CN104411310A - 山柰小花提取物或黄酮类化合物的肌肉疾病预防或治疗及肌肉功能改善用途 - Google Patents
山柰小花提取物或黄酮类化合物的肌肉疾病预防或治疗及肌肉功能改善用途 Download PDFInfo
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Abstract
本发明涉及包含山柰小花(Kaempferia parviflora Wall.ex Baker)提取物的用于治疗肉疾的药物组合物,更详细地说,涉及包含山柰小花提取物或由其分离的黄酮类化合物作为有效成分的用于治疗肌肉疾病的药物组合物或用于改善肌肉功能的食品组合物。本发明的山柰小花提取物及由其分离的黄酮类化合物减少肌肉内蛋白质的异化作用、增加肌肉细胞分化及同化作用,从而在制造用于治疗肌肉疾病的药物组合物或用于改善肌肉功能的食品组合物方面有效。
Description
技术领域
本申请主张2012年5月16日申请的韩国专利申请第10-2012-0051776号(申请号)的优先权,将上述说明书的全部内容作为本申请的参考文献。
本发明涉及山柰小花(Kaempferia parviflora Wall.ex Baker)提取物或黄酮类化合物在预防或治疗肌肉疾病中的用途,更详细地说,涉及包含山柰小花提取物或由其分离的黄酮类化合物作为有效成分的用于治疗肌肉疾病治疗的药物组合物、用于改善肌肉功能的食品组合物。
背景技术
据统计,通常在65-70岁的人口中有约24%的人经历由老化引起的肌萎缩,其中有20%左右的人丧失肌肉功能(J.Gerontol.A Biol.Sci.Med.Sci.60(2):21316,2005)。随着身体老化,涉及合成蛋白质的作用、即同化作用(anabolism)的成长激素、性激素、类胰岛素成长因子等激素分泌减少,肌肉的蛋白质合成降低,循环炎症性细胞因子(cytokine)、尤其肿瘤坏死因子-α(tumor necrosis factor-;TNF-)的数值增加。导致肌肉纤维的再生能力下降的主要原因在于,作为炎症性细胞因子之一的TNF-α与受损的肌肉纤维融合或抑制分化,分解肌肉内蛋白质的作用、即异化作用(catabolism)得到促进,其结果,引起骨骼肌组织的损失(Clin.Nutr.26(5):52434,2007)。
作为由老化引起的慢性炎症,诱发肌萎缩的主要信号转导体系、即forkheadbox(foxo)通路被活化的话,涉及蛋白质分解的E3ubiquitin ligase、即atrogin-1和MuRF1的表达增加(Cell Metab.6(6):47283,2007)。另一方面,PI3K/AKT信号传递通路抑制foxo的活性,使蛋白质合成相关因子、即mammalian target of rapamycin(mTOR)活化,诱导肌肉成长(Int.J.Biochem.Cell Biol.37(10):1985-96,2005)。尤其,PI3K/AKT及mTOR作为通过运动而活化的信号机构,能够对增加肌肉量、提高运动能力发挥作用(Acta.Physiol.(Oxf).191(1):67-75,2007)。
肌肉细胞分化通过myoD、myf5、myogenin、mrf4这类的多种肌肉调节因子(muscleregulatory factors;MRFs)来调节。MyoD表示肌肉特异基因的表达,诱导间充质干细胞分化为肌肉细胞系列。Myogenin表达的诱导通过myoD活性来调节。受损的肌肉细胞的再生能够预防或治疗由老化或慢性炎症引起的肌萎缩症(J.Histochem.Cytochem.54(11):1177-91,2006)。
由老化引起的肌萎缩不只是肌肉功能自身的问题,还与骨多孔症、其他疾病的转移、落伤造成的负伤等紧密相关。而且,为了尽可能地抑制由老化引起的肌肉量的损失,尽早进行适当的运动和营养治疗非常重要(Exp.Gerontol.37(4):477-89,2002)。
发明内容
