CN110582289A - 基因体稳定性增强剂 - Google Patents
基因体稳定性增强剂 Download PDFInfo
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- CN110582289A CN110582289A CN201880029409.2A CN201880029409A CN110582289A CN 110582289 A CN110582289 A CN 110582289A CN 201880029409 A CN201880029409 A CN 201880029409A CN 110582289 A CN110582289 A CN 110582289A
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- royal jelly
- gnetum
- peptidase
- acid
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Abstract
本申请公开的是一种基因体稳定性增强剂,其含有选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C(Gnetin C)构成的组中的至少一种作为有效成分。
Description
技术领域
本申请涉及一种基因体稳定性增强剂。
背景技术
大部分的正常细胞在一定次数的分裂后就会停止增殖。静止状态的细胞只要保持基因体稳定性,就可防止形质转换。该静止状态在ARF/p53途径的控制下,伴随组蛋白(histone)H2AX水平的降低而形成。同样的增殖停止的细胞状态也广泛地被认为构成正常保持恒定性的脏器的细胞。在H2AX水平降低的状态下,在细胞停止增殖的同时,变为DNA损伤的修复能力降低的状态。因此,在增殖停止的细胞中,伴随因过剩的增殖刺激引起的DNA复制应激,诱导出基因体不稳定性。另一方面,这样的细胞具有伴随H2AX瞬时诱导的修复能力的活化机制。
组蛋白H2AX对于DNA损伤修复因子在损伤部位的局部定位是重要的。若DNA发生双股断裂,则其周边的H2AX会被磷酸化。许多DNA损伤修复因子通过与该被磷酸化的H2AX(称作γ-H2AX)相互作用而局部定位于损伤部位。因此,通过以免疫染色等检测γ-H2AX,能够作为DNA损伤的标记物进行使用。
例如,在非专利文献1及2中,为了调查对白藜芦醇类的癌细胞的有效性,通过检测γ-H2AX来确认白藜芦醇类诱导DNA损伤。生成癌细胞的DNA损伤的结果是,可得到细胞凋亡的诱导效果。
如此,非专利文献1及2中记载的是被磷酸化的H2AX的检测,并没有研究H2AX自身的表达量。如上所述,通过使H2AX瞬时诱导,能够活化DNA的修复能力而增加基因体稳定性。
非专利文献3报告了:在白藜芦醇及蜂王浆的处理中发现“增殖停止的正常细胞”中的“伴随H2AX瞬时表达的DNA修复”。
非专利文献4报告了“与DNA修复相关的第十因子(Factor X)因白藜芦醇而瞬时诱导”。
也有如下报告:富含蜂王浆及白藜芦醇诱导体的倪藤(Melinjo),发挥出抗癌作用、抗老化作用、寿命延长作用等。(专利文献1、2、及非专利文献5~8)。
此外,基因修复机制的突变引起的疾病的色素性干皮症、亨汀顿舞蹈症(Huntington's disease)、维尔纳综合征(Werner syndrome)、布卢姆综合征(Bloomsyndrome)、林奇综合征(Lynch syndrome)等未发现有效的治疗方法。
现有技术文献
专利文献
专利文献1:日本专利第5923699号公报
专利文献2:日本专利第5979810号公报
非专利文献
非专利文献1:Carsinogenesis(2011)32(1):93-101
非专利文献2:Ann Hematol(2011)90:173-183
非专利文献3:吉冈研一,23-C-10以致癌诱导应激为起因,连动诱发“基因体不稳定性/突变/细胞形质转换”的分子机制研究,网站<http://crdb.ncc.go.jp/search/DRTV050.action?rpno=012013007100000>
