CN103917232A - 异泽兰黄素的新用途 - Google Patents
异泽兰黄素的新用途 Download PDFInfo
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- CN103917232A CN103917232A CN201280046194.8A CN201280046194A CN103917232A CN 103917232 A CN103917232 A CN 103917232A CN 201280046194 A CN201280046194 A CN 201280046194A CN 103917232 A CN103917232 A CN 103917232A
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- eupatilin
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Abstract
本发明提供一种异泽兰黄素的医药及/或食品用途,所述异泽兰黄素用于治疗、改善及/或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病。根据本发明,不存在或较少存在有副作用的可能性,能够有效地治疗、改善及/或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病。
Description
技术领域
本发明涉及一种异泽兰黄素的新用途,更详细说是涉及一种异泽兰黄素的对于骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)等因雌激素不足引起的疾病或症状的治疗、改善或预防用途。
背景技术
异泽兰黄素(eupatilin)被认为是可作为炎症性肠疾病治疗剂来使用(参照韩国专利第10-0414453号),其可以阻止作为Ras致癌基因的活化所必需的酶的法呢基转移酶的活性及血管生成,可作为致癌基因表达抑制剂、抗癌剂、癌转移抑制剂、糖尿病性视网膜病变及角膜移植时生成的新生血管引起的失明的预防剂来使用(参照韩国公开专利特2002-0090672)。并且,在抗癌上,被认为是通过阻止基质金属蛋白酶(Matrix metalloproteinase:MMP)的活性和入侵、移动,可抑制乳腺癌的发展和转移(参照韩国公开专利第10-2006-0121998号)。
另外,雌激素(estrogen)是在卵巢生产的激素,指的是具有碳数为18个的甾烷核的甾类化合物,一般所公知的有雌素酮E1、雌二醇E2、雌三醇E3三个种类。除了调节生理周期的功能以外,雌激素还可在多个脏器起到多种作用。例如,在肝调节胆固醇生产,在骨中维持骨密度,并作用于子宫壁的成熟。并且,最近发现在神经细胞的生存和脂肪生成过程中也起到重要的作用。
当上述的雌激素在绝经期因卵巢功能的停止而使其在体内的浓度降低时,血中的雌激素减少,引起包含热潮红、发汗、失眠症、抑郁症及头痛等的通常的更年期障碍,并且因骨密度降低而可能发生骨疾病。并且,由于体内的雌激素的减少,在血管系统中形成斑块(plaque)的危险将会增大,引起粥样硬化症等心血管疾病,神经细胞的损伤引起的帕金森病和阿耳滋海默氏病等退行性脑疾病增加,并会引起因脂肪生成过程的调节失控导致的肥胖(Deroo BJ,Korach KS.(2006)“Estrogen receptors and human disease”J Clin Invest.Mar;116(3):561-70.PMID:16511588)。
为了改善如上所述的雌激素减少引起的更年期障碍等,使用投入动物源性雌激素的激素疗法,但是通过WHI(Women's health initiative,妇女健康倡议协会)的广泛随机-安慰剂-控制研究发表,报告了其具有乳腺癌、心血管疾病、中风、血液凝结等潜在的副作用(Rossouw JE,Anderson GL,Prentice RL,et al.(2002)."Risks and benefits of estrogen plus progestin in healthy postmenopausalwomen:principal results From the Women's Health Initiative randomizedcontrolled trial".JAMA288(3):32133.PMID12117397,Anderson GL,LimacherM,Assaf AR,et al.(2004)."Effects of conjugated equine estrogen inpostmenopausal women with hysterectomy:the Women's Health Initiativerandomized controlled trial".JAMA291(14):170112.PMID15082697)。