对来自天然物的肌肉功能调节物质进行研究的结果,发现山柰小花(Kaempferiaparviflora Wall.ex Baker)提取物及其包含的黄酮类化合物具备减少肌肉内蛋白质异化作用、增加肌肉细胞分化及同化作用的活性,从而完成了本发明。
本发明的目的在于,提供一种用于预防或治疗肌肉疾病的药物组合物,其包含山柰小花(Kaempferia parviflora)提取物作为有效成分。
本发明提供一种用于预防或治疗肌肉疾病的药物组合物,其包含下述化学式4所示的化合物或其盐作有效成分。
[化学式4]
在上述化学式4中,R1、R2及R3分别表示氢或甲氧基(methoxy)。
本发明提供一种用于改善肌肉功能或增强运动执行能力的食品组合物,其包含山柰小花提取物作为有效成分。
本发明提供一种用于改善肌肉功能或增强运动执行能力的食品组合物,其包含上述化学式4所示的化合物或其盐作为有效成分。
用于解决课题的手段
为了实现上述本发明的目的,本发明提供一种用于预防或治疗肌肉疾病的药物组合物,其包含山柰小花(Kaempferia parviflora)提取物作为有效成分。
为了实现本发明的另一目的,本发明提供一种用于预防或治疗肌肉疾病的药物组合物,其包含上述化学式4所示的化合物或其盐作为有效成分。
为了实现本发明的另一目的,本发明提供一种用于改善肌肉功能或增强运动执行能力的食品组合物,其包含山柰小花提取物作为有效成分。
为了实现本发明的另一目的,本发明提供一种用于改善肌肉功能或增强运动执行能力的食品组合物,其包含上述化学式4所示的化合物或其盐作为有效成分。
下面详细说明本发明。
本发明提供一种用于预防或治疗肌肉疾病的药物组合物,其包含山柰小花(Kaempferia parviflora)提取物作为有效成分。
上述提取物没有特别限定,可以是山柰小花(Kaempferia parviflora)的根茎提取物。
山柰小花是姜科(Zingiberaceae family)植物的一种,又称为黑姜(blackginger)。
本发明的山柰小花提取物可以利用公知的天然物提取方法来提取,优选利用选自由水、碳原子数为1-6的有机溶剂和亚临界或超临界流体组成的组中的一种以上的溶剂来提取,更优选碳原子数为1-6的醇类水溶液。上述碳原子数为1-6的有机溶剂可以选自由碳原子数1-6的醇(alcohol)、丙酮(acetone)、醚(ether)、苯(benzene)、三氯甲烷(chloroform)、乙酸乙酯(ethyl acetate)、二氯甲烷(methylene chloride)、己烷(hexane)、环己烷(cyclohexane)及石油醚(petroleum ether)组成的组。
另外,本发明的山柰小花提取物可以利用适于食品加工的精制水、乙醇和亚临界水或超临界二氧化碳对经过干燥的山柰小花根茎进行提取、精制来得到,或者可以从直接将山柰小花植物压榨而得的油分离并精制来得到。
本发明提供一种用于预防或治疗肌肉疾病的药物组合物,其包含上述化学式4所示的化合物或其盐作为有效成分。
上述化学式4的化合物优选选自由5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮及3,5,7,3’4’-五甲氧基黄酮组成的组。
上述5,7-二甲氧基黄酮(5,7-dimethoxyflavone)、5,7,4’-三甲氧基黄酮(5,7,4'-trimethoxyflavone)、3,5,7,3’4’-五甲氧基黄酮(3,5,7,3’,4’-pentamethoxyflavone)是均属于黄酮类化合物的化合物。
在本发明的组合物中,上述5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮、及3,5,7,3’4’-五甲氧基黄酮可以通过化学合成方法来合成,或者从山柰小花或其他植物提取后分离而得的。
