CN110151802A - 包含日本桤木提取物的用于预防、治疗或改善脱发疾病的组合物 - Google Patents
包含日本桤木提取物的用于预防、治疗或改善脱发疾病的组合物 Download PDFInfo
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- CN110151802A CN110151802A CN201811624387.2A CN201811624387A CN110151802A CN 110151802 A CN110151802 A CN 110151802A CN 201811624387 A CN201811624387 A CN 201811624387A CN 110151802 A CN110151802 A CN 110151802A
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Abstract
本发明涉及可预防、改善或治疗脱发疾病的组合物,上述组合物包含具有细胞凋亡抑制活性及抗氧化活性的日本桤木提取物。
Description
技术领域
本发明涉及包含日本桤木提取物的用于预防、治疗或改善脱发疾病的组合物。
背景技术
众所周知,自生在韩国的日本桤木(Alnus japonica)的树枝在韩医药中被称为赤杨,具有清热、降火作用,在民间用于高热、衄血、腹泻、牙痛、解酒、癌症等(非专利文献1)。
另一方面,众所周知,被称为赤杨(red alder)的同属植物即A.rubra在北美用于慢性疱疹病、湿疹、瘙痒症等多种慢性顽固性皮肤病(非专利文献2)。
可知,自古以来A.属植物已广泛用于东方和西方国家的各种疾病,尤其,共同使用于皮肤疾病。
直到最近,发表了多个从A.属植物中提取二芳基庚酸(diarylheptanoid)类的化合物,并与对抗氧化活性、抗炎活性、抗特应性活性等的A.属植物的资源利用性相关的研究(非专利文献3及非专利文献4)。
认为,作为一种强有力且有效的生理活性的主要功效物质,已知的在A.属植物中以高含量存在的主要的二芳基庚酸类化合物的奥瑞因起到核心作用,其中,“奥瑞因”为“oregonin”的音译。仔细观察在A.属植物的化学统计分类研究中作为指标物质重点研究奥瑞因的国内外研究趋势就可以知道其原因(非专利文献5及非专利文献6)。
作为在本研究中主要进行的研究内容的细胞凋亡和蛋白质印迹实验中测定的生物标志物,即对于B淋巴细胞瘤-2(Bcl-2)、Bcl-2相关X蛋白(Bax)、半胱天冬酶-3(caspase-3)、聚腺苷酸二磷酸核糖转移酶(PARP)的科学依据如下。可将细胞因内部和外部因素导致的死亡大致分为细胞凋亡(apoptosis)和细胞坏死(necrosis)。
其中,众所周知,细胞凋亡是由通过根据细胞内部的信号的多种蛋白质活性的调节和基因的表达来程序化的细胞凋亡过程引起的主动进行的细胞的死亡(非专利文献7)。
作为外部因素,代表性地产生由辐射、高温休克、毒素、细菌或病毒感染等引起的细胞的损伤或严重压力引起的细胞凋亡反应,其异常导致多种疾病,而诱导正常细胞的凋亡可能与脏器的损伤有关。
据报告,在与细胞凋亡有关的基因中,代表性地,存在作为抑制细胞凋亡的基因的B淋巴细胞瘤-2和诱导B淋巴细胞瘤-2的基因的Bcl-2相关X蛋白,因此受拮抗调节(非专利文献8)。
并且,众所周知,在诱导细胞凋亡的途径中被活化的蛋白质分解酶(protease)中,多个半胱天冬酶(caspase)是细胞凋亡过程中按各小器官活化成各种各样的最重要的执行者,可通过这个酶的活性来判断细胞凋亡程度及途径(非专利文献9)。
当半胱天冬酶类的酶被活化时,通过分解多种靶蛋白质来不可逆地进行细胞凋亡,尤其,半胱天冬酶-3使参与DNA修复(DNA repair)、DNA稳定性(DNA stability)及转录调节的聚腺苷酸二磷酸核糖转移酶蛋白等表达增加,诱导聚腺苷酸二磷酸核糖转移酶蛋白的切割,从而进入最终细胞凋亡步骤(非专利文献10)。