非专利文献4:吉冈研一,白川仁,根据营养成分的预防癌化/老化效果及基因体稳定性控制机制的研究,网站<http://www.mishima-kaiun.or.jp/assist/docs/SJNo2-yoshioka,.pdf>
非专利文献5:日本药理学杂志(Folia pharmacol.Japon.)(1987)89:73-80
非专利文献6:Cancer Medicine(2015)4(11):1767-1780
非专利文献7:PLoS One(2011)6(8):e23527
非专利文献8:Bioscience,Biotechnology,and Biochemistry(2015)79(12):2044-2049
发明内容
发明所要解决的问题
本申请的目的在于提供一种基因体稳定性增强剂,其具有优异的基因体稳定性的增强作用。
用于解决问题的方案
本发明人等为了达成上述目的而反复深入研究,其结果是得到了如下见解:酶分解蜂王浆诱导H2AX的作用比未酶分解蜂王浆更高,并且,倪藤种子提取物及买麻藤素C诱导H2AX的作用比反式白藜芦醇更高。
本申请基于此见解而更进一步反复研究而完成,从而提供以下的基因体稳定性增强剂。
第一项.一种基因体稳定性增强剂,其含有选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C(Gnetin C)构成的组中的至少一种作为有效成分。
第二项.根据第一项所述的基因体稳定性增强剂,其为化妆品、饮食品、医药品、或医药部外品。
第三项.一种使基因体稳定性增强的方法,其包含将选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C构成的组中的至少一种的有效量施用于哺乳动物的工序。
第四项.一种选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C构成的组中的至少一种的在基因体稳定性增强剂的制造中的应用。
第五项.根据第四项所述的应用,其中,所述的基因体稳定性增强剂为化妆品、饮食品、医药品、或医药部外品。
第六项.一种基因体稳定性增强用组合物,其含有选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C构成的组中的至少一种作为有效成分。
第七项.根据第六项所述的基因体稳定性增强用组合物,其为化妆品、饮食品、医药品、或医药部外品。
发明效果
酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C具有优异的H2AX表达诱导作用,因此作为基因体稳定性增强剂的有效成分是有用的。
本申请的基因体稳定性增强剂具有优异的基因体稳定性增强作用,因此可期待与基因体不稳定(基因修复机制的异常)相关的疾病,即色素性干皮症、亨汀顿舞蹈症、维尔纳综合征、布卢姆综合征、林奇综合征等的发病预防及症状减轻的效果。
附图说明
图1为表示试验例1中的针对H2AX表达的西方墨点法解析的结果的照片(上)、及表示H2AX表达量(相对值)的图表(下)。左:未处理蜂王浆,右:酶分解蜂王浆。
图2为表示试验例2中的针对H2AX表达的西方墨点法解析的结果的照片(上)、及表示H2AX表达量(相对值)的图表(下)。左:反式白藜芦醇,右:倪藤。
图3为表示试验例3中的针对H2AX表达的西方墨点法解析的结果的照片(上)、及表示H2AX表达量(相对值)的图表(下)。左:反式白藜芦醇,中:倪藤,右:买麻藤素C。
图4为表示试验例4中的Msh2的同型合子及异型合子基因剔除小鼠的生存率的图表。◆:Msh2(-/-)一般的饲料n=11,■:Msh2(-/-)添加0.3%倪藤种子提取物的饲料n=8,▲:Msh2(+/-)一般的饲料n=10,×:Msh2(+/-)添加0.3%倪藤种子提取物的饲料n=10。
图5为表示试验例5中的在Msh2的基因剔除小鼠的肠管形成的肿瘤数的图表。+:倪藤种子提取物施用组,-:对照组。
具体实施方式
以下,详细说明本申请。
需要说明的是,本说明书中“包含、含有(comprise)”也包括“本质上由…组成(essentially consist of)”的意义及“由…组成(consist of)”的意义。