本发明的上述黄酮类化合物可以以其本身或其盐或其可药用的盐的形态使用。上述“可药用”是指在生理学上容许使用,且在施用于人类时,通常不引起过敏反应或与其类似的反应,作为上述盐,优选为由可药用的游离酸(freeacid)形成的酸加成盐。上述游离酸可以使用有机酸和无机酸。上述有机酸可以包含柠檬酸、乙酸、乳酸、酒石酸、马来酸、富马酸、甲酸、丙酸、草酸、三氟乙酸、苯甲酸、葡萄糖酸、间磺酸(metasulfonic acid)、乙醇酸、琥珀酸、4-甲苯磺酸、谷氨酸和天冬氨酸,但并不限于此。另外,上述无机酸可以并不限于此,还可以包含盐酸、溴酸、硫酸和磷酸。
山柰小花是姜科(Zingiberaceae family)植物的一种,也被称为黑姜(Blackginger)。本发明的山柰小花提取物包含黄酮类化合物、特别是大量的5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮、3,5,7,3’4’-五甲氧基黄酮。
在从山柰小花的提取物分离和精制本发明的黄酮类化合物时,可以单独或配合使用填充有硅胶(silica gel)或活性氧化铝(alumina)等各种合成树脂的柱层析和高效液相色谱(HPLC)等,但提取及分离精制方法并不一定限于上述方法。
本发明人证实了山柰小花提取物及由其精制的化学式4的化合物具备肌肉蛋白质异化作用抑制、同化作用促进、肌肉细胞分化促进效果及肌肉量增加效果(参照实验例1至3)。
而且,上述山柰小花提取物及由其精制的化学式4的化合物能够治疗肌肉疾病,上述肌肉疾病是指由肌肉消耗或退化引起的疾病。作为上述疾病的例子,可以举出迟缓症(atony)、肌萎缩症(muscular atrophy)、肌营养不良症(muscular dystrophy)、肌肉退化、肌无力症及肌肉减少症(Sacopenia)。肌肉消耗以肌肉量的渐进性损失、肌肉尤其骨骼肌或随意肌及心脏肌肉的弱化及退化为特征。肌肉消耗及退化由先天性原因、后天性原因、老化等引起。本发明的组合物具备肌肉增加促进效果,肌肉种类没有特别限定。肌肉增加是提高身体成分中的尤其是肌肉的性能,能够通过身体锻炼及持久力提高来增加肌肉量,也可以通过向体内投入具备肌肉增加效果的物质来增加肌肉量。
本发明的药物组合物可以单独包含山柰小花提取物或化学式4所示的化合物,或者可以进一步包含在药物组合物的制造中通常使用的适当的载体、赋形剂或稀释剂。
在将本发明的药物组合物口服施用的情况下,本发明的药物组合物可以根据本领域中公知的方法,与适当的口服施用载体一起剂型化,剂型可以为粉末、颗粒、片剂、丸剂、包衣片剂、胶囊、液剂、胶剂、糖浆、悬浊液、饼剂(wafer)等。作为适当的载体的例子,包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇等糖类;包括玉米淀粉、麦淀粉、米淀粉及土豆淀粉等淀粉类;包括纤维素、甲基纤维素、羧甲基纤维素钠及羟丙基甲基-纤维素等纤维素类;凝胶、聚乙烯吡咯烷酮等填充剂。另外,还可以根据情况,添加交联聚乙烯吡咯烷酮、寒天、海藻酸或海藻酸钠等分裂剂。此外,上述药物组合物可以进一步包含抗凝剂、润滑剂、润湿剂、香料、乳化剂和防腐剂等。
另外,在非口服施用的情况下,本发明的药物组合物可以根据本领域公知的方法,与适当的非口服用载体一起制备成注射剂,剂型化为经皮给药剂及鼻腔吸入剂的形态。在上述注射剂的情况下,必须进行灭菌,以避免受细菌及真菌这类微生物的污染。在注射剂的情况下,作为适当的载体的例子,没有特别限定,可以举出包含水、乙醇、多元醇(例如,甘油、丙二醇及液态聚乙二醇等)、它们的混合物和/或植物油的溶剂或分散介质。作为更优选的载体,可以使用汉克斯液、林格液、三乙醇胺的PBS(phosphatebuffered saline)或注射用灭菌水、10%乙醇、40%丙二醇及5%右旋糖等的等张溶液等。
为了保护上述注射剂不受微生物污染,还可以进一步添加对羟基苯甲酸酯、二氯叔丁醇、苯酚、山梨酸、硫汞撒等各种抗菌剂及抗真菌剂。另外,上述注射剂在大部分的情况下还包含糖或氯化钠等的等张化剂。