因此,亟待开发出不存在或较少存在如上所述的副作用可能性,表现出雌激素效果而对因雌激素不足引起的骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)等表现出效果的物质。
发明内容
技术问题
本发明所要解决的技术课题在于提供一种不存在或较少存在有癌等副作用的可能性,表现出雌激素效果而对因雌激素不足引起的骨疾病(bonedisease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovasculardisease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)等表现出效果的物质的新用途。
技术方案
本发明人发现,由如下的化学式1表示的异泽兰黄素不存在或较少存在有副作用可能性,并表现出雌激素活性,从而完成了本发明。
化学式1
在本发明中,“雌激素活性”指的是表现出与包括人类的哺乳动物的体内生成的雌激素所表现出的生理活性相同或类似的活性。
本发明提供一种异泽兰黄素的医药及/或食品用途,其用于治疗、改善及/或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病。
并且,本发明还提供一种药物组合物,用于治疗或预防选自骨疾病(bonedisease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovasculardisease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病,该药物组合物包含作为活性成分的异泽兰黄素(eupatilin)。
所述异泽兰黄素是由化学式1表示的公知的化合物,其可以是合成的,也可以是从含有异泽兰黄素的天然物分离的,还可以是自己制备或在市场上销售的。所述异泽兰黄素可以是其药物学上可接受的盐的形态,除此之外也可以是溶剂化物、前体药物。
所述选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病是起因于雌激素不足,所述雌激素不足是起因于卵巢切除或绝经中的至少一种。
所述骨疾病是选自骨多孔症、骨减少症或牙周疾病中的至少一种。
所述心血管疾病是粥样硬化症。
所述退行性脑疾病是选自帕金森病或阿耳滋海默氏病中的至少一种。
所述治疗或预防是由异泽兰黄素的雌激素活性实现,所述雌激素活性是选择性雌激素活性。
所述选择性雌激素活性表现出雌激素活性,且选择性地抑制癌细胞增殖,所述癌细胞是乳腺癌细胞或子宫内膜癌细胞。
所述雌激素活性是由异泽兰黄素对于雌激素受体β的拮抗(agonist)作用实现,优选地是由作为组织选择性拮抗剂的作用实现。所述“组织选择性拮抗剂”是表示按组织选择性地起到拮抗作用。
所述骨疾病的治疗或预防是由异泽兰黄素的骨形成因子活性增加实现。
本发明的组合物针对组合物总重量,包括0.1-99.9%重量%的所述活性成分。
并且,本发明还提供一种食品组合物,用于改善或预防选自骨疾病(bonedisease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovasculardisease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病,该食品组合物包含作为活性成分的异泽兰黄素(eupatilin)。
除非有另外说明,本发明的药物组合物中提及的内容在不矛盾的情况下,同样适用于所述食品组合物。所述“改善”包括于“治疗”,表示状态或症状好转。
所述食品组合物可多样地包含于包括饮料的食品,可以是饮料、口香糖、茶、健康功能食品等形态,所述健康功能食品可以由锭剂、胶囊剂等剂型进行制剂化。所述健康功能食品指的是基于韩国健康功能食品相关的法律第10219号的使用具有对人体有用的功能性的原料或成分并制造(包括加工。以下等同)的食品,“功能性”指的是对于人体的结构及功能,调节营养素或生理性作用等取得对于保健用途有用的效果。所述食品组合物可包括通常的食品添加物,所述食品添加物可举例有酮类、甘氨酸、枸橼酸钠、烟碱酸、肉桂酸等化学性合成物,柿子色素、甘草萃取物、结晶纤维素、高粱色素、瓜胶等天然添加物,L-谷氨酸钠制剂、面类碱性添加剂、保存剂、焦油色素制剂等混合制剂类型。
