CN104918614B - Vegfc产生促进剂 - Google Patents
Vegfc产生促进剂 Download PDFInfo
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- CN104918614B CN104918614B CN201380061795.0A CN201380061795A CN104918614B CN 104918614 B CN104918614 B CN 104918614B CN 201380061795 A CN201380061795 A CN 201380061795A CN 104918614 B CN104918614 B CN 104918614B
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- vegfc
- accelerating agent
- oedema
- skin
- lymphoedema
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Abstract
本发明的课题是，从由VEGFC的表达促进带来的淋巴管功能活化的观点出发，发现对水肿、淋巴浮肿、皮肤老化、或肥胖的预防或控制有效的新香料成分。本发明提供一种水肿改善剂、淋巴管活化剂和VEGFC产生促进剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
Description
技术领域
本发明涉及通过诱导血管内皮生长因子C(VEGFC)表达，促进淋巴管功能活化的水肿、淋巴浮肿、皱纹或肥胖改善剂。
背景技术
皮肤脉管系统存在于真皮中，由血管和淋巴管构成。为了保持体内稳态，已移动至血管外的组织液必须再回流至静脉中。皮肤的静脉向中枢高效地输送血流。然而，静脉本身缺乏引入组织液的能力。因此可以理解，引入组织液的组织，即淋巴管在皮肤中也是必须的结构。
淋巴管通过进行存在于皮肤中的废物、恒常从血管漏出的水分、蛋白质的回收，从而为了使细胞周围的微环境保持稳定状态而担负重要的作用。此外认为，担负介由T淋巴细胞的输送来抵抗来自外界的感染因子、外部因素的作用。
作为淋巴管的功能不全的病态，已知水肿、淋巴浮肿等症状(非专利文献1：Jussila,L.&Alitalo,K.(2002)Physiol Rev 82,673-700)。此外，已知淋巴管的功能不限于对水肿担负重要的作用，而且对伴随紫外线的皮肤的光老化(皱纹形成)也担负重要的作用(非专利文献2：Kajiya,K.&Detmar,M.(2006)J Invest Dermatol 126,919-21)。
根据迄今为止的研究，作为特异性存在于淋巴管中的跨膜受体而鉴定出VEGFR-3，发现了VEGFC和VEGFD作为其配体。VEGFC作用于淋巴管而促进淋巴管内皮细胞的增殖、游走进而促进管腔形成，从而活化淋巴管的功能(非专利文献1：Jussila,L.&Alitalo,K.(2002)Physiol Rev 82,673-700)。此外，摸索出对作为水肿的疾病状态的浮肿通过导入VEGFC进行基因治疗的可能性(非专利文献3：Saaristo,A.,Tammela,T.,Timonen,J.,Yla-Herttuala,S.,Tukiainen,E.,Asko-Seljavaara,S.&Alitalo,K.(2004)Faseb J 18,1707-9)。
此外最近，已知如果导致淋巴管功能异常的基因变异小鼠成熟则呈现肥胖。关于淋巴管的形成和功能的异常呈现肥胖的机制，获得了在淋巴管中流动的淋巴液促进祖肥大细胞向脂肪分化这样的认识(非专利文献4：Harvey,N.L.等,Nat Genet 2005,37,1072-81)。即，已经报道了由于淋巴管的功能异常，使淋巴液向淋巴管外漏出，这与脂肪的分化、进而肥胖形成相关。因此，期待VEGFC促进剂也作为使淋巴管功能性新生的肥胖预防的治疗药。
VEGF家族基因存在VEGF-A～E。其中，VEGFB和VEGFE作为仅作用于血管的因子被鉴定出。已知VEGFA是存在于皮肤中对淋巴管起作用但反过来会使淋巴管的功能恶化的因子(非专利文献5：Nagy,J.A.,Vasile,E.,Feng,D.,Sundberg,C.,Brown,L.F.,Detmar,M.J.,Lawitts,J.A.,Benjamin,L.,Tan,X.,Manseau,E.J.,Dvorak,A.M.&Dvorak,H.F.(2002)JExp Med 196,1497-506)。