在经皮给药剂的情况下,包括软膏剂、霜剂、乳液剂、胶剂、外用液剂、贴膏、肥皂樟脑搽剂、喷雾剂等的形态。上述“经皮给药”是指,将药物组合物局部施用于皮肤,使药物组合物中包含的有效量的活性成分进入到皮肤内部。这些剂型在制药学中通常公知的处方书、即文献(Remington's Pharmaceutical Science,15th Edition,1975,Mack Publishing Company,Easton,Pennsylvania)中有所记载。
在吸入给药剂的情况下,本发明中使用的化合物可以通过适当的推进剂,例如、二氯氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体,由加压包或烟雾机以气雾喷雾(aerosolspray)形态方便地施用。在加压气雾的情况下,给药单位根据施用计测的量的阀来决定。例如,在吸入器或吹入器中使用的明胶胶囊及药筒(cartridge)能够以包含化合物及乳糖或淀粉等适当的粉末基剂的粉末混合物来剂型化。除此之外的可药用的载体可以参考在下述文献中记载的物质(Remington'sPharmaceutical Sciences,19th ed.,Mack Publishing Company,Easton,PA,1995)。
另外,本发明的药物组合物还可以进一步包含一个以上的缓冲剂(例如,食盐水或PBS)、糖类(carbohydrate)(例如,葡萄糖、甘露糖、蔗糖或右旋糖苷)、抗氧化剂、抑霉剂、螯合剂(例如,EDTA或谷胱甘肽)、佐剂(例如,氢氧化铝)、悬浮剂、增稠剂和/或保存剂。
本发明的提取物或化合物的优选用量可以根据患者的状态及体重、患病程度、药物形态、给药路径及期间由本领域技术人员适当选择。但是们为了实现优异的效果,本发明的化合物以0.001至300mg/day/体重kg进行给药,优选以0.01至200mg/day/体重kg进行给药。但是,上述药学上有效的量可根据疾病及其严重程度、患者的年龄、体重、健康状态、性别、给药途径和治疗时间等各种因素来适当改变。
上述“可药用的”是指生理学上容许,且在施用于人类时,不阻碍活性成分的作用,通常不会引起诸如胃肠功能障碍、眩晕之类的过敏反应或与其类似的反应的非毒性组合物。上述载体包括所有种类的溶剂、分散介质、水包油或油包水乳剂、水性组合物、脂质体、微珠(microbead)及微粒体(microsome)。
本发明的组合物可以通过各种路径向大鼠、小鼠、家畜、人类等哺乳动物施用。施用的全部方式几乎都可以想到,可以通过例如口服、直肠或静脉、肌肉、皮下、子宫内硬膜或脑血管内(intracerebroventricular)注射来施用。
本发明提供山柰小花提取物或上述化学式4的化合物或其盐在制备肌肉疾病的预防或治疗剂中的用途。
本发明提供一种预防或治疗肌肉疾病的方法,其特征在于,将山柰小花提取物或上述化学式4的化合物或其盐以有效量施用于需要它的个体。
本发明的山柰小花提取物或上述化学式4的化合物本身或它的可药用的盐,能够以有效量通过包括口服、经皮、皮下、静脉或肌肉的多种路径施用。上述“有效量”是指施用于患者时,能够显现出肌肉疾病的治疗及预防效果的量,上述“个体(subject)”是指动物,优选哺乳动物,尤其包括人类的动物,也可以是来自动物的细胞、组织、器官等。上述个体也可以是需要治疗的患者(patient)。
上述本发明的山柰小花提取物、上述化学式4的化合物或其可药用的盐,可以将其自身直接施用,或者如上所述制备成多种剂型来使用,优选施用直至能够显现所希望的效果、即肌肉疾病预防或治疗效果。本发明的化合物及其可药用的盐可以根据本领域公知的方法以多种路径施用。即,口服或非口服,例如口腔、肌肉内、静脉内、皮内、动脉内、骨髓内、硬膜内、腹腔内、鼻腔内、腔内、直肠内、舌下或皮下施用,或者向胃肠管、粘膜或呼吸机给药。例如,采用直接涂布于皮肤的方法,或将上述多肽制备成注射用剂型,用30规格的细注射针注入一定量到皮肤下层,或者用注射针轻轻地刺入(prick)皮肤的方法,施用本发明的提取物、化合物或其可药用的盐。优选直接涂布到皮肤。另外,本发明的化合物及可药用的盐能够与在靶细胞或组织(例:皮肤细胞或皮肤组织)中诱发高亲和性结合的分子结合或者在上述分子内包装的形态施用。本发明的化合物及可药用的盐能够利用本领域公知的技术,与固醇(例:胆固醇)、基质(例:阳离子基质、病毒小体或脂质体)或靶细胞特异性结合剂(例:由靶细胞特异性受体认知的配体)结合。适当的偶联剂或交联剂包括例如蛋白质A、碳二亚胺、3-(2-吡啶二巯基)丙酸N-羟基琥珀酰亚胺酯(SPDP)等。