因此,为了阻断由在正常细胞中诱导细胞凋亡的外部刺激,例如,药物或氧化应激等引起的细胞凋亡,调节上述因素(factor)等的表达是非常重要的。
另一方面,因包括遗传因素的多种直接或间接影响,脱发患者急增,可以说是,处于发生脱发症状的年龄段越来越低的严重的趋势(非专利文献11)。
因脱发症状引起的严重的精神压力而可能感到社交活动困难,因此,实际上不能将脱毛症状的改善或治疗仅仅视为简单的美容目的。
如此,随着对于脱发症状的问题成为一个热点,对开发新的功能性材料已做出了很多努力,但是依然进行用于发掘具有明确的功效的同时确保人体稳定性的来源于天然物的改善及治疗脱毛症状的新材料的研究(非专利文献12)。
(现有技术文献)
(非专利文献)
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发明内容
发明要解决的问题
本发明的一目的在于,提供如下的用于预防、治疗或改善脱发疾病的组合物,即,包含日本桤木提取物作为有效成分,具有位于作为调节毛囊的发达和生长的器官的毛乳头的毛乳头细胞(Hair Follicle Dermal Papilla Cell,HFDPC)的细胞凋亡抑制活性及抗氧化活性。
用于解决问题的方案
本研究中,为了研究从日本桤木提取的奥瑞因是否有效抑制毛乳头细胞的细胞凋亡,通过使用因位于作为调节毛囊的发达和生长的器官的毛乳头的毛乳头细胞的凋亡而导致脱发症状恶化的实验模型,来进行了本研究。
本发明的一实例涉及包含日本桤木提取物作为有效成分,并具有对于毛乳头细胞的细胞凋亡的抑制活性及抗氧化活性的药学组合物。
并且,本发明的日本桤木可使用枝、叶、果、树皮、根等部位,优选地可使用日本桤木树枝,但并不限定于此。
在本发明中,日本桤木提取物在其提取方法中,可应用包括简单的提取方法至可提取脂溶性成分的方法的所有方法,以便于提取的方式粉碎日本桤木并通过提取溶剂来进行提取,可通过对其进行过滤及浓缩来获得。
作为提取溶剂,有水、乙醇、甲醇、丁醇、正己烷、正庚烷或二甲基亚砜(DMSO)等,其中,还可混合两种以上的溶剂来用作提取溶剂,但并不限定于此,本技术领域的技术人员可根据所要提取的原料的量、提取方法等从公知的方法适当选择。对于提取时间及温度,本技术领域的技术人员也可通过考虑提取效率、提取溶剂等来从公知的方法适当选择。
并且,利用减压过滤等公知的过滤方法过滤通过提取方法提取的提取物后,可通过蒸馏等来浓缩。这种提取、过滤及浓缩方法是本技术领域中公知的,因此,本技术领域的技术人员可通过适当选择来制备日本桤木提取物。
本发明的一实例提供包含日本桤木提取物的用于预防、治疗或改善脱发疾病的组合物。
另一方面,在本发明中,“预防”可不受限制地包括通过利用包含抑制毛乳头细胞的细胞凋亡且具有抗氧化活性的本发明的日本桤木提取物的组合物来阻断脱发疾病的症状,或者抑制或延迟其症状的所有行为。
并且,在本发明中,“治疗”可不受限制地包括通过利用包含抑制毛乳头细胞的细胞凋亡且具有抗氧化活性的本发明的日本桤木提取物的组合物来改善或有利于脱发疾病症状的所有行为。
在本发明中,药学组合物的特征在于,可以为胶囊、片剂、颗粒、注射剂、软膏剂、粉末或饮料形态,药学组合物的特征在于,以人类为对象。
本发明的药学组合物并不限定于此,但根据各个常规的方法可剂型化成散剂、颗粒剂、胶囊、片剂、水悬浮液等口服型剂型、外用剂、栓剂及灭菌注射溶液的形态来使用。
本发明的药学组合物可包含药学上可接受的载体。作为药学上可接受的载体,口服给药时可使用结合剂,润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定化剂、悬浮剂、色素、香料等,在注射剂的情况下,可混合使用缓冲剂、保鲜剂、镇痛剂、增溶剂、等渗剂、稳定剂等,在局部给药的情况下,可使用基剂、赋形剂、润滑剂、保鲜剂等。
本发明的药学组合物的剂型是可通过与如上所述的药学上可接受的载体混合来制备成各种各样的。例如,当口服给药时,可制备成片剂、药片、胶囊、酏剂(elixir)、悬浮液、糖浆、干胶片等形态,在注射剂的情况下,可制备成单位给药安瓿或多次给药形态。除此之外,可制备成溶液、悬浮液、胶囊、缓释型制剂等。