本申请的基因体稳定性增强剂的特征在于:含有选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C构成的组中的至少一种作为有效成分。
蜂王浆为将蜜蜂中日龄3~12天的工蜂由下咽头腺及大颚腺分泌的分泌物混合而制成的乳白色的胶状物质。作为蜂王浆中的主要生理活性成分,例如可列举出:以蜂王浆所特有的10-羟基癸烯酸(以下,记为“癸烯酸”)等的有机酸类为首,蛋白质、脂质、糖类、维生素B族、叶酸、烟酸、泛酸等维生素类、各种矿物质类等。作为该蜂王浆的生理活性及药理作用,已知有抗菌作用、免疫增强作用、抗抑郁作用、抗肿瘤作用、抗炎症作用、血流量增加作用等。此外,也报告了降低抗癌剂的副作用及放射线伤害时的延命效果。
酶分解蜂王浆的制造所使用的蜂王浆没有特别限制,能够使用:生蜂王浆、使生蜂王浆干燥并粉末化的蜂王浆粉末、或通过水或含水乙醇等提取生蜂王浆的物质。
蜂王浆的产地没有特别限制,可为日本、中国、巴西、欧洲各国、大洋洲各国、美国等任一国。
本申请作为对象的酶分解蜂王浆是以蛋白质分解酶处理蜂王浆而成的物质。优选为低过敏原化酶分解蜂王浆,其通过肽酶处理抑制因蜂王浆所含有的蛋白质导致的过敏反应。因此,本申请的酶分解蜂王浆除了蜂王浆中所含有的蛋白质的肽酶分解物以外,也能包含所述的癸烯酸等有机酸类、脂质、糖类、维生素类、及各种矿物质类。
作为用于将蜂王浆酶分解的酶,能够适当列举肽酶。所使用的肽酶具有内肽酶作用及外肽酶作用的至少一种即可,但优选至少具有内肽酶作用的物质,更优选为具有这两种的作用的物质。
本申请的酶分解蜂王浆优选为将蜂王浆所含有的蛋白质水解而低过敏原化的物质。因此,优选的是,使用至少具有内肽酶作用的肽酶(内肽酶),优选使用具有内肽酶作用及外肽酶作用的两者的肽酶,将蜂王浆水解。此处,具有内肽酶作用及外肽酶作用的两者的肽酶,可单独使用同时具有这两种作用的肽酶,此外,也可组合使用具有内肽酶作用的肽酶(内肽酶)及具有外肽酶作用的肽酶(外肽酶)。
作为能够用于本申请的内肽酶,只要是至少具有内肽酶活性的蛋白质分解酶,即可为任何酶。例如,能够广泛示例出:动物来源(例如:胰蛋白酶、胰凝乳蛋白酶等)、植物来源(例如:木瓜蛋白酶等)、或微生物来源(例如:乳酸菌、酵母、霉菌、枯草杆菌、放线菌等)的内肽酶。
外肽酶只要是至少具有外肽酶活性的蛋白质分解酶,就可为任何酶。例如能够示例出:羧肽酶、氨肽酶、或微生物来源(例如:乳酸菌、曲霉属菌、根霉属菌等)的外肽酶、或也兼具内肽酶活性的胰酶、胃蛋白酶等。
然而,在肽酶中,存在实质上仅具有外肽酶作用的外肽酶、实质上仅具有内肽酶作用的内肽酶、以及具有外肽酶作用及内肽酶作用这两者的肽酶。其中,针对具有外肽酶作用及内肽酶作用这两者的酶,在内肽酶作用强的情况下,能够作为“内肽酶”使用,在外肽酶作用强的情况下,能够作为“外肽酶”使用;在外肽酶作用与内肽酶作用相等或几乎相等的情况下,能够作为同时具有内肽酶作用及外肽酶作用的肽酶使用。
这样的肽酶之中,作为具有外肽酶作用的酶的优选例,例如可列举出:米曲菌(Aspergillus orizae)产生肽酶(商品名:Umamizyme G、Promod 192P、Promod 194P、Sumizyme FLAP)、酱油曲霉菌(Aspergillus sojae)产生肽酶(商品名:SternzymeB15024)、曲霉属产生肽酶(商品名:Kokulase P)、米根霉菌(Rhizopus oryzae)产生肽酶(商品名:Peptidase R)等。
此外,作为具有内肽酶作用的肽酶的优选例,例如可列举出:枯草杆菌(Bacillussubtilis)产生肽酶(商品名:Orientase 22BF、Nukureishin)、地衣芽孢杆菌(Bacilluslicheniformis)产生肽酶(商品名:Alcalase)、嗜热脂肪芽孢杆菌(Bacillusstearothermophilus)产生肽酶(商品名:Protease S)、液化淀粉芽孢杆菌(Bacillusamyloliquefaciens)产生肽酶(商品名:Neutrase)、芽孢杆菌属产生肽酶(商品名:Protamex)等。