这些剂型在制药学中公知的处方书文献(Remington's Pharmaceutical Science,15thEdition,1975,Mack Publishing Company,Easton,Pennsylvania)中有所记载。
另外,本发明提供一种用于改善肌肉功能或增强运动执行能力的食品组合物,包含山柰小花提取物或化学式4的化合物或其盐作为有效成分。
肌肉功能改善是指肌肉量的增加、肌力强化、肌肉疲劳恢复能力等肌肉原本性质或功能的强化。另外,本发明的山柰小花提取物、黄酮类化合物增加PI3K/AKT及mTOR表达量(参照实验例2),这些因素涉及增加肌肉量、提高运动能力(Acta.Physiol.(Oxf).191(1):67-75,2007)。
本发明的食品组合物包括功能性食品(functional food)、营养补充剂(nutritionalsupplement)、保健食品(health food)和食品添加剂(food additives)等所有形态。上述类型的食品组合物可根据本领域中公知的通常的方法来制成各种形态。
例如,作为保健食品,可以将本发明的山柰小花提取物或化学式4的化合物或其盐本身制成茶、果汁和饮料的形态来饮用,或者进行颗粒化、胶囊化及粉末化来摄取。另外,本发明的山柰小花提取物或化学式4的化合物或其盐可以与已知具有肌肉功能增进的效果的公知的物质或活性成分一起混合而制成组合物的形态。
此外,作为功能性食品,可以在饮料(包含酒精性饮料)、水果及其加工食品(例如,水果罐头、瓶装罐、果酱、桔子酱(marmalade)等);鱼类、肉类及其加工食品(例如,火腿、香肠、培根等);面包类和面类(例如,乌冬面、荞麦面、拉面、意大利面、通心粉(macaroni)等);果汁、各种饮料、饼干、麦芽糖、乳制品(例如,黄油、乳酪等);食用植物油脂、人造奶油、植物性蛋白质、蒸煮食品(retortfood)、冷冻食品、各种调味料(例如、大酱、酱油、调味酱等)等中添加山柰小花(Kaempferiaparviflora)提取物或本发明的黄酮类化合物来制造。
本发明的食品组合物中的上述本发明的山柰小花提取物或化学式4的化合物或其盐的优选含量没有特别限定,优选在最终制造的食品中的含量在0.01至100重量%。
另外,为了将本发明的山柰小花提取物或化学式4的化合物或其盐以食品添加剂的形态使用,可以制造成粉末或浓缩液形态来使用。
发明效果
如上所述,本发明的山柰小花提取物及由其分离的黄酮类化合物能够减少肌肉内蛋白质的异化作用、增加肌肉细胞分化及同化作用,从而在制造用于治疗肌肉疾病的药物组合物或改善肌肉功能的食品组合物方面有效。
附图说明
图1示出根据是否使用本发明的5,7-二甲氧基黄酮进行处理,利用RT-PCR,确认在肌肉细胞中,atrogin-1、MuRF1的mRNA表达量是否减少。
图2示出根据是否使用本发明的5,7-二甲氧基黄酮进行处理,利用RT-PCR,确认在肌肉细胞中,myogenin、myoD的mRNA表达量是否增加。
图3示出根据是否使用本发明的5,7-二甲氧基黄酮进行处理,利用免疫印迹,确认在肌肉细胞中,PI3K、p-AKT、p-mTOR的蛋白质表达量是否增加。
图4示出在肌肉细胞中山柰小花提取物增加肌肉分化调节因子、即myogenin及myoD的mRNA表达量的效果。
图5示出在肌肉细胞中山柰小花提取物增加与蛋白质同化作用相关的因子、即PI3K、p-AKT及p-mTOR的效果。
具体实施方式
下面通过实施例进一步详细说明本发明。
但是,下述实施例只是例示性的,本发明的内容不限于下述实施例.