本发明还提供一种用于治疗或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病的方法,其包括向需要使用异泽兰黄素的包括人类的哺乳动物使用异泽兰黄素的步骤,并提供一种异泽兰黄素在制备用于治疗或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病的制剂的用途。所述使用的异泽兰黄素可以是有效量的异泽兰黄素。
除非有另外说明,本发明的药物组合物中提及的内容在不产生矛盾的情况下,也同样适用于本发明的方法及用途。
所述异泽兰黄素或组合物可以口服或非肠道的方式使用于包括人类的哺乳动物,可将活性成分与药物学中可接受的载体一起配合并制剂化而进行使用。在制剂化的情况下,可使用一般使用的填充剂、增量剂、粘合剂、湿润剂、崩解剂及表面活性剂等稀释剂或赋形剂。用于口服使用的固形制剂包括锭剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固形制剂通过在本发明的组合物中添加至少一个以上的赋形剂,例如添加淀粉、碳酸钙、蔗糖、乳糖及/或明胶等来制备。并且,还使用有镁、滑石等润滑剂。用于口服使用的液态制剂有悬浮剂、内服液剂、乳剂及糖浆剂等,除了经常使用的单纯稀释剂的水、液状石蜡以外,还可包括多种赋形剂,例如湿润剂、甜味剂、芳香剂及/或保存剂等。用于非肠道使用的制剂包括可注射的液剂、悬浮剂、乳剂、冻结干燥剂、鼻腔洗涤剂及栓剂。可注射的液剂、悬浮剂、乳剂可通过将水、无水溶剂或悬浮溶剂和活性成分混合而制备,作为无水溶剂和悬浮溶剂可以是丙二醇、聚乙二醇、橄榄油等植物油、油酸乙酯等可注射酯等。作为栓剂的基剂可使用witepsol、macrogol、吐温61(tween61)、可可脂、月桂油、甘油及/或明胶等。在非肠道使用时,可通过静脉注射或肌内注射进行使用。
在本发明的组合物中包括或在用途及方法中使用的异泽兰黄素,以成人女性为基准,可以1天0.0001~100mg/kg,优选地以0.001~10mg/kg的用量使用。可以一天使用一次或分为多次使用。但是,本发明的范围并非限定于上述使用量及使用次数。
所述异泽兰黄素可通过添加药物学上或食品学上可接受的载体、赋形剂或稀释剂等来进行制剂化,关于制剂化的内容可参照Remington's PharmaceuticalScience(最新版),Mack Publishing Company,Easton,PA等文献。
有益效果
根据本发明,不存在或较少存在副作用可能性,能够有效地治疗、改善及/或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病。
附图说明
图1是用于确认雌二醇E2对乳腺癌细胞(MCF-7细胞株)造成的影响的荧光素酶实验结果图表;
图2是用于确认雌二醇E2对子宫内膜癌细胞(Ishikawa(石川)细胞株)造成的影响的荧光素酶实验结果图表;
图3是用于确认异泽兰黄素对乳腺癌细胞(MCF-7细胞株)造成的影响的荧光素酶实验结果图表;
图4是用于确认异泽兰黄素对子宫内膜癌细胞(Ishikawa(石川)细胞株)造成的影响的荧光素酶实验结果图表;
图5是用于确认雌激素对骨细胞造成的影响的荧光素酶实验结果图表;
图6是用于确认异泽兰黄素对骨细胞造成的影响的荧光素酶实验结果图表。
具体实施方式
以下,通过实施例及制备例对本发明进行更加详细的说明,但是以下的实施例及制备例仅是用于例示本发明,因此,本发明的内容并不受限于以下的实施例或制备例。
<实施例1>异泽兰黄素的雌激素活性的确认
表现出雌激素活性的物质对于因雌激素不足引起的骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)有效已是众所周知(参照Estrogen receptors and human disease.Deroo BJ,Korach KS.J ClinInvest.2006Mar;116(3):561-70.Review.PMID:16511588)。因此,通过在以下的实验中确认异泽兰黄素在多种雌激素反应细胞(estrogen responsive cell)表现出与雌激素类似的活性,来确认异泽兰黄素对于骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)等有效。
1-1.异泽兰黄素的制备