另一方面,作为适合于制剂化的载体、赋形剂及稀释剂的例,可使用乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽多酚、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁或矿物油等。并且,还可包含填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂、防腐剂等。
根据本发明的药学组合物的给药途径并不限定于此,但包括口腔、静脉内、肌肉内、动脉内、髓内、硬膜内、心脏内、经皮、皮下、腹腔内、鼻腔内、肠管、局部、舌下或直肠。优选为口服或非口服给药。
在本发明中,“非口服”包括皮下、皮内、静脉内、肌肉内、关节内、滑液囊内、胸骨内、硬膜内、病灶内及颅骨内注射或注入技术。本发明的药学组合物还可以用于直肠给药的栓剂的形态给药。
本发明的药学组合物根据包括所使用的特定化合物的活性、年龄、体重、一般健康、性别、饮食、给药时间、给药途径、排出率、药物配合及需要预防或治疗的特定疾病的严重程度的各种要素,可多样地改变,药学组合物的给药量根据患者的状态、体重、疾病的程度、药物形态、给药途径及时间而不同,但是可由本技术领域的技术人员适当选择,每日可给药0.0001mg/kg至50mg/kg或0.001mg/kg至50mg/kg。可以每天给药一次,还可以分为多次给药。给药量不以任何方式限制本发明的范围。
根据本发明的医药组合物可剂型成丸剂、糖衣剂、胶囊、液剂、凝胶、糖浆、浆料、悬浮剂。
本发明的再一实例涉及包含日本桤木提取物作为有效成分的用于预防或改善脱发疾病的化妆品组合物。
另一方面,在本发明中,“改善”可不受限制地包括通过利用包含抑制毛乳头细胞的细胞凋亡且具有抗氧化活性的本发明的日本桤木提取物的组合物来改善或有利于脱发疾病症状的所有行为。
在本发明中,化妆品组合物可制备成化妆水、营养霜、营养精华、按摩霜、美容沐浴添加剂、润肤露、身体乳、沐浴油、婴儿油、婴儿粉、沐浴凝胶、沐浴霜、防晒乳液、防晒霜、晒黑霜、润肤露、护肤霜、防紫外线化妆品、洁面乳、脱发剂化妆用、面部和身体乳液、面部和身体霜、皮肤美白霜、护手霜、润发露、美容霜、茉莉油,沐浴皂、水皂、美容皂、洗发水、洗手液(手清洁剂)、药用肥皂非医用、霜皂、洗面奶、全身清洁剂、头皮清洁剂、护发素、化妆皂、牙齿美白用凝胶、牙膏等形态。
为此,本发明的组合物还可包含通常用于化妆品组合物的制备的溶剂或适当的载体、赋形剂或稀释剂。
可进一步添加到本发明的化妆品组合物中的溶剂的类型没有特别限制,但是,例如,可使用水、食盐水、二甲基亚砜或它们的组合,作为载体、赋形剂或稀释剂包括纯净水、油、蜡、脂肪酸、脂肪酸醇、脂肪酸酯、表面活性剂、吸湿剂(humectant)、增稠剂、抗氧化剂、粘度稳定化剂、螯合剂、缓冲剂、低级醇等,但并不限定于此。并且,根据需要可包含美白剂、保湿剂、维生素、防晒剂、香水、颜料、抗生素、抗菌剂、抗真菌剂。
作为油可利用氢化植物油、蓖麻油、棉籽油、橄榄油、棕榈油、荷荷巴油、鳄梨油,作为蜡可利用蜜蜡、鲸蜡、巴西棕榈蜡、小烛树蜡、蒙丹蜡、地蜡、液体石蜡、羊毛脂蜡。
作为脂肪酸可利用硬脂酸、亚油酸、亚麻酸、油酸,作为脂肪酸醇可利用十六醇、辛基十二烷醇、油醇、泛醇、羊毛脂醇、硬脂醇、十六烷醇,作为脂肪酸酯可利用肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸丁酯。作为表面活性剂可使用本技术领域中公知的阳离子表面活性剂、阴离子表面活性剂及非离子表面活性剂,优选地,尽可能使用来源于天然物的表面活性剂。
除此之外,可包含化妆品领域中公知的吸湿剂、增稠剂、抗氧化剂等,它们的种类和量根据本技术领域中公知。
本发明的另一实例涉及包含日本桤木提取物作为有效成分的用于预防或改善脱发疾病的食品组合物。
本发明的再一目的在于,提供包含日本桤木提取物作为有效成分的用于预防或改善基于毛乳头细胞的细胞凋亡的疾病的食品组合物。