<实施例1>
山柰小花(黑姜)乙醇提取物的制造
用混合器将干燥的山柰小花根茎(rhizome)粉碎后,将粉碎的山柰小花试样100g放入95%的乙醇1L中,在常温下浸泡48小时进行提取。用沃特曼(Whatman)2号滤纸对提取的试样进行过滤,利用真空旋转浓缩机对过滤后的提取液进行浓缩,去除溶剂成分之后,得到山柰小花乙醇提取物(9.56g)。
<实施例2>
从黑姜乙醇提取物分离出黄酮类化合物
<2-1>5,7-二甲氧基黄酮的分离及结构确定
将上述实施例1中得到的浓缩的山柰小花乙醇提取物担载于以6x15cm填充了硅胶的柱内,利用将乙酸乙酯和甲醇以10:0.5(v/v)的比例混合的溶剂体系进行分离。根据上述分离顺序,分离成共5个组分,对各个组分进行浓缩干燥。将5个组分中的第3个组分(组分3)利用Rp-18柱层析(Lichroprep RP-1825~40um,Merck&Co.,美国)以70%甲醇进行分离。根据上述分离顺序,分离成共2个组分并进行浓缩干燥。将上述2个组分中的第2个组分(组分3-2)担载于以6x15cm填充了硅胶的柱内,利用将乙酸乙酯和甲醇以10:0.4(v/v)的比例混合的溶剂体系进行分离,最终使上述2个组分中的第1个组分(组分3-2-1)浓缩干燥,分离出紫外线遮蔽物质。
为了确定上述分离的单一活性物质的结构,在500MHz和125MHz(溶剂:CDCl3)下分别测定1H-NMR谱和13C-NMR谱。本化合物在EI/MS中、在m/z282处观测到[M],从而证明分子量为282。将以上的关于1H-NMR、13C-NMR、及EI/MS的结果与以往发表的研究报告(Sutthanut K.et al.,J.Chromatogr A.,1143:227-233,2007)进行比较分析并鉴定的结果,确认到上述分离的单一物质为下述化学式1所示的5,7-二甲氧基黄酮。
[化学式1]
<2-2>5,7,4’-三甲氧基黄酮的分离及结构确定
将上述实施例1中得到的浓缩的山柰小花乙醇提取物担载于以6x15cm填充了硅胶的柱内,利用将乙酸乙酯和甲醇以10:0.5(v/v)的比例混合的溶剂体系进行分离。根据上述分离顺序,分离成共5个组分,对各个组分进行浓缩干燥。将5个组分中的第4个组分(组分4)利用Rp-18柱层析(Lichroprep RP-1825~40um,Merck&Co.,美国)以70%甲醇进行分离。根据上述分离顺序,分离成共2个组分并进行浓缩干燥。最终使上述2个组分中的第2个组分(组分4-2)浓缩干燥,分离出紫外线遮蔽物质。
为了确定上述分离的单一活性物质的结构,在500MHz和125MHz(溶剂:CDCl3)下分别测定1H-NMR谱和13C-NMR谱。本化合物在EI/MS中、在m/z 312处观测到[M],从而证明分子量为312。将以上的关于1H-NMR、13C-NMR、及EI/MS的结果与以往发表的研究报告(Sutthanut K.et al.,J.Chromatogr A.,1143:227-233,2007)进行比较分析并鉴定的结果,确认到上述分离的单一物质为下述化学式2所示的5,7,4’-三甲氧基黄酮。
[化学式2]
<2-3>3,5,7,3’,4’-五甲氧基黄酮分离
将上述实施例1中得到的浓缩的山柰小花乙醇提取物担载于以6x15cm填充了硅胶的柱内,利用将乙酸乙酯和甲醇以10:0.5(v/v)的比例混合的溶剂体系进行分离。根据上述分离顺序,分离成共5个组分,对各个组分进行浓缩干燥。将5个组分中的第3个组分(组分3)利用Rp-18柱层析((Lichroprep RP-1825~40um,Merck&Co.,美国)以70%甲醇进行分离。根据上述分离顺序,分离成共2个组分并进行浓缩干燥。最终使上述2个组分中的第1个组分(组分3-1)浓缩干燥,分离出紫外线遮蔽物质。
为了确定上述分离的单一活性物质的结构,在500MHz和125MHz(溶剂:CDCl3)下分别测定1H-NMR谱和13C-NMR谱。本化合物在EI/MS中、在m/z372处观测到[M],从而证明分子量为372。将以上的关于1H-NMR、13C-NMR、及EI/MS的结果与以往发表的研究报告(Sutthanut K.et al.,J.Chromatogr A.,1143:227-233,2007)进行比较分析并鉴定的结果,确认到上述分离的单一物质为下述化学式3所示的3,5,7,3’,4’-五甲氧基黄酮。
[化学式3]
<实验例1>
在细胞模型中,肌肉内蛋白质异化作用减少效果