进而,具有外肽酶作用及内肽酶作用这两者的肽酶,特别是作为碱性肽酶的优选例,例如可列举出:灰色链霉菌(Streptomyces griseus)产生肽酶(商品名:Actinase AS)、米曲菌(Aspergillus orizae)产生肽酶(商品名:Protease A、Flavourzyme)、蜂蜜霉菌(Aspergillus melleus)产生肽酶(商品名:Protease P)等。根据使用这肽酶的酶处理,具有下述优点:能够以一阶段酶处理将蛋白质低分子化,因此操作简便,同时也能够防止蜂王浆所含有的有用成分的生理活性的消失及大幅降低。
对于蜂王浆的肽酶的使用量因使用的蜂王浆浓度、酶效价、反应温度及反应时间而不同,但一般来说,优选的是,肽酶以蜂王浆所含有的蛋白质每1克为50~10000作用单位的比例使用肽酶。需要说明的是,此时,向蜂王浆内添加肽酶可一次添加,也可每次少量地添加。
肽酶处理时蜂王浆的pH值对应于使用酶的最佳pH值,pH2~12,优选选自pH7.5~10,更优选选自pH7.8~9的范围。具体而言,在将肽酶添加至所述蜂王浆内前,以根据使用酶的种类而成为pH2~12,优选pH7.5~10,更优选pH7.8~9的范围内的方式,通过酸、碱剂、或缓冲剂的添加而调整期望的pH值。在这样的情况下,作为酸,能够示例出:盐酸、硫酸、硝酸、磷酸、醋酸等;作为碱剂,能够示例出:氢氧化钠、氢氧化钾、碳酸钾等;此外,作为缓冲剂,能够示例出:磷酸缓冲剂、柠檬酸缓冲剂等。
肽酶处理的温度没有特别限制,包含肽酶作用、优选内肽酶作用、更优选表达内肽酶作用及外肽酶作用这两种作用的最佳温度范围的能供于实用的范围,即,通常选自30℃~70℃的范围。温度比肽酶的最佳温度(优选约为40℃~50℃)低温或高温,例如,通过维持在50℃~60℃的范围,也能够防止在肽酶处理工序中的腐败。肽酶处理的时间取决于使用酶的种类、及反应温度、pH值等反应条件,没有特别限定。
需要说明的是,蜂王浆能够直接、或以溶解或分散于水状态下供于蛋白质分解酶处理。在为干燥形态的情况下,优选的是,在溶解于水的状态下供于蛋白质分解酶处理。
肽酶处理的停止通过使肽酶失活或除去肽酶来进行。失活操作可通过加热处理(例如,在85℃下15分钟等)来进行。
本申请中的酶分解蜂王浆只要是至少如上所述那样肽酶处理后的蜂王浆即可,不仅仅是肽酶处理,也包含与其他酶的组合处理,例如,与肽酶处理组合而糖分解酶处理后的蜂王浆。
作为本申请中的酶分解蜂王浆,也能够使用将酶分解后的蜂王浆干燥及粉末化的物质。作为干燥方法,能够使用通风干燥、晒干等自然干燥、利用电等加热干燥的强制干燥、流动层干燥、喷雾干燥、高频干燥、冷冻干燥等一般食品加工所采用的公知的方法,优选为冷冻干燥。作为用于粉末化的粉碎方法,能够利用使用粉碎机(磨机)(例如:针磨机、锤磨机、球磨机、喷射磨机、辊磨机、胶体磨机等)粉碎的方法等公知的方法进行。
买麻藤(别名倪藤,学名Gnetum gnemon L.,英文名Gnemon tree,印度尼西亚名Melinjo、Belinjo)为买麻藤科的植物,在东南亚栽培。
在本申请中,买麻藤的使用部位没有特别限制,可列举出果实(或种子)、花、叶等,优选为种子。此外,买麻藤也能够使用加工物,作为这样的加工,可列举干燥、加热干燥、切割、粉碎等。
在本说明书中,买麻藤种子是由种皮、薄皮、及胚/胚乳(内乳)构成的。作为买麻藤种子的形状及形态,只要可得到本申请的效果,就能够使用任何形状及形态,优选为长径:约1.3~2.3cm、短径:约0.6~1.3cm,花生状的形状的种子。作为买麻藤种子,只要是包含买麻藤种子的形态的种子,就能够在本申请使用,可列举例如买麻藤种子上具有果皮的形态的买麻藤果实。
本申请中的买麻藤种子也包含加工物,作为这样的买麻藤种子的加工物,可列举出:(通过阳光晒干等)干燥状态物、加热干燥状态物等。此外,作为买麻藤种子,能够使用未经切割及粉碎的保持原形的状态物,以及经切片及粉碎的买麻藤种子的加工物。在本申请中,也可使用买麻藤种子的胚/胚乳(内乳)、或仅有种皮的买麻藤种子的加工物。