包含本发明的组合物作为有效成分的食品组合物可制备成各种食品类,例如,饮料、口香糖、茶、维生素复合物、粉末、颗粒、片剂、胶囊、饼干、打糕、面包等形态。本发明的食品组合物由几乎没有毒性及副作用的植物提取物构成,因此,即使以预防为目的长期使用,也可以安全使用。
当本发明的组合物包含在食品组合物时,能够以总重量的0.1%至50%的比率添加。
其中,在食品组合物制备成饮料形态的情况下,除了以提出的比率包含食品组合物之外,没有特别限制,如常规的饮料一般可包含各种香味剂或天然碳水化合物等作为额外的成分。即,作为天然碳水化合物可包含单糖,如葡萄糖等;二糖,如果糖等;多糖,如蔗糖等;常规的糖,如糊精,环糊精等;糖醇,如木糖醇、山梨糖醇、赤藓糖等。作为香味剂可列举天然香味剂(索马甜、甜叶菊提取物(例如,莱鲍迪甙A、甘草甜素等)及合成香味剂(糖精、阿斯巴甜等)等。
除此之外,本发明的食品组合物可包含各种营养剂、维生素、矿物(电解质)、合成风味剂及天然风味剂等风味剂、着色剂、果胶酸、及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定化剂、防腐剂、甘油、酒精、使用于碳酸饮料的碳酸化剂等。
可单独或组合使用这些成分。这些添加剂的比率并不重要,但是,通常选自每100重量份的本发明的组合物中0.1重量份至50重量份的范围。
发明的效果
根据本发明的药学组合物、化妆品组合物及食品组合物包含抑制毛乳头细胞的细胞凋亡且具有抗氧化活性的日本桤木提取物,来可有效地用于预防、治疗或改善脱发疾病。
附图说明
有助于理解本发明而包括的作为详细说明的一部分的附图提供对本发明的实施例,结合详细说明来描述本发明的技术特征。
图1为示出根据本发明一实施例的奥瑞因标准品及日本桤木提取物标品的高压液相色谱(HPLC)的图。
图2为示出根据本发明一实施例的奥瑞因标品的LC/MS谱的图。
图3为示出根据本发明一实施例的DPPH自由基清除作用的测定数据的图。
图4为示出根据本发明一实施例的ABTS自由基清除作用的测定数据的图。
图5为与根据本发明一实施例的奥瑞因的细胞凋亡抑制活性相关的实验数据。
具体实施方式
以下,通过下述实施例详细说明本发明。但是,下述实施例仅用于例示,本发明的内容并不限定于以下实施例。
实验准备
实验材料
日本桤木(A.japonica)由国立树木园提供并使用于实验,标准品由南部大学天然功能材料实验室保管(AJ2017-09)。
实验设备及试剂
1H及13C-NMR谱利用JEOL-JNM-AL300(300MHz,75MHz)测。
高压液相色谱(High pressure liquid chromatography,HPLC)利用了Waters2695设备(美国),详细地,分别利用了2487Dual rhamda吸光度检测器(AbsorbanceDetector),保护柱(Guard column):菲罗门(Phenomenex)KJ0-4282保护柱,柱:VDSpher100C18-E(100A,4.6*250mm,5μm),柱箱温度(Column oven temperature):25℃(degreecelcious),流动相(Mobile phase):1%的乙酸(Acetic acid)(A),1%的乙腈中的乙酸(Acetic acid in acetonitrile),数据系统(Data system):Empower 2软件(美国沃特世公司(Waters Co.,USA))。
LC/MS利用了岛津(Shimadzu)prominence UFLC-MS系统,Pump A:LC-30AD,泵B(Pump B):LC-30AD,检测器(Detector):SPD-20A,自动采样器(Auto sampler):SIL-20AXR,柱箱(Column Oven):CTO-20A,系统控制器(Communications Bus Module):CBM-20A,MS:ESI-IT-TOF MS。