在DMEM(10%FBS,100U/mL penicillin,100g/mL streptomycin)中培养作为肌肉细胞的L6myoblast(American Type Culture Collection,Manassas,VA,USA)。当细胞密度达到约80~85%时,将细胞培养基更换为添加了2%的FBS的DMEM成长培养基,进行了6天分化后,进行实验。为了在分化的L6细胞中诱导肌肉减少,对TNF-α处理24小时之后,按照浓度(1,5μM)对在上述实施例2-1中制造的5,7-二甲氧基黄酮进行处理。为了确认与肌肉内蛋白质异化作用相关的主要ligase、即atrogin-1和MuRF1的mRNA表达量,执行了RT-PCR。从分化的细胞,使用TRIzol试剂(Invitrogen,Carlsbad,CA,USA),收获总RNA,进行了逆转录之后,按照如下方式进行RT-PCR分析。首先,为了cDNA合成,用reverse transcriptase将上述RNA逆转。RT-PCR采用下面的特异性引物进行。
β-actin
Forward primer:5'-AGCCATGTACGTAGCCATCC-3'(序列号1)
Reverse primer:5'-CTCTCAGCTGTGGTGGTGAA-3'(序列号2)
Atrogin-1
Forward primer:5'-CCCTGAGTGGCATCGCCCAA-3'(序列号3)
Reverse primer:5'-AGGTCCCGCCCATCGCTCA-3'(序列号4)
MuRF1
Forward primer:5'-TCTACTCGGCCACAGGCGCT-3'(序列号5)
Reverse primer:5'-CTTGACAGCTCCCGCCGCAA-3'(序列号6)
各个相对的mRNA表达量值用β-actin值标准化。如图1所示,由基因转录的水准可知,5,7-二甲氧基黄酮减少了与肌肉内蛋白质异化作用相关的主要ligase、即atrogin-1和MuRF1的mRNA水准。
<实验例2>
在细胞模型中的肌肉分化及同化作用增加效果
<2-1>肌肉细胞分化增加效果
从采用与上述实验例1相同的方法分化的细胞收获总RNA,进行了逆转录之后,执行了RT-PCR。此时,除了5,7-二甲氧基黄酮之外,还对山柰小花提取物(1,10μg/ml)进行处理,利用以与实验例1相同的方法分化的细胞执行RT-PCR.
Myogenin
Forward primer:5'-TGGGCTGCCACAAGCCAGAC-3'(序列号7)
Reverse primer:5'-CAGCCCAGCCACTGGCATCA-3'(序列号8)
MyoD
Forward primer:5'-GGATGGTGCCCCTGGGTCCT-3'(序列号9)
Reverse primer:5'-TGGCCTTCGCTGTGAGTCGC-3'(序列号10)
各个相对的mRNA表达量值用β-actin值标准化。如图2所示,在基因转录的水准中,5,7-二甲氧基黄酮增加了肌肉分化调节因子、即myogenin和myoD的mRNA水准。另外,图4中也证实了山柰小花提取物增加myogenin和myoD的mRNA水准。
<2-2>肌肉细胞蛋白质同化作用增加效果
用包含proteinase inhibitor cocktail的RIPA缓冲溶液将采用与上述实验例1相同的方法处理的L6细胞溶解。将上述试样煮沸5分钟后,将同量的蛋白质(20μg)用10%SDS-PAGE电泳分离。用硝化纤维膜转导电泳后分离的蛋白质,执行免疫印迹(westernblot)。与1次抗体进行了反应之后,利用TBST,清洗3次各10分钟。此时,本发明使用的1次抗体的种类和稀释率为1:1000。2次抗体反应是在执行了上述1次抗体反应之后的膜中加入2次抗体(anti-rabbit horseradish)而在常温下反应了2小时。此时,2次抗体的稀释率设为1:5000。Protein band使用ECL western blottingdetection reagents(Amersham,Tokyo,Japan)来发色。确认到了与肌肉内蛋白质同化作用相关的PI3K、p-AKT、p-mTOR的蛋白质表达,由a-tubulin显示出蛋白质担载量恒定。采用与上述方法相同的方法执行,作为处理物质,除了5,7-二甲氧基黄酮之外,用山柰小花提取物(1,10μg/ml)执行,5,7-二甲氧基黄酮处理结果示于图3,山柰小花提取物处理结果示于图5。
如图3及图5所示,5,7-二甲氧基黄酮和山柰小花提取物均增加了PI3K、p-AKT、p-mTOR的蛋白质表达量。该结果意味着处理物质增加了肌肉量,提高了运动能力。
<实验例3>
由动物模型确认肌肉量增加效果