在本申请中,理想的是使用买麻藤种子的提取物,该提取物的制造方法没有特别限制,例如能够使用通过将买麻藤种子浸渍于浸渍液而进行提取的方法(例如:日本特开2013-82701号公报所述的方法)等来进行。
作为上述浸渍液,能够使用水、有机溶剂或含水有机溶剂。作为有机溶剂,优选为能与水自由地混合的溶剂,作为这样的溶剂,可列举出:甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-丁醇、2-甲基-1-丙醇、2-甲基-2-丙醇、1-戊醇、2-戊醇、3-戊醇等碳数1~5的低级醇;二乙醚等醚类;乙酸甲酯、乙酸乙酯等酯类;丙酮等酮类;醋酸、冰醋酸、丙酸等有机酸等。有机溶剂优选为低级醇。
进行浸渍时的浸渍液的温度,能够根据买麻藤种子及浸渍液的量等而适当设定,例如为10℃~50℃,优选为20℃~40℃。进行浸渍的时间能够根据买麻藤种子及浸渍液的量等而适当设定,优选为3天以上,更优选为3天~7天。
回收的浸渍液可以直接使用,也可根据需求通过超滤、分子筛色谱法(凝胶过滤)、吸附色谱法、离子交换色谱法、亲和色谱法、高效液相色谱法(HPLC)、透析法、它们的组合等进行精炼。
买麻藤种子的提取物也能够采取回收的浸渍液(包含根据需要进一步进行精制的浸渍液)、浓缩该浸渍液的浓缩液、及通过进行冷冻干燥、喷雾干燥等去除该浸渍液的溶剂的固体物质的任何状态。此处,浸渍液的浓缩、冷冻干燥及喷雾干燥能够根据常规方法进行。本申请的买麻藤种子的提取物的形态优选为粉末状。
买麻藤素C为下述化学式所示的多酚的一种。
买麻藤素C(Gnetin C)不论自制品或市售品皆可使用。此处,自制买麻藤素C的方法没有特别限制,可列举从含买麻藤素C的植物提取的方法、使微生物产生的方法(例如参照Adil E Bala et al.,“Antifungal activity of resveratrol oligomers fromCyphostemma crotalarioides”,Pesticide Science,Vol.55,Issue 2,Pages 206-208等)、及化学合成方法。
含买麻藤素C的植物没有特别限制,优选可列举属于买麻藤科的植物(IbrahimIliya et al.,“Stilbenoids from the stem of Gnetum latifolium(Gnetaceae)”,Phytochemistry,2002Dec;61(8):959-61;Ibrahim Iliya et al.,“Dimeric Stilbenesfrom Stem Lianas of Gnetum Africanum”,HeteroCycles,VOL.57;NO.6;PAGE.1057-1062(2002))。
具体来说,能够例示为属于买麻藤科的Gnetum latifolium、Gnetum Africanum及Gnetum gnemon(买麻藤),优选为买麻藤。针对所使用植物的部位,只要是包含许多买麻藤素C的部位,就不特别限制为果实(或是种子)、花、叶等部位,优选为果实(或是种子),更优选为果实的胚乳。
此处,在从植物提取买麻藤素C的情况下,其方法没有特别限制,例如,所述的提取方法可使用日本特开2013-82701号公报所述的提取方法等。买麻藤素C可使用未经离析或精制的状态物(粗提取物),及经离析或精制物的任一种。精制方法能够使用上述的方法。
需要说明的是,精制不需要进行到纯度100%。本申请所使用的买麻藤素C的纯度通常为50质量%以上即可,优选为80质量%以上,更优选为90质量%以上。
此外,在用微生物产生买麻藤素C的情况下,或通过化学合成取得的情况下,优选为实施与上述同样的精制处理。
本申请中的买麻藤素C包含游离状态或盐的状态这两种。作为盐,可列举例如:钠盐、钾盐、镁盐、钙盐、铝盐等与无机碱的盐;甲胺、乙胺、乙醇胺等的有机碱的盐;赖氨酸、鸟氨酸、精氨酸等与碱性氨基酸的盐及铵盐。该盐也可为酸加成盐,作为相关的盐,可具体列举出:盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸;甲酸、醋酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸等有机酸;与天冬氨酸、谷氨酸等酸性氨基酸的酸加成盐。此外,本申请中的买麻藤素C也包括其水合物、溶剂化物、多晶型等。