分别设定LC条件为柱(Column):Waters ACQUITY UPLC BEH C18 2.1×150mm,1.7um,柱箱温度:35℃,紫外线检测器(UV detector):280nm,注射量(injection volume):1ul,流速(flow):0.21ml/min,溶剂A(Solvent A):0.1%的甲酸(formic acid)水溶液,溶剂B(Solvent B):乙腈(Acetonitrile),溶剂条件(solvent condition),MS条件为喷雾气体流速(Nebulizing gas flow):1.5L/min,CDL温度:200℃,加热块温度(Heat BlockTemperature):200℃并使用于实验。
薄层色谱(Thin layer chromatography,TLC)板使用了预涂硅胶(pre-coatedsilica gel)60F254板(德国达姆施塔默克公司(Merck,Darmstadt,Germany))。
提取及分离
切割200g的日本桤木树枝后,在常温下用70%的乙醇(EtOH)提取一次并过滤。减压浓缩其提取液并通过冷冻干燥来最终获取23.01g,以高压液相色谱(HPLC)加载用进行定量并用于实验。
准确地取1mg作为从以往由实验室保管的日本桤木树枝分离、纯化的标品的奥瑞因(1),加入80%的甲醇(MeOH),以使总量为1ml,制备了原液(stock solution)(1000ppm)。通过稀释此原液来制备了125ppm、250ppm、500ppm、1000ppm浓度的标准溶液。分别取20μl的标准溶液以获得标准溶液充分离的高压液相色谱。并且,为了实验的再现性,通过反复实验求出标准溶液和日本桤木树枝提取物未知试液的反应时间(retention time)的平均和标准误差。
如下设定标品的分析条件后,通过反复纯化收集具有与奥瑞因标准品相同的RT值的峰(peak)并获取单一化合物来测定NMR和LC/MS数据。
分析条件
高压液相色谱方法(HPLC Method)分析条件
-流动相(Mobile phase):水(溶剂A)、乙腈(Acetonitrile)(溶剂B)
-梯度洗脱(Gradient program):0~12分钟10B%、12~24分钟25B%、24~25分钟40B%
-流量(Flow rate):1ml/min
-波长(Wavelength):280nm
-注入量(Inject volumn):20μl
-总运行时间(Total run time):40分钟
-柱箱温度(Column oven temperature):25℃
-保护柱(Guard column):菲罗门(Phenomenex)KJ0-4282保护柱
-柱:VDSpher 100C18-E(5μm,250×4.6mm)
表1
0分钟 | 12分钟 | 24分钟 | 25分钟 | |
溶剂A(H<sub>2</sub>0) | 100 | 90 | 75 | 60 |
溶剂B(CH<sub>3</sub>CN) | 0 | 10 | 25 | 40 |
表1为根据水(溶剂A)、乙腈(溶剂B)的溶剂体系(Solvent System)的高压液相色谱方法。
LC方法分析条件
LC条件
-柱(Column):Waters ACQUITY UPLC BEH C18 2.1×150mm,1.7μm的柱箱温度:35℃
-紫外线检测器(UV detector):254nm
-注射量(injection volume):1μl
-流量:0.21ml/min
-溶剂A:0.1%的甲酸(formic acid)水溶液
-溶剂B:乙腈
MS条件
-喷雾气体流速(Nebulizing gas flow):1.5L/分钟
-CDL温度:200℃
-加热块温度:200℃
表2
0分钟 | 20分钟 | 24分钟 | 25分钟 | 30分钟 | |
溶剂A | 95 | 40 | 40 | 95 | 95 |
溶剂B | 5 | 60 | 60 | 5 | 5 |
表2为对于溶剂A(0.1%的甲酸(formic acid)水溶液)及溶剂(乙腈)的溶剂体系(Solvent System)的LC/MS方法。