对于皮肤，虽然已经报道了VEGFD在真皮中微量存在，但是由于VEGFD的敲除小鼠完全没有对皮肤淋巴管的形成和功能带来异常，因此认为VEGFD不是皮肤的淋巴管形成所不可缺少的因子(非专利文献6：Baldwin,M.E.,Halford,M.M.,Roufail,S.,Williams,R.A.,Hibbs,M.L.,Grail,D.,Kubo,H.,Stacker,S.A.&Achen,M.G.(2005)Mol Cell Biol25,2441-9)。另一方面，皮肤中的VEGFC在表皮中强表达。在表皮高表达了VEGFC的小鼠存在于真皮中的淋巴管数增加了(非专利文献7：Jeltsch,M.,Kaipainen,A.,Joukov,V.,Meng,X.,Lakso,M.,Rauvala,H.,Swartz,M.,Fukumura,D.,Jain,R.K.&Alitalo,K.(1997)Science 276,1423-5)，另一方面，获得如下认识：在表皮高表达作为VEGFC的受体的VEGFR-3的中和抗体，而阻断处于表皮的VEGFC的效果，结果真皮的淋巴管数极端减少，形成浮肿(非专利文献8：Makinen,T.,Jussila,L.,Veikkola,T.,Karpanen,T.,Kettunen,M.I.,Pulkkanen,K.J.,Kauppinen,R.,Jackson,D.G.,Kubo,H.,Nishikawa,S.,Yla-Herttuala,S.&Alitalo,K.(2001)Nat Med 7,199-205)。由此，可知存在于皮肤真皮内的淋巴管的功能可通过在表皮表达的VEGFC来控制，由于VEGFC丧失功能而呈现水肿(浮肿)。
迄今为止，报道了特定的萜类及其衍生物具有VEGF产生促进作用，作为创伤治愈剂、育发/生发剂和具有肤色改善效果的皮肤外用剂是有用的(专利文献1)，报道了杏仁提取物、胡萝卜提取物、缬草提取物、山楂提取物、草木犀提取物、野芝麻提取物和鸢尾根提取物等植物提取物具有VEGFC产生促进作用(专利文献2)。
现有技术文献
专利文献
专利文献1：日本特开2004-2258号公报
专利文献2：日本特开2008-189609号公报
非专利文献
非专利文献1：Physiol Rev 82,673-700(2002).
非专利文献2：J Invest Dermatol 126,919-21(2006).
非专利文献3：Faseb J 18,1707-9(2004).
非专利文献4：Nat Genet 37,1072-81(2005).
非专利文献5：J Exp Med 196,1497-506(2002).
非专利文献6：Mol Cell Biol 25,2441-9(2005).
非专利文献7：Science 276,1423-5(1997).
非专利文献8：Nat Med 7,199-205(2001).
发明内容
发明所要解决的课题
本发明的课题在于，通过诱导VEGFC的表达来活化淋巴管功能，发现对水肿、淋巴浮肿、皱纹形成、或肥胖的预防或控制有效的新成分。
用于解决课题的方法
本发明人为了解决上述课题而进行了反复深入研究，结果发现，玫瑰醚、香茅醇乙酸酯和绿花白千层油等香料成分诱导VEGFC的表达。即发现，诱导VEGFC表达的这些成分促进淋巴管功能的活化，对防止或抑制水肿、淋巴浮肿、伴随紫外线的皮肤的光老化引起的皱纹的形成、或肥胖是极其有效的。
本发明的构成如下。
[1]一种VEGFC产生促进剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[2]一种淋巴管新生和/或功能促进剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[3]一种水肿改善剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[4]一种淋巴浮肿改善剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[5]一种皱纹改善剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[6]一种肥胖改善剂，其特征在于，含有选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分。
[7]根据[1]所述的VEGFC产生促进剂，其防止或抑制水肿。
[8]根据[2]所述的淋巴管新生和/或功能促进剂，其防止或抑制水肿。
[9]根据[1]所述的VEGFC产生促进剂，其防止或抑制淋巴浮肿。
[10]根据[2]所述的淋巴管新生和/或功能促进剂，其防止或抑制淋巴浮肿。
[11]根据[1]所述的VEGFC产生促进剂，其防止或抑制皱纹的形成。
[12]根据[2]所述的淋巴管新生和/或功能促进剂，其防止或抑制皱纹的形成。
[13]根据[1]所述的VEGFC产生促进剂，其防止或抑制肥胖。