本申请的基因体稳定性增强剂中的酶处理蜂王浆的含量没有特别限制,优选为0.01质量%或w/v%以上,更优选为1.4质量%~100质量%或w/v%,更进一步优选为30质量%~65质量%或w/v%。
本申请的基因体稳定性增强剂中的买麻藤或其提取物的含量没有特别限制,优选为0.01质量%或w/v%以上,更优选为0.03质量%~100质量%或w/v%,更进一步优选为30质量%~65质量%或w/v%。
本申请的基因体稳定性增强剂中的买麻藤素C的含量没有特别限制,优选为0.001质量%或w/v%以上,更优选为0.01质量%~100质量%或w/v%,更进一步优选为1质量%~40质量%或w/v%。
本申请的基因体稳定性增强剂包含:化妆品、饮食品(特别是以保健、维持健康、增进等为目的的饮食品(例如:健康食品、功能性食品、营养组合物(nutritionalcomposition)、营养辅助食品、补充剂、保健用食品、特定保健用食品、营养功能食品、功能性表达食品))、医药部外品及医药品(特别是口服药物)的意义。此外,本申请的基因体稳定性增强剂也包含:赋予基因体稳定性增强作用的添加剂的意义。
上述的化妆品除了上述的有效成分以外,也能够根据需要而适当配合通常化妆品所使用的成分,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、酒精类、粉末成分、色材、水性成分、水、各种皮肤营养剂等。
化妆品包含所有适用于动物(包括人类)的皮肤、粘膜、体毛、头发、头皮、指甲、牙齿、脸皮、嘴唇等的化妆品。
化妆品的剂型能够采用水溶液系、可溶化系、乳化系、粉末系、油液系、凝胶系、软膏系、气溶胶系、水-油双层系、水-油-粉末三层系等广泛的剂型。
化妆品的用途为任意,例如,若为基础化妆品,则可列举出:洗面乳、化妆水、乳液、乳霜、啫喱、精华液、美容液、美容涂敷剂(pack)、面膜(mask)等;若为彩妆化妆品,则可列举出:粉底、口红、腮红、眼影、眼线、睫毛膏等;若为指甲化妆料,则可列举出:指甲油、底层护甲油、表层护甲油、去光水等;作为其他,可列举出:洗面乳、(膏状或液体)牙膏、漱口水、按摩用剂、清洁用剂、须后水、须前水、剃须膏、沐浴露、肥皂、洗发精、润丝精(Rinse)、护发乳、头发造型品、养发剂、生发剂、止汗剂、入浴剂等。
上述的饮食品除了上述的有效成分以外能够根据需要而配合赋形剂、光泽剂、矿物质类、维生素类、黄酮类、醌类、多酚类、氨基酸、核酸、必需脂肪酸、清凉剂、粘结剂、甜味剂、崩解剂、润滑剂、着色剂、香料、稳定剂、防腐剂、缓释调整剂、表面活性剂、溶解剂、润湿剂等。
饮食品包含所有动物(包括人类)能摄取的饮食品。饮食品的种类没有特别限制,例如可列举出:饮料类(如咖啡、果汁、茶饮料这样的清凉饮料、乳饮料、乳酸菌饮料、酸奶饮料、碳酸饮料、如日本酒、洋酒、水果酒这样的酒等);抹酱类(卡士达酱等);糊膏类(水果糊等);西点类(巧克力、甜甜圈、馅饼、泡芙(cream puff)、口香糖、果冻、糖果、饼干、蛋糕、布丁等);日式糕点(大福、麻糬、日式馒头、卡斯特拉、馅蜜、羊羹等);冰点心类(冰淇淋、冰棒、雪糕(sherbet)等);食品类(咖哩、牛丼、杂烩粥、味噌汤、汤、肉酱、意大利面、渍物、果酱等);调味料类(调味汁(dressing)、日式香松、增味剂、汤底等)等。
关于使用补充剂时的剂量单位形式没有特别限定,可适当选择,例如可列举出:锭剂(例如素锭、糖衣锭、膜衣锭、咀嚼锭、口服锭等)、胶囊剂、颗粒剂、液剂、散剂、糖浆、糊膏、饮剂等。
饮食品的摄取量能够根据摄取者的体重、年龄、性别、症状等各种条件而适当设定。
上述的医药品能够仅使用上述的有效成分,也能够与维生素、生药等日本药典所述的其他医药成分混合使用。
在本申请的基因体稳定性增强剂作为医药品进行制备的情况下,可将上述有效成分与医药品中容许的无毒性载体、稀释剂或赋形剂一同制备片剂(包括素锭、糖衣锭、发泡锭、膜衣锭、咀嚼锭、口服剂等)、胶囊剂、丸剂、粉末剂(散剂)、细粒剂、颗粒剂、液剂、悬浊液、乳浊液、糖浆、糊膏等型态,可成为口服的制剂。