分析结果
图1为示出奥瑞因标准品及日本桤木提取物标品的高压液相色谱的实验数据的图。具体地,图1a为奥瑞因标准品的高压液相色谱,图1b为日本桤木提取物标品的高压液相色谱。
表3
样品 | 反应时间(分钟) |
奥瑞因标准品 | 15.561±0.019 |
日本桤木提取物(A.japonica Extract)标品 | 15.107±0.021 |
表3为分析具有与奥瑞因标准品相同的反应时间的标品(日本桤木提取物)的峰反应时间的结果。
奥瑞因标品(Oregonin(1))
图2为示出根据本发明一实施例的奥瑞因标品的LC/MS谱的图。具体地,图2a为示出奥瑞因标品的正LC/MS(Positive LC/MS)谱的图,图2b为示出奥瑞因标品的负LC/MS(Negative LC/MS)谱的图。
参照图2,奥瑞因标品的LC/MS谱正模式(Positive mode)为501[M+H]+,LC/MS谱负模式(Negative mode)为477[M-H]-。
1H-NMR(300MHz,DMSO-d6+D2O):δ6.61-6.53(4H in total,H-2',2”,5',5”),6.42-6.37(2H in total,H-6”,6'),4.25(1H,brd,J=7.8Hz,xyl-1),4.13(1H,m,H-5),3.72(1H,dd,J=11.4,6Hz xyl-5e),3.27(1H,m,xyl-4),3.07-2.50(8H in total,H-1,2,4,7),1.66-1.59(2H in total,m,H-6)。
表4
表4为13C-NMR(75MHz,DMSO-d6+D2O)的谱(spectra)。
DPPH自由基消除活性分析
DPPH自由基消除活性通过非专利文献13中公开的方法来进行。
向100μl的按各浓度制备的试样溶液(对照(control):99.5%的乙醇(ethanol))中加入1.9ml的0.1mM DPPH溶液(99.5%的乙醇)。各试样制备成5种浓度。
利用涡旋混合器(Vortex mixer)震荡10秒钟后,在37℃的温度下培养(incubation)30分钟,利用分光光度计(spectrophotometer)在492nm下测定吸光度。
作为阳性对照药物制备5种浓度的L-抗坏血酸(L-ascorbic acid)来测定。各试样的抗氧化作用由IC50值(将DPPH自由基形成抑制为50%时所需的浓度)表示。
ABTS自由基消除活性分析
ABTS自由基消除活性通过修改非专利文献14中公开的方法来测定。
将ABTS(美国西格玛公司(Sigma Co.USA))试剂溶解于蒸馏水来准备成7.0mm的浓度,将过硫酸钾(potassium perdulfate)(美国西格玛公司)溶解于蒸馏水来准备成2.45mM的浓度,并将两个溶液以1:1混合,通过在暗室中放置12~16小时来制备基团原液(radicalstock solution),用磷酸盐缓冲液(PBS buffer)(pH 7.4)稀释所制备的溶液,以使在750nm下测定吸光度时出现0.7~1.0之间的吸光度。
按浓度准备试样,在96孔板(well plate)中,将样品:ABTS反比率应调至1:9来置于暗室反应30分钟,待反应结束后,在750nm的波长下测定吸光度。
准备毛乳头细胞(HFDPC Cell)
毛乳头细胞(HFDPC cell)购自普诺生(PromoCell)(德国海德堡(Heidelberg,Germany))来使用,培养基基于制造商指示(manufacture’s instroduction)选择使用。
毛乳头细胞在保持37℃的温度及5%的CO2的恒温箱(incubator)中培养。
培养基每两天更换一次,在细胞密度达到80~90%之前进行继代培养。解冻冷冻保管的细胞后,仅使用2~3代(passage),使用后,将细胞高压灭菌后丢弃(非专利文献15)。
蛋白质印迹分析(Western blotting)