使5周龄大白鼠适应环境1周后,供给2周TNF-α100ng/g,诱导了肌萎缩之后,按体重随机分组,分为6组,每组8只。作为实验组,使山柰小花提取物以500mg/kg体重的比例悬浊于0.25%羧甲基纤维素(carboxymethylcellulose),使5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮、3,5,7,3’4’-五甲氧基黄酮以300mg/kg体重的比例悬浊于0.25%羧甲基纤维素(carboxymethylcellulose),1天1次,连续8周在指定时间给药。作为对比组,使用了向在实验组所摄取的相同量的0.25%羧甲基纤维素中供给了TNF-α的组。
将试样施用8周之后,将右腿肚下侧肌肉切去,用微量天平(microbalance)(MettlerPE160,USA)测定了重量。其结果,如表1所示,与对比组相比,投入了山柰小花提取物、5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮、3,5,7,3’4’-五甲氧基黄酮的组,肌肉的重量分别有效(p<0.01)增加125%、126%、118%、120%。该结果表示本发明的山柰小花提取物及由其分离的黄酮类化合物对肌肉量增加发挥有效作用。
【表1】
按处理物质分类的腿肚肌肉重量
处理物质 | 腿肚肌肉重量(mg) |
TNF-a | 437 |
山柰小花提取物 | 547 |
5,7-二甲氧基黄酮 | 551 |
5,7,4’-三甲氧基黄酮 | 519 |
3,5,7,3’,4’-五甲氧基黄酮 | 528 |
工业上的可应用性
本发明的山柰小花提取物及由其分离的黄酮类化合物能够减少肌肉内蛋白质的异化作用、增加肌肉细胞分化及同化作用,从而能够制造用于治疗肌肉疾病的药物组合物或改善肌肉功能的食品组合物,工业利用价值高。
Claims (15)
1.一种用于预防或治疗肌肉疾病的药物组合物,其特征在于,包含山柰小花(Kaempferia parviflora)提取物作为有效成分。
2.根据权利要求1所述的药物组合物,其特征在于,上述提取物是采用碳原子数为1-6的醇类水溶液提取的。
3.山柰小花(Kaempferia parviflora)提取物用于制造肌肉疾病预防药或治疗药的用途。
4.一种肌肉疾病的预防或治疗方法,其特征在于,将山柰小花(Kaempferiaparviflora)提取物以有效量投入给需要它们的个体。
5.一种用于预防或治疗肌肉疾病的药物组合物,其特征在于,包含下述化学式4所示的化合物或其盐作为有效成分,
在上述化学式4中,R1、R2及R3分别表示氢或甲氧基(methoxy)。
6.根据权利要求5所述的药物组合物,其特征在于,
上述化合物是选自由5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮及3,5,7,3’,4’-五甲氧基黄酮组成的组中的化合物。
7.上述化学式4的化合物或其盐用于制造肌肉疾病预防药或治疗药的用途。
8.一种肌肉疾病预防或治疗方法,其特征在于,将上述化学式4所示的化合物或其盐以有效量投入给需要它们的个体。
9.根据权利要求1、3、5、7的任一项所述的药物组合物,其特征在于,上述肌肉疾病是选自由迟缓症(atony)、肌萎缩症(muscular atrophy)、肌营养不良症(musculardystrophy)、肌肉退化、肌无力症及肌肉减少症(Sacopenia)组成的组中的一种以上的疾病。
10.一种用于改善肌肉功能的食品组合物,其特征在于,包含山柰小花提取物作为有效成分。
11.一种用于改善肌肉功能的食品组合物,其特征在于,包含下述化学式4所示的化合物或其盐作为有效成分,
在上述化学式4中,R1、R2及R3分别表示氢或甲氧基(methoxy)。
12.根据权利要求11所述的食品组合物,其特征在于,
上述化合物是选自由5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮及3,5,7,3’,4’-五甲氧基黄酮组成的组中的化合物。
13.一种用于增强运动执行能力的食品组合物,其特征在于,包含山柰小花提取物作为有效成分。
14.一种用于增强运动执行能力的食品组合物,其特征在于,包含下述化学式4所示的化合物或其盐作为有效成分,
在上述化学式4中,R1、R2及R3分别表示氢或甲氧基(methoxy)。
15.根据权利要求14所述的食品组合物,其特征在于,
上述化合物是选自由5,7-二甲氧基黄酮、5,7,4’-三甲氧基黄酮及3,5,7,3’,4’-五甲氧基黄酮组成的组中的化合物。
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