医药品的施用量能够根据患者的体重、年龄、性别、症状等各种条件而适当决定。
需要说明的是,本申请的医药品及化妆品也包含医药部外品。
以上说明的本申请的基因体稳定性增强剂适用于包括人类的哺乳动物。
本申请的基因体稳定性增强剂含有作为有效成分的酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C如后述实施例所示,与未酶分解蜂王浆及反式白藜芦醇相比,诱导H2AX作用更高。因此,本申请的基因体稳定性增强剂具有优异的H2AX表达诱导作用,因此可以预料到发挥出优异的基因体稳定性增强作用。
本申请的基因体稳定性增强剂具有优异的基因体稳定性增强作用,因此为了预防与基因体不稳定(基因修复机制的异常)相关的疾病,即色素性干皮症、亨汀顿舞蹈症、维尔纳综合征、布卢姆综合征、林奇综合征(遗传性非息肉病性大肠癌)等的发病、症状减轻及治疗而能够适当使用。
实施例
以下,通过实施例进一步详细说明本申请。但是,本申请并不受限于这些实施例。
材料
蜂王浆的酶分解物按照日本专利第3994120号公报的实施例1进行制备。以使酶分解蜂王浆及蜂王浆的冷冻干燥粉末的最终浓度达到100μg/mL的方式,将其溶解于添加10%FBS的α-MEM培养基,进行过滤灭菌。
针对倪藤种子提取物,按照日本特开2009-013123号公报的第[0024]段的记载将倪藤的干燥果实的破碎物在室温下浸渍于含水乙醇,将所得的提取液减压浓缩,得到含63.2质量%固体成分的倪藤种子提取物。
针对买麻藤素C,将上述所得的倪藤种子提取物2.5g以管柱色谱法(凝胶的种类:Cosmosil 75C18-PREP(Nacalai Tesque公司制)、管柱尺寸:),使用甲醇含量为10容量%、25容量%、40容量%、80容量%及100容量%的含水甲醇作为洗脱液,依次逐步进行洗脱(流过各洗脱液600mL、每100mL进行分取)。所得的各成分以下述条件的HPLC进行确认后,确认出买麻藤素C以保持时间33.5分钟(含有1容量%醋酸及80容量%甲醇的含水甲醇溶出分离物)溶出。
<HPLC条件>
管柱:东曹(TOSOH)制TSKgel ODS-100V、5μm、4.6×150mm
移动层:A液:含有1.0容量%醋酸的水、B液:含有1.0容量%醋酸的甲醇
梯度条件:0分钟→10分钟:A:B=65:35(v/v)→63:37(v/v)、10分钟→20分钟:A:B=63:37(v/v)→56:44(v/v)、20分钟→40分钟:A:B=48:52(v/v)
检测波长:320nm
流速:0.8mL/min
将上述分离物浓缩后,以下述条件的中压管柱色谱法依次溶出。
<中压管柱色谱法条件>
凝胶种类:硅胶、Daisogel IR-60-40/63-W
管柱尺寸:
检测波长:320nm
移动层:A液:甲醇、B液:氯仿
梯度条件:0分钟→2分钟:A:B=11:89(v/v)、2分钟→8分钟:A:B=11:89(v/v)→18:82(v/v)、8分钟→12分钟:A:B=18:82(v/v)、12分钟→14分钟:A:B=21:79(v/v)、14分钟→20分钟:A:B=21:79(v/v)→29:71(v/v)、20分钟→24分钟:A:B=29:71(v/v)、24分钟→30分钟:A:B=29:71(v/v)→36:64(v/v)、30分钟→34分钟:36:64(v/v)
流速:60ml/min
溶出液以各60mL分装,将检测波长:320nm显示吸收波峰的第29支至第30支的分离物以蒸馏器浓缩,从而获得买麻藤素C(35.2mg、纯度97%)。
反式白藜芦醇由Sigma-Aldrich公司取得。
试验例1
正常细胞的增殖停止因伴随H2AX(向DNA损伤修复因子组的DNA损伤部位的聚集诱导为必须)水平的降低而被诱导,因此DNA修复能力也同时降低。基因体不稳定性在此背景下因增殖刺激而被诱导,这变得明确。而且,解析了酶分解蜂王浆(酶处理RJ)及蜂王浆(未处理RJ)的对H2AX表达的影响。
将MEF(mouse embryo fibroblast)细胞在含有添加25μg/ml的酶处理RJ或未处理RJ的10%FCS(fetal calf serum)的DMEM培养基中,在37℃、5%CO2条件下,以3T3法进行培养。回收培养了0、3、6、12、24小时的细胞,用H2AX抗体(Bethyl Laboratories,Inc.)及β-actin抗体(AC-74,Sigma-Aldrich)进行西方墨点法解析。