将细胞用磷酸缓冲盐溶液(PBS)清洗两次,加入裂解缓冲液(lysis buffer)(50mM的三(羟甲基)氨基甲烷(Tris-HCl)[pH 7.4]、1%的NP-40、0.25%的脱氧胆酸钠(sodiumdeoxycholate)、150mM的NaCl、1mM的乙二胺四乙酸(EDTA)、1mM的苯甲基磺酰氟(PMSF)、1mM的原钒酸钠(sodium orthovanadate)、1mM的NaF、1μg/mL的抑肽酶(aprotinin)、1μg/mL的亮肽素(leupeptin)及1μg/mL的抑肽素(pepstatin)),在冰上培养约5分钟后,以14000rpm离心15分钟,取上清液加入十二烷基硫酸钠(SDS)样品缓冲液后,在100℃的温度下加热5分钟来诱导蛋白质变性。
利用10%的十二烷基硫酸钠聚丙烯酰氨凝胶电泳(SDS PAGE)分离蛋白质,将分离的蛋白质移至聚偏二氟乙烯(Polyvinylidene fluoride,PVDF)膜,并利用各个抗体实施蛋白质印迹分析(Western blotting)。所使用的抗体使用了供应商给出的稀释比率,供应商通过圣克鲁斯(Santacruz)(美国犹他州(UT,USA))及韩国西格玛奥德里奇(Sigma-AldrichKorea)购买使用(非专利文献16)。
实施例
奥瑞因的结构鉴别
在TLC板(TLC plate)上,比较基于10%的H2SO4及FeCl3溶液显色和1H、13C-NMR、MS谱数据与非专利文献17,确认分别一致,奥瑞因的结构鉴别利用标品(奥瑞因)(1)来进行最终鉴别。
DPPH及ABTS自由基消除活性(抗氧化活性)
为了检测日本桤木树枝提取物和由此分离的奥瑞因的抗氧化活性,通过两种实验方法,即DPPH自由基消除和ABTS自由基消除测定法,分别比较作为公知为阳性对照组的强的抗氧化剂的维生素C与IC50的抗氧化活性。
图3为示出根据本发明一实施例的DPPH自由基清除作用的测定数据的图,图4为示出根据本发明一实施例的ABTS自由基清除作用的测定数据的图。
参照图3及图4可知,当比较日本桤木树枝提取物和由此分离的奥瑞因与阳性对照组维生素C时,在两种实验中均具有强的抗氧化活性。
具体地,测定日本桤木树枝提取物的DPPH基团消除能力为57.64±0.62ug/ml,ABTS消除能力为13.18±0.11ug/ml。
测定奥瑞因的DPPH基团消除能为14.46±0.08ug/ml,ABTS消除能为4.05±0.04ug/ml.
分别测定作为阳性对照组的维生素C(Vitamin C)的DPPH基团消除能力为18.18±0.10ug/ml,ABTS消除能力为14.96±0.29μg/ml。
当比较日本桤木树枝提取物和由此分离的奥瑞因与阳性对照组时,可知在两种实验中均具有非常强的抗氧化活性。
基于奥瑞因处理的氧化应激诱导的细胞凋亡(oxidative
stress-induced
apoptosis)诱导分子的降低功效
图5为与根据本发明一实施例的奥瑞因的细胞凋亡抑制活性相关的实验数据。
以下,参照图5,将奥瑞因及H2O2处理于Bcl-2相关X蛋白、B淋巴细胞瘤-2、聚腺苷酸二磷酸核糖转移酶-1及半胱天冬酶-3蛋白的情况下,基于Bcl-2相关X蛋白、B淋巴细胞瘤-2、聚腺苷酸二磷酸核糖转移酶-1及半胱天冬酶-3蛋白的表达状态,对奥瑞因的细胞凋亡抑制活性进行说明。
为了测定由为了诱导毛乳头细胞的细胞毒性而处理的过氧化氢(hydrogenperoxide)诱导的细胞凋亡,将600μM的H2O2处理于细胞。
根据非专利文献18及非专利文献19,已知Bcl-2相关X蛋白(B淋巴细胞瘤-2-associated X protein)为代表性的细胞凋亡诱发蛋白质分子。
参照图5,可知H2O2的处理使Bcl-2相关X蛋白分子的表达显著增加。
与此相反,可知按浓度处理的奥瑞因以浓度依赖性地使Bcl-2相关X蛋白的表达显著降低。根据这些结果,证明奥瑞因有效抑制细胞凋亡。
与基于奥瑞因处理的氧化应激诱导的细胞凋亡相关的抑制分子的增加功效