由白南仁教授(庆熙大学,韩国)提供了通过公知的方法(参照Inhibitoryeffect of eupatilin and jaceosidin isolated from Artemisia princeps oncarrageenan-induced inflammation in mice.J Ethnopharmacol.2009Sep25;125(3):497-500.等)从江华艾蒿分离、提炼后,经确认结构及纯度而制备的异泽兰黄素(5,7-dihydroxy-3’,4’,6-trimethoxyflavone;CAS Registry Number:22368-21-4)。具体说,将在韩国江华岛地区采集的魁蒿为凭证标本(voucherspecimen)(KHUO5067)存放于庆熙大学天然物化学实验室。将与所存放的标本(specimen)相同种类的魁蒿利用80%酒精萃取并在减压状态下蒸发后,悬浮于水,并用乙酸乙酯(EtOAc)萃取。将该乙酸乙酯馏分以正己烷(n-hexane)和乙酸乙酯(EtOAc)的分级式梯度(7:1,5:1,3:1,1:1,v/v)色谱法分析于硅胶(siica gel)(4cm×20cm)上,取得20个馏分(SSE-1~SSE-20)。将馏分16(SSE-16)利用CHCl3-MeOH(30:1,v/v)再进行分馏,取得化合物1(compound1)(SSE-16-4)。通过物理化学性质、光谱分析和与现有文献的比较,compound1被确认为是异泽兰黄素。利用HPLC系统(Young Lin仪器,韩国)分析的纯度为95%以上。异泽兰黄素:呈黄色的粉末。mp226-228℃;IR(KBr,cm-1)3390,3266,1655,1514;EI-MS m/z(70eV):344[M+]
1-2.细胞的准备
从ATCC(American Type Culture Collection美国标准菌库)取得MCF-7(雌激素受体阳性人乳腺癌细胞株)、Ishikawa(雌激素受体阳性子宫内膜癌细胞株)、MG-63(人骨肉瘤(osteosarcoma);成骨(osteoblast)样细胞株)。BG-1(子宫癌细胞株)由Dr.Korach(NIH,美国)提供。在含有10%胎牛血清(fetal bovine serum;FBS)、100U/ml青霉素及100U/ml链霉素的达尔伯克氏改良伊格尔培养基(Dulbecco's modified Eable's medium;DMEM)中,在37摄氏度、5%二氧化碳条件下培养。
1-3.荧光素酶实验(luciferase assay)
荧光素酶实验是,通过测量雌激素受体与表现出雌激素活性的物质结合而表现出荧光素酶活性的程度,来判定雌激素活性与否的实验,其通过如下所述的方法进行实验。除非有另外提及,使用了从Gibco(Karlwruhe,德国)购买的试剂。
荧光素酶报告质粒使用了3×ERE TATA luc.(Addgene,Cambridge,美国),为了调节转染率而一同转染了内部控制质粒phRenilla-luciferase-CMV(Promega,Mannheim,德国)。在6孔板以2×105细胞/孔的浓度,在补充有100U/ml青霉素、100mg/ml链霉素、1mM丙酮酸钠、1mM谷酰胺及得到活性炭葡聚糖处理的10%胎牛血清(fetal bovine serum;FBS)的无酚红DMEM(Dulbecco's modified Eable's medium)实施培养。在将细胞培养为50~60%汇合(confulence)后去除培养基,细胞按照制备商的指示在37摄氏度、5%二氧化碳条件下,在含有质粒DNA构造和2μg/ml聚乙烯亚胺(PEI)的无血清OPTI-MEM培养基上放置6小时。转染了每孔1μg的3×ERE TATA luc和100ng的phRL-CMV质粒。
在经过转染期间后,替换为补充有经活性炭葡聚糖处理的10% FBS的无酚DMEM,细胞在进行异泽兰黄素处理之前,在37摄氏度、5%二氧化碳条件下培养了一夜。
在培养18小时后,将培养基替换为含异泽兰黄素的培养基。在24小时后萃取蛋白质,并按照制造商的指示,利用双荧光素酶试剂盒(Dual LuciferaseAssay kit;Promega,Madison,WI)以光度计(luminometer,Molecular devices,Sunnyvale,CA)测量了萤火虫和海肾荧光素酶活性(firefly and Renilla luciferaseactivity)。
将所有实验以3倍数、最少实施了3次。为了荧光素酶实验而制备了总细胞裂解物(lysate),分析了萤火虫荧光素酶活性,并按照制造商(Promega)的指示,标准化为海肾荧光素酶活性。并且,为了降低(knock down)特定蛋白质的细胞数值,制备了将小干扰RNAs(small interfering RNAs;siRNAs)与3×ERE TATA luc及phRL-CMV一同转染的细胞,并与未经siRNA处理的细胞相同地进行了异泽兰黄素等处理。siRNA是使用了从bioneer公司(大田,韩国)购买的,将浓度处理为50nM。siERα表示抑制ERα的表达的siRNA,siERβ表示抑制ERβ的表达的siRNA。