西方墨点法解析的结果及使用ImageJ(Rasband,W.S.,ImageJ,U.S.NationalInstitutes of Health,Bethesda,Maryland,USA,http://imagej.nih.gov/ij/,1997-2016.)将西方墨点法解析的结果数值化的图表如图1所示。酶分解RJ及未处理RJ处理均发现H2AX瞬时表达的诱导。条带8比起条带2,H2AX表达量为2.1倍量。此结果显示,酶分解RJ的H2AX的瞬时表达诱导能力有未处理RJ的2.1倍量。
试验例2
使用与试验例1同样的方法,解析倪藤及反式白藜芦醇的对H2AX表达的影响。需要说明的是,本次为添加0.26、0.52、1.0、2.1w/v%的倪藤种子提取物或反式白藜芦醇至培养基,回收培养1小时的细胞。
西方墨点法解析的结果及将西方墨点法解析的结果数值化的图表如图2所示。其结果是,倪藤及反式白藜芦醇均发现H2AX瞬时表达的诱导。条带9比起条带4,H2AX表达量为2.7倍量。此结果显示,倪藤的H2AX的瞬时表达诱导能力有反式白藜芦醇的2.7倍。
试验例3
使用与试验例1同样方法,解析反式白藜芦醇、倪藤及买麻藤素C的对H2AX表达的影响。需要说明的是,本次为添加2.5μM(0.52μg/ml)的反式白藜芦醇、0.52μg/ml的倪藤种子提取物、或2.5μM的买麻藤素C至培养基,回收培养0、1.5、3、6、12、24小时的细胞。
西方墨点法解析的结果及使用ImageJ(Rasband,W.S.,ImageJ,U.S.NationalInstitutes of Health,Bethesda,Maryland,USA,http://imagej.nih.gov/ij/,1997-2016.)将西方墨点法解析的结果数值化的图表如图3所示。其结果是,反式白藜芦醇、倪藤及买麻藤素C均发现H2AX瞬时表达的诱导。倪藤(条带4)及买麻藤素C(条带4)的H2AX的表达量分别比反式白藜芦醇(条带3)高1.9倍、1.8倍。此结果显示,倪藤及买麻藤素C的H2AX的瞬时表达诱导能力有反式白藜芦醇的1.9倍、1.8倍。
试验例4
为了检证倪藤对生物体的基因体稳定性增强效果,使用欠缺错配修复因子的Msh2-KO小鼠{产生基因体不稳定性的一类的微卫星不稳定性(MSI)的林奇综合征模型}进行实验。已知此小鼠从月龄10个月左右开始,经过大约半年左右的期间即会死去。
结果由图4所示。将施用有H2AX的瞬时表达诱导能力的倪藤种子提取物0.3质量%(360mg/kg体重/天)组(■)及给予一般饲料组(◆)进行比较,其结果是,在食用一般饲料的组中,半数以上经过20周即死亡,相对于此,食用含有倪藤种子提取物的饲料的组,此期间没有确认到小鼠死亡。
这明确显示:在基因修复功能低下时,通过具有H2AX瞬时表达的诱导活性的“基因体稳定性增强剂”会出现“延长寿命的效果”。
试验例5
检证倪藤的摄取是否会发挥预防的效果。将0.03w/v%的倪藤种子提取物(36mg/kg体重/天)施用于8-12周龄的Msh2-KO小鼠的组,或作为对照组而施用灭菌水的小鼠,给予含有致癌剂的溴酸钾(0.02%)的水作为饮料水。在24周后,对形成于肠管的肿瘤数进行计数,比较倪藤组及对照组。欠缺错配修复因子的Msh2-KO小鼠易生成基因体不稳定,且因化学致癌物质的BrKO3而容易在消化管中形成肿瘤。
结果如图5所示。在施用倪藤种子提取物的组中,观察到抑制明确的致癌等级的效果。此现象显示,即使是易生成基因体不稳定性的体质,通过预防性地摄取倪藤种子提取物,也能够防止癌症发病。
Claims (2)
1.一种基因体稳定性增强剂,其含有选自由酶分解蜂王浆、买麻藤或其提取物、及买麻藤素C构成的组中的至少一种作为有效成分。
2.根据权利要求1所述的基因体稳定性增强剂,其为化妆品、饮食品、医药品、或医药部外品。
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