[14]根据[2]所述的淋巴管新生和/或功能促进剂，其防止或抑制肥胖。
[15]一种用于防止或抑制水肿、淋巴浮肿、皱纹的形成和/或肥胖的美容方法或治疗方法，其包括将[1]所述的VEGFC产生促进剂涂抹于需要防止或抑制这些症状的对象的皮肤。
[16]一种用于防止或抑制水肿、淋巴浮肿、皱纹的形成和/或肥胖的美容方法或治疗方法，其包括将[2]所述的淋巴管新生和/或功能促进剂涂抹于需要防止或抑制这些症状的对象的皮肤。
[19][1]所述的VEGFC产生促进剂的用于防止或抑制水肿、淋巴浮肿、皱纹的形成和/或肥胖的应用。
[20][2]所述的淋巴管新生和/或功能促进剂的用于防止或抑制水肿、淋巴浮肿、皱纹的形成和/或肥胖的应用。
发明的效果
通过将选自玫瑰醚、香茅醇乙酸酯和绿花白千层油中的一种或多种成分应用于生物体，从而诱导生物体内的血管内皮生长因子C(VEGFC)的表达，促进淋巴管功能的活化。通过这样的作用，能够预防、改善水肿、淋巴浮肿、皱纹、或肥胖。
附图说明
图1为显示玫瑰醚、香茅醇乙酸酯和绿花白千层油的VEGFC诱导活性的图。
具体实施方式
定义：
本说明书中的用语“水肿”，与“浮肿”以相同含义使用，是组织液或淋巴液因某种原因而积存在细胞内、细胞间隙、或体腔内的状态，在皮下组织中也可见。此外本说明书中的用语“淋巴浮肿”，是指由于淋巴管的闭塞，而在末梢的部分积存组织液的状态。
诱导作为淋巴管活化因子的VEGFC的药剂的筛选，如下述实施例中详细记载的那样，通过使各种候选香料作用于作为人表皮来源的培养细胞的HaCat细胞株，进行VEGFC的定量，以该VEGFC的量作为VEGFC诱导活性，选择具有VEGFC诱导活性的香料作为有效成分。
其结果发现，玫瑰醚、香茅醇乙酸酯和绿花白千层油诱导VEGFC。
·玫瑰醚(Rose oxide)
玫瑰醚是具有以下化学结构，分子内具有2个不对称碳的有机化合物。
具有带甜味的蔷薇那样的香气，作为吡喃系、单萜系香料，可用于化妆品、肥皂。天然上，可以由蔷薇、玫瑰油、杏、薄荷获得，存在多种几何异构体、光学异构体。工业上，将由香茅醇的光氧化反应获得的烯丙基氢过氧化物用亚硫酸钠还原而制成二醇，然后用硫酸闭环，从而顺式型与反式型各等量获得。作为香料的市售品中，顺式-外消旋体为中心。
·香茅醇乙酸酯(Ctronellyl acetate)
香茅醇乙酸酯为通过下式表示，常温下作为无色透明的液体存在的有机化合物。
由于具有与蔷薇、薰衣草相似的特有香气，因此可用作食品、化妆品的香料。天然上包含于香茅油、香叶油等精油中，工业上由香茅醇合成。
·绿花白千层油(Niaouli oil)
绿花白千层油为由以印度尼西亚、澳大利亚、新西兰等太平洋地区、印度洋的马达加斯加岛作为原产的桃金娘科植物的绿花白千层(学名Melaleuca virdiflora)的叶或枝，通过水蒸气蒸馏而采集的精油。具有杀菌作用，可用于化妆品、肥皂、入浴剂等。
本发明涉及的上述香料成分对促进淋巴管的形成和功能是极其有效的。作为伴随淋巴管的功能不全的症状，不仅可见水肿、淋巴浮肿等，而且可见伴随紫外线的皮肤的光老化(皱纹形成等)和肥胖。本发明涉及的药剂对防止、抑制水肿、淋巴浮肿并且伴随紫外线的皮肤的光老化以及肥胖是有效的。此外，认为上述香料成分对先天性淋巴浮肿的治疗也是有效的。
所谓皮肤的光老化，是指一般被认为是反复被日光照射的结果的皮肤外观和功能的变化。作为日光的构成要素的紫外线(UV)，特别是中间UV(被称为UVB，波长290-320nm)主要引起光老化。引起光老化所需要的UVB的被照射量现在还不知道。然而，引起红斑、晒黑的水平下的UVB的反复照射通常与光老化相关。在临床上，光老化可特定为皮肤粗糙、皱纹的形成、斑的着色、土色化、松弛的形成、毛细管扩张症的发病、黑痣的发生、紫癜的发病、容易受伤、萎缩、纤维化的色素除去区域的产生、前恶性肿瘤和恶性肿瘤的发病等。光老化通常在脸、耳、头、颈和手那样的经常暴露于日光的皮肤处发生。
本发明的VEGFC产生促进剂、淋巴管新生和/或功能促进剂、水肿改善剂、淋巴浮肿改善剂、皱纹改善剂或肥胖改善剂(以下也称为“本剂”)能够根据其使用目的适当确定用量、施与形态、剂型。例如，本剂中的香料成分在药剂总量中典型配合0.0001～0.1％，适合配合0.001～0.01％，最适合配合0.005～0.01％。本剂的施与形态没有特别限制，可以为经口、非经口、外用、吸入等，但从可以由吸入和经皮两者起作用方面出发，优选为皮肤外用剂。作为剂型，可以为例如香水、古龙水、香波/护发素类、护肤用品、洗澡液、身体冲洗、爽身粉类、芳香剂、除臭剂、浴用制剂、乳液(lotion)、霜、肥皂、牙粉、气雾剂制品等化妆品、其它香料一般所使用的任一形态。进一步也可以用于吸入药等药品。