为了进行比较,将用作为雌激素的17-β-雌二醇(以下,简称为E2)来代替异泽兰黄素进行处理的群为比较群,并将除了未进行异泽兰黄素或E2处理以外,与异泽兰黄素处理群相同地进行处理的未处理群作为对照群。
异泽兰黄素和E2处理浓度记载于以下的表,将对于未处理群的荧光素酶活性设定为基准值1,并在表中示出相对的倍数。
以下表中示出对于各种细胞的荧光素酶实验结果。表1为对于MCF7细胞株的结果,表2为对于BG-1细胞株的结果,表3为对于Ishikawa细胞的结果,表4为对于MG63细胞株的结果。
[表1]
[表2]
[表3]
[表4]
根据上述结果可知,异泽兰黄素在多种作为雌激素反应细胞(estrogenresponsive cell)的乳腺癌细胞、子宫癌细胞、子宫内膜癌细胞、成骨细胞等中,表现出与作为雌激素的雌二醇E2类似的活性。
根据上述结果可知,表现出雌激素活性的异泽兰黄素对于因雌激素不足引起的骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)等的治疗、改善及/或预防有效。
<实施例2>基于异泽兰黄素的选择性雌激素活性的副作用抑制效果的确认
通过如下的实验,确认了异泽兰黄素可抑制现有的表现出雌激素活性的动物源性雌激素活性物质可能会引发的如癌等副作用的效果。
2-1.癌细胞增殖抑制效果的确认
通过MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐;Sigma-Aldrich)实验(assay)计算出细胞存活率,确认了异泽兰黄素的癌细胞增殖抑制效果。
将MCF7乳腺癌细胞植种于96-孔板后,培养了24小时。用10-8M、10-7ME2或0.1μg/ml、1μg/ml异泽兰黄素处理了细胞48小时。在采集日,将50μeMTT溶液(PBS中5mg/ml)添加到培养基,并在37摄氏度条件下培养了4小时。去除含MTT培养基,将细胞在DMSO(100ul)溶解了30分钟。利用微孔板分光光度计(SpectraMax;Molecular Devices,Sunnyvale,CA)在540nm光学密度(optical density)下确定了细胞存活率。
对于E2处理群的对照群设为作为媒介(vehicle)的乙醇(ethanol),对于异泽兰黄素(eupatilin)处理群的对照群设为DMSO。
将对于对照群的值设为100,存活率表示的是相对比率,致死率也表示在将对于对照群的值设为100时的相对比率。
将其结果示出于以下表。表5示出雌二醇E2处理时乳腺癌细胞株的存活率确认结果,表6示出异泽兰黄素处理时乳腺癌细胞株的致死率确认结果。
[表5]
[表6]
2-2.癌细胞增殖抑制机理(mechanism)的确认
利用上述1-3.中实施的荧光素酶实验中对于siRNA处理的癌细胞的结果,通过确认异泽兰黄素对于以siERα处理来抑制ERα的表达的癌细胞或是以siERβ处理来抑制ERβ的表达的癌细胞的影响,来试图阐明癌细胞增殖抑制机理。E2是针对进行了10-7M浓度处理的情况,异泽兰黄素是针对进行了0.1及1.0μg/ml浓度处理的情况。
将其结果示出于图1~图4。
图1示出对于乳腺癌细胞(MCF-7细胞株)的雌激素E2处理结果,图2示出对于子宫内膜癌细胞(Ishikawa细胞株)的雌激素E2处理结果,图3示出对于乳腺癌细胞(MCF-7细胞株)的异泽兰黄素处理结果,图4示出对于子宫内膜癌细胞(Ishikawa细胞株)的异泽兰黄素处理结果。在图1~图4中,CON表示siRNA未处理群,siERα表示抑制ERα的siRNA处理群,siERβ表示抑制ERβ的siRNA处理群。并且,在图1~图2中,-表示E2未处理,+表示E2处理,在图3~图4中,-表示异泽兰黄素未处理,0.1、1分别表示异泽兰黄素0.1、1.0μg/ml浓度处理。
如图1~图4所示,雌激素E2在乳腺癌细胞和子宫内膜癌细胞中仅将ERα作为细胞增殖因子,主要诱导细胞增殖,而异泽兰黄素对于ERα和ERβ两者均起到作用。即,异泽兰黄素在癌细胞中除了对于雌激素受体α(ERα)以外,还对于雌激素受体β(ERβ)作用为拮抗剂(agonist)。
