重量%;铵浓度:7重量%;铜浓度:3.6重量%)中,将其混合,并通过常规的湿纺法纺丝,在精制步骤和干燥步骤后,得到芳香型纤维。
[颗粒剂]
(1)三氯蔗糖 0.1
(2)本发明的Period基因的表达调节剂(百里香油) 0.1
(3)矫味剂 5.0
(4)赋形剂(Ceolus) 10.0
(5)麦芽糖醇 剩余部分
[片剂(咀嚼型)]
(1)肌醇 11.0
(2)麦芽糖醇 21.0
(3)蔗糖 0.5
(4)鲑鱼精提取物(DNA Na) 0.1
(5)酵母提取物 0.1
(6)本发明的Period基因的表达调节剂(百里香油) 0.1
(7)矫味剂 5.0
(8)赋形剂 剩余部分
[片剂]
(1)滑润剂(蔗糖脂肪酸酯等) 1.0
(2)***胶水溶液(5%) 2.0
(3)酸化剂 1.0
(4)着色剂 适量
(5)本发明的Period基因的表达调节剂(百里香油) 0.1
(6)糖(糖粉、山梨糖等) 剩余部分
[糖果]
(1)食糖 50.0
(2)淀粉糖浆 47.95
(3)有机酸 2.0
(4)本发明的Period基因的表达调节剂(百里香油) 0.05
[口胶剂]
(1)食糖 43.0
(2)胶基(Gum base) 30.95
(3)葡萄糖 10.0
(4)淀粉糖浆 16.0
(5)本发明的Period基因的表达调节剂(百里香油) 0.05
通过以典型的应用方式试验性使用各产品形式,这些组合物实施例的产品能够调节Period基因的表达和调节活的生物体的昼夜节律。
Claims (2)
1.一种或多种选自花椒提取物、刺柏油、柏木油、格蓬油、胡椒油、百里香油、日本萍蓬草提取物和阿尼菊提取物的物质的用途,用于作为活性成分制备昼夜节律的调节剂。
2.一种或多种选自花椒提取物、刺柏油、雪松油、熏衣草油、丁香花蕾油、柏木油、玫瑰油、依兰油、格蓬油、卑柠油、胡椒油、百里香油、罗勒油和β-石竹烯、日本萍蓬草提取物、黑茶提取物和阿尼菊提取物的物质的用途,用于作为活性成分制备Period基因的表达调节剂。
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2011
- 2011-03-30 US US13/638,633 patent/US20130022692A1/en not_active Abandoned
- 2011-03-30 ES ES11762283.7T patent/ES2567160T3/es active Active
- 2011-03-30 KR KR1020127028529A patent/KR101770706B1/ko active IP Right Grant
- 2011-03-30 CN CN201180017292.4A patent/CN103025339B/zh active Active
- 2011-03-30 EP EP11762283.7A patent/EP2554178B1/en active Active
- 2011-03-30 JP JP2012508101A patent/JP5868313B2/ja active Active
- 2011-03-30 WO PCT/JP2011/001941 patent/WO2011122041A1/ja active Application Filing
- 2011-03-31 TW TW100111422A patent/TWI552756B/zh not_active IP Right Cessation
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2013
- 2013-09-25 HK HK13110946.9A patent/HK1183450A1/zh unknown
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Also Published As
Publication number | Publication date |
---|---|
EP2554178B1 (en) | 2016-01-13 |
JPWO2011122041A1 (ja) | 2013-07-04 |
KR101770706B1 (ko) | 2017-08-23 |
EP2554178A4 (en) | 2013-08-28 |
EP2554178A1 (en) | 2013-02-06 |
TWI552756B (zh) | 2016-10-11 |
KR20130040854A (ko) | 2013-04-24 |
US20130022692A1 (en) | 2013-01-24 |
CN103025339A (zh) | 2013-04-03 |
ES2567160T3 (es) | 2016-04-20 |
HK1183450A1 (zh) | 2013-12-27 |
WO2011122041A1 (ja) | 2011-10-06 |
JP5868313B2 (ja) | 2016-02-24 |
TW201201824A (en) | 2012-01-16 |
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