此外，本剂中，除了上述必须成分以外，通常可以根据需要适当配合化妆品、药品等皮肤外用剂中使用的成分，例如美白剂、保湿剂、抗氧化剂、油性成分、紫外线吸收剂、表面活性剂、增稠剂、醇类、粉末成分、着色剂、水性成分、水、各种皮肤营养剂等。
此外，也可以适当配合乙二胺四乙酸二钠、乙二胺四乙酸三钠、柠檬酸钠、多磷酸钠、偏磷酸钠、葡糖酸等金属螯合剂、咖啡因、丹宁、维拉帕米、凝血酸及其衍生物、甘草提取物、光甘草定、木瓜的果实的热水提取物、各种生药、生育酚乙酸酯、甘草酸及其衍生物或其盐等药剂、维生素C、抗坏血酸磷酸镁、抗坏血酸葡糖苷、熊果苷、曲酸等美白剂、葡萄糖、果糖、甘露糖、蔗糖、海藻糖等糖类、视黄酸、视黄醇、乙酸视黄醇酯、棕榈酸视黄醇酯等维生素A类等。
实施例
用含有10％FBS(Standard fetal bovine serum(标准胎牛血清),Hyclone)的DMEM培养基(Gibco low glucose DMEM,Life technologiesTM)培养作为人表皮来源的培养细胞的HaCaT细胞(German Cancer Research Center(德国癌症研究中心),Heidelberg(海德堡),Germany(德国))，在24孔板中接种使每一孔的细胞数为15×104个。从接种起24小时后，将培养基换成无血清的DMEM，培养24小时。然后，添加溶解于乙醇的各种香料(香料的终浓度为0.001～0.01％)。将乙醇作为对照使用。48小时培养后回收培养基上清液，按照ELISA试剂盒(QuantikineR Human VEGF-C Immunoassay(R&D Systems,Minneapolis,MN)的协议，定量培养上清液中的VEGFC量。此外，在回收了培养上清液后的细胞中添加alamarBlue((TREK Diagnostic Systems,Cleveland,US)，作为荧光强度(Ex 544nm,Em590nm)测定细胞量。将上清液中的VEGFC量除以荧光强度，并将对照(乙醇)设为100的各细胞的相对VEGFC诱导活性示于图1中。作为合成香料的玫瑰醚、香茅醇乙酸酯和天然香料的绿花白千层油(购入方：Biolandes)在各自浓度不具有细胞毒性而显示图1那样的VEGFC诱导活性。
配合例
以下，显示本发明的VEGFC产生促进剂的配合例，但本发明的实施不限定于以下。
化妆水
化妆水
乳液
乳液
乳液
霜
霜
凝胶
气雾剂
气雾剂
香水
按摩用凝胶
按摩霜
Claims (6)
1.香茅醇乙酸酯在VEGFC产生促进剂的制造中的应用。
2.香茅醇乙酸酯作为VEGFC产生促进剂在淋巴管新生和/或功能促进剂的制造中的应用。
3.香茅醇乙酸酯作为VEGFC产生促进剂在水肿改善剂的制造中的应用。
4.香茅醇乙酸酯作为VEGFC产生促进剂在淋巴浮肿改善剂的制造中的应用。
5.香茅醇乙酸酯作为VEGFC产生促进剂在皱纹改善剂的制造中的应用。
6.香茅醇乙酸酯作为VEGFC产生促进剂在肥胖改善剂的制造中的应用。
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| CN114469906A (zh) * | 2022-03-16 | 2022-05-13 | 中国农业大学 | 香茅醇在制备抗皮肤光损伤产品中的用途 |
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| EP2902022B1 (en) | 2020-10-28 |
| EP2902022A4 (en) | 2016-03-23 |
| WO2014051113A1 (ja) | 2014-04-03 |
| TWI653055B (zh) | 2019-03-11 |
| US11213472B2 (en) | 2022-01-04 |
| KR20150063485A (ko) | 2015-06-09 |
| HK1214950A1 (zh) | 2016-08-12 |
| US20170281500A1 (en) | 2017-10-05 |
| JPWO2014051113A1 (ja) | 2016-08-25 |
| US20150328137A1 (en) | 2015-11-19 |
| CN104918614A (zh) | 2015-09-16 |
| JP6061940B2 (ja) | 2017-01-18 |
| US10624829B2 (en) | 2020-04-21 |
| TW201417835A (zh) | 2014-05-16 |
| EP2902022A1 (en) | 2015-08-05 |
| KR102135989B1 (ko) | 2020-07-20 |
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