根据上述2-1.和2-2.的结果可知,异泽兰黄素与雌二醇不同可以抑制癌细胞增殖,这是因为雌二醇主要作用于ERα,而异泽兰黄素在乳腺癌细胞和子宫内膜癌细胞等中对于ERβ也起到作用,从而抑制ERα的作用并抑制癌细胞的增殖。这也是得到了现有研究结果的支持(参照Deroo BJ,Korach KS.(2006)“Estrogen receptors and human disease”J Clin Invest.Mar;116(3):561-70.PMID:16511588)。
由此可知,异泽兰黄素诱发乳腺癌、子宫内膜癌等的可能性少或低,相反的对其进行抑制,具有减少或消除如雌二醇的雌激素所表现出的副作用的可能性。
<实施例3>异泽兰黄素的骨损失抑制效果的确认
通过确认异泽兰黄素具有在骨细胞中增加骨密度的效果,通过以下的方法确认了对于因雌激素不足引起的骨疾病如骨多孔症、骨减少症或牙周疾病有效。
3-1.异泽兰黄素在骨细胞中的骨密度增加的确认
通过在经异泽兰黄素处理的MG-63细胞中检测ALP活性,确认了异泽兰黄素在骨细胞中增加骨密度。成骨细胞在细胞分化时特定地表现出碱性磷酸酶(Alkaline phosphatase;ALP)活性,因此,可通过检测ALP活性来确认成骨细胞的细胞分化与否和其程度。利用ALP将对硝基苯酚磷酸盐(p-nitrophenylphosphate)分解为对硝基苯酚(p-nitrophenol)和磷酸盐(phosphate),计算为各个物质对于在405nm下的对照群的吸光度的吸光度的比值来测量ALP活性,从而观察了对于成骨细胞的影响。
具体说,在植种MG-63细胞后稳定18小时后,E2以10-7M、异泽兰黄素以0.2、2.0μg/ml浓度进行了处理。在处理24小时后,制备裂解物(lysate)并缓慢地摇动30分钟,通过检测对硝基苯酚在对硝基苯酚磷酸盐(在pH9.8条件下用MgCl2补充的1M二乙醇胺缓冲液中的20mM)中的游离来实验了ALP活性。在405nm下检测了吸光度。利用0~0.1U/ml PBS-T范围中多种浓度的牛血清白蛋白(bovine serum albumin;BSA;Sigma)浓度制作了检量线。用对应的细胞裂解物中蛋白质浓度校正了ALP数值。通过BCA蛋白实验(bicinchoninic acid protein assay;Thermo Scientific)定量了培养蛋白质含量。将得到的结果与仅添加了100nM浓度的BSA而未添加试料的对照群进行了比较。
将其结果示出于以下表7。表7为确认了异泽兰黄素在MG-63细胞株中对ALP活性造成的影响的结果。
[表7]
通过表7所示可知,异泽兰黄素与雌激素E2相同地在骨细胞中增加ALP活性,并且如此的活性增加依赖于浓度。
通过骨细胞中的ALP活性增加可知,成骨细胞活跃地进行分化。因此可知,异泽兰黄素对于因雌激素不足引起的骨疾病如骨多孔症、骨减少症或牙周疾病有效。
3-2.骨细胞中异泽兰黄素的骨密度增加机理的确认
利用对于上述1-3.中实施的荧光素酶实验中进行siRNA处理的MG-63的结果,通过确认异泽兰黄素对于进行siERα处理而抑制了ERα的表达的骨细胞,或是对于进行siERβ处理而抑制了ERβ的表达的骨细胞的影响,来尝试确认癌细胞增殖抑制机理。E2是针对进行了10-7M浓度处理的情况,异泽兰黄素是针对进行了0.1、1.0μg/ml浓度处理的情况。
将其结果示出于图5~6。图5示出雌激素E2处理结果,图6示出异泽兰黄素处理结果。在图5和图6中,CON表示siRNA未处理群,siERα表示抑制ERα表达的siRNA处理群,siERβ表示抑制ERβ表达的siRNA处理群。并且,在图5中,-表示E2未处理,+表示E2处理,在图6中,-表示异泽兰黄素未处理,+表示异泽兰黄素处理。
如图5~6所示可知,与在骨细胞中雌激素E2选择性地作用于ERβ的情况相同地,异泽兰黄素也选择性地作用于ERβ。从雌激素E2选择性地作用于ERβ并在骨细胞中增加骨密度(参照Medicarpin,a legume phytoalexin,stimulates osteoblast differentiation and promotes peak bone mass achievement inrats:evidence for estrogen receptorβ-mediated osteogenic action of medicarpin,JNutr Biochem.2011,PMID:21333515;Estrogen receptor-beta modulates synthesisof bone matrix proteins in human osteoblast-like MG63cells.J Cell Biochem.2003PMID:12682916)可知,异泽兰黄素也将选择性地作用于ERβ并在骨细胞中增加骨密度。即,异泽兰黄素在骨细胞中对于雌激素受体β作用为拮抗剂(agonist),特别是作用为在骨等器官中选择性地作用的器官选择性拮抗剂。