以与上述相同的方法,为了测定由为了诱发毛乳头细胞的细胞毒性而处理的过氧化氢诱导的细胞凋亡,将600μM的H2O2处理于细胞。
根据非专利文献20及非专利文献21,已知B淋巴细胞瘤-2为代表性的参与抗细胞凋亡的蛋白质分子。
参照图5,可知H2O2的处理使B淋巴细胞瘤-2分子的表达显著减少。
与此相反,按浓度处理的奥瑞因以浓度依赖性地使B淋巴细胞瘤-2的表达显著增加。根据这些结果,证明奥瑞因有效抑制细胞凋亡。
由基于奥瑞因处理的氧化应激诱导的细胞凋亡诱导的聚腺苷酸二磷酸核糖转移
酶-1蛋白的表达抑制效果
聚腺苷酸二磷酸核糖转移酶-1存在于细胞的核,通过使用大量的烟酰胺腺嘌呤二核苷酸(NAD)来对靶蛋白诱导聚-二磷酸腺苷核糖基化(poly-ADP ribosylation),由此活化参与下位细胞凋亡的信号传递。
根据非专利文献22及非专利文献23,聚腺苷酸二磷酸核糖转移酶-1的活化用作细胞凋亡进行指标。
参照图5,处理于毛乳头细胞的600μM的H2O2使细胞中聚腺苷酸二磷酸核糖转移酶-1的表达显著增加,这些结果证明使细胞凋亡进行。
与此相反,确认奥瑞因的处理以浓度依赖性地显著抑制聚腺苷酸二磷酸核糖转移酶-1的蛋白表达。根据这些结果,证明奥瑞因有效抑制细胞凋亡。
由基于奥瑞因处理的氧化应激诱导的细胞凋亡诱导的半胱天冬酶-3蛋白的表达
抑制效果
半胱天冬酶-3作为担当细胞的细胞凋亡的最终步骤的分子,是通过上述多种分子的表达和细胞信号传递机制来担当不可逆的细胞死亡(irriversible cell death)的蛋白质。
根据非专利文献24及非专利文献25,半胱天冬酶-3的活化或蛋白质表达量增加的确认用作对细胞凋亡的重要的最终指标。
参照图5,处理于毛乳头细胞的600μM的H2O2使细胞中半胱天冬酶-3的蛋白质表达显著增加,这些结果证明最终进行细胞的凋亡。
与此相反,确认奥瑞因的处理以浓度依赖性地显著抑制半胱天冬酶-3蛋白表达。根据这些结果,证明奥瑞因有效抑制细胞凋亡。
鸣谢
本研究通过由韩国政府(教育部)资助的韩国研究基金会提供支持(社会需求型产学合作领军大学培养项目(LINC+)(社会需求部门重点项目))。
Claims (10)
1.一种用于预防或治疗脱发疾病的药学组合物,其特征在于,包含日本桤木提取物作为有效成分。
2.根据权利要求1所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述日本桤木提取物为日本桤木的枝、叶、果、树皮以及根中的一种以上。
3.根据权利要求1所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述日本桤木提取物包含奥瑞因(oregonin)作为有效成分。
4.根据权利要求3所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述奥瑞因通过减少Bcl-2相关X蛋白的表达来具有对细胞凋亡的抑制活性。
5.根据权利要求3所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述奥瑞因通过增加B淋巴细胞瘤-2的表达来具有对细胞凋亡的抑制活性。
6.根据权利要求3所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述奥瑞因通过减少聚腺苷酸二磷酸核糖转移酶-1来具有对细胞凋亡的抑制活性。
7.根据权利要求3所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述奥瑞因通过减少半胱天冬酶-3的表达来具有对细胞凋亡的抑制活性。
8.根据权利要求3所述的用于预防或治疗脱发疾病的药学组合物,其特征在于,上述奥瑞因具有抗氧化活性。
9.一种用于预防或治疗脱发疾病的化妆品组合物,其特征在于,包含日本桤木提取物作为有效成分。
10.一种用于预防或治疗脱发疾病的食品组合物,其特征在于,包含日本桤木提取物作为有效成分。
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