从上述3-1和3-2的结果可知,异泽兰黄素在骨细胞中与雌激素E2相同地选择性地作用于ERβ,在骨细胞中增加骨密度。
由此可知,异泽兰黄素对于因雌激素不足引起的骨疾病如骨多孔症、骨减少症或牙周疾病有效。
其结果,如实施例1~3所述可知,异泽兰黄素以器官选择性地起到作用,使雌激素如雌二醇所表现出的副作用的可能性低或不存在,同时对于骨疾病等有效。
由此可知,异泽兰黄素对于选自包括骨多孔症、骨减少症或牙周疾病等的骨疾病(bone disease)、更年期障碍(menopausal disorder)、包括粥样硬化症等的心血管疾病(cardiovascular disease)、包括帕金森病或阿耳滋海默氏病等的退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病的治疗、改善及/或预防有效。
<制备例1>药学组合物的制备
将按照与实施例1-1相同的方法准备的异泽兰黄素300mg、玉米淀粉100mg、乳糖100mg、硬脂酸镁2mg填充于明胶胶囊以制备胶囊剂。
<制备例2>食品组合物的制备
在按照与实施例1-1相同的方法准备的异泽兰黄素(4重量%)、液态果糖(0.5重量%)、寡糖(2重量%)、白糖(2重量%)及盐(0.5重量%)中添加水对准残余量后,均质地进行混合并瞬时灭菌,从而制备了健康饮料。
工业利用性
本发明不存在或较少存在有癌等副作用,并且可对于选自骨疾病(bonedisease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovasculardisease)、神经退行性疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病有效地进行治疗、改善及/或预防,因此具有工业利用性。
Claims (13)
1.一种药物组合物,用于治疗或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病,该药物组合物包含作为活性成分的异泽兰黄素(eupatilin)。
2.根据权利要求1所述的药物组合物,其中所述选自骨疾病(bonedisease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovasculardisease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病是起因于雌激素不足。
3.根据权利要求2所述的药物组合物,其中所述雌激素不足是起因于卵巢切除或绝经中的至少一种。
4.根据权利要求1所述的药物组合物,其中所述骨疾病是选自骨多孔症、骨减少症或牙周疾病中的至少一种。
5.根据权利要求1所述的药物组合物,其中所述心血管疾病是粥样硬化症。
6.根据权利要求1所述的药物组合物,其中所述退行性脑疾病是选自帕金森病或阿耳滋海默氏病中的至少一种。
7.根据权利要求1所述的药物组合物,其中所述治疗或预防是由异泽兰黄素的雌激素活性实现。
8.根据权利要求7所述的药物组合物,其中所述雌激素活性是选择性雌激素活性。
9.根据权利要求8所述的药物组合物,其中所述选择性雌激素活性表现出雌激素活性,且选择性地抑制癌细胞增殖。
10.根据权利要求9所述的药物组合物,其中所述癌细胞是乳腺癌细胞或子宫内膜癌细胞。
11.根据权利要求7至10中任一项所述的药物组合物,其中所述雌激素活性是由异泽兰黄素对于雌激素受体β的拮抗(agonist)作用实现。
12.根据权利要求1所述的药物组合物,其中所述骨疾病的治疗或预防是由异泽兰黄素的骨形成因子活性增加实现。
13.一种食品组合物,用于改善或预防选自骨疾病(bone disease)、更年期障碍(menopausal disorder)、心血管疾病(cardiovascular disease)、退行性脑疾病(neurodegenerative disease)或肥胖(Obesity)中的至少一种疾病,该食品组合物包含作为活性成分的异泽兰黄素(eupatilin)。
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CN110496120A (zh) * | 2019-09-09 | 2019-11-26 | 南开大学 | 表皮生长因子受体拮抗剂及其应用 |
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