CN114302718A - 线粒体功能活化剂 - Google Patents
线粒体功能活化剂 Download PDFInfo
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- CN114302718A CN114302718A CN202080061222.8A CN202080061222A CN114302718A CN 114302718 A CN114302718 A CN 114302718A CN 202080061222 A CN202080061222 A CN 202080061222A CN 114302718 A CN114302718 A CN 114302718A
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- alanine
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Abstract
本发明的目的在于提供一种使线粒体的功能活性化的药物,特别是提供一种廉价的药物。所述技术问题能够通过包含本发明的β‑丙氨酸或甘氨酸或它们的盐的线粒体功能活化剂来解决。
Description
技术领域
本发明涉及线粒体功能活化剂、线粒体功能活化用食品组合物及线粒体功能的活化方法。根据本发明,能够增加细胞中的线粒体数量,并且能够提高线粒体的活性。
背景技术
已知线粒体为真核生物的细胞器,其负责产生ATP,且在细胞凋亡中发挥重要作用。线粒体大量存在于肝脏、肾脏、肌肉或脑等代谢活跃的组织的细胞中。例如,肌肉的快肌纤维中线粒体少,但慢肌纤维或心肌中大量存在线粒体,由糖原(glycogen)经由乳酸产生ATP。
作为因线粒体的功能障碍导致的疾病,可列举出线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病等各种疾病,可期待通过提高线粒体的活性而改善症状。此外,即使是健康的人,也能够通过使骨骼肌的线粒体的功能活性化而提高运动能力。
现有技术文献
专利文献
专利文献1:日本专利特开2015-97507号公报
专利文献2:日本专利特开2014-162792号公报
发明内容
本发明要解决的技术问题
作为使线粒体的功能活性化的化合物,已知有肌肽或鹅肌肽(专利文献1)及β-柠檬酰基-L-谷氨酸(专利文献2)。然而,这些物质的线粒体的功能的活性化并不充分。此外,因肌肽、鹅肌肽及β-柠檬酰基-L-谷氨酸为二肽而价格昂贵,谋求一种能够以廉价使线粒体活性化的方法。
因此,本发明的目的在于提供一种使线粒体的功能活性化的药物,特别是提供一种廉价的药物。
解决技术问题的技术手段
本发明的发明人对使线粒体的功能活性化的药物进行了深入研究,结果惊人地发现β-丙氨酸或甘氨酸具有优异的线粒体功能活性作用。
本发明是基于该发现而完成的。
因此,本发明涉及下述方案:
[1]一种线粒体功能活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐;
[2]根据[1]所述的线粒体功能活化剂,其用于提高脂肪燃烧或提高有氧运动能力;
[3]根据[1]所述的线粒体功能活化剂,其用于预防或治疗因线粒体功能障碍导致的疾病;
[4]根据[3]所述的线粒体功能活化剂,其中,所述因线粒体功能障碍导致的疾病为线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病;
[5]根据[4]所述的线粒体功能活化剂,其中,所述线粒体病为Leigh氏脑病、脑卒中样发作综合征(MELAS)、慢性进行性眼外肌瘫痪综合征(CPEO)、Kearns-Sayre综合征(KSS)、肌阵挛性癫痫伴破碎红纤维综合征(MERRF)、皮尔逊病(Pearson病)、Leber遗传性视神经病(LHON)、线粒体脑肌病、Barth综合征或乳酸酸中毒;
[6]根据[4]所述的线粒体功能活化剂,其中,所述神经变性疾病为肌肉萎缩性侧索硬化症(ALS)、帕金森病、阿尔茨海默病、亨廷顿病、佛莱德立希失调症(Friedreich′sataxia)、多系统萎缩症、进行性核上性麻痹、脊髓小脑变性症、脊髓性肌萎缩症、脊髓延髓肌萎缩症或腓骨肌萎缩症(Charcot-Marie-Tooth);
[7]根据[4]所述的线粒体功能活化剂,其中,所述免疫性神经疾病为吉兰-巴雷综合征(Guillain-Barre syndrome)、多发性硬化症、Fisher综合征(Fisher syndrome)、慢性炎性脱髓鞘性多发性神经病或重症肌无力症;
[8]根据[4]所述的线粒体功能活化剂,其中,所述脑缺血性疾病为脑梗塞;
[9]根据[4]所述的线粒体功能活化剂,其中,所述肾脏疾病为肾衰竭、淀粉样变肾病(renal amyloidosis)、膜性肾病、局灶节段性肾小球硬化症、IgA肾病、急性肾小管坏死、肾病综合征(Nephrotic syndrome)、糖尿病性肾病、痛风性肾病、肾性浮肿、肾肿瘤、肾缺血障碍、肾缺血再灌注损伤或多囊肾;
[10]根据[4]所述的线粒体功能活化剂,其中,所述肌肉疾病为进行性肌营养不良、强直性肌营养不良、先天性肌病、代谢性肌病、远端型肌病、炎症性肌病、增龄性肌萎缩(肌少症、sarcopenia)或废用性肌肉萎缩;
[11]根据[4]所述的线粒体功能活化剂,其中,所述心脏疾病为心肌梗塞、心衰竭、缺血性心脏病或心肌病;
[12]一种线粒体功能活化用食品组合物,其包含β-丙氨酸或甘氨酸、或者它们的盐;
[13]一种线粒体功能的活化方法,其包括向对象给予所述的线粒体功能活化剂的工序;
[14]根据[13]所述的线粒体功能的活化方法,其用于提高所述对象的脂肪燃烧或提高有氧运动能力;
[15]一种用于增强有氧运动时的能力或增强慢肌的运动训练方法,其包括使对象摄取[1]所述的线粒体功能活化剂的工序;
[16]一种用于增强有氧运动时的能力或增强慢肌的饮食方法,其包括使对象摄取[1]所述的线粒体功能活化剂的工序;
[17]一种Pgc-1α基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐;
[18]一种Acaa1b基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐;及
[19]一种Acaa2基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐。
此外,本说明书还公开了以下方案:
[20]一种预防或治疗因线粒体功能障碍导致的疾病的方法,其包括对因线粒体功能障碍导致的疾病给予治疗有效量的β-丙氨酸或甘氨酸、或者它们的盐的工序;及
[21]根据[17]所述的预防或治疗因线粒体功能障碍导致的疾病的方法,其中,所述因线粒体功能障碍导致的疾病为线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病。
发明效果
根据本发明的线粒体功能活化剂及线粒体功能活化用食品组合物,能够增加细胞中的线粒体数量,并且能够提高线粒体的活性。此外,β-丙氨酸及甘氨酸容易获得,能够提供廉价的线粒体功能活化剂等。
附图说明
图1为示出以β-丙氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的线粒体数量的增加的图表。
图2为示出以β-丙氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的活性化的线粒体数量的增加的图表。
图3为示出以甘氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的线粒体数量的增加的图表。
图4为示出以甘氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的活性化的线粒体数量的增加的图表。
图5为示出以甘氨酸对分化为肌管细胞的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的线粒体数量的增加的图表。
图6为示出以甘氨酸对分化为肌管细胞的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了2小时及48小时处理时的活性化的线粒体数量的增加的图表。
图7为示出以β-丙氨酸或甘氨酸对分化为肌管细胞的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了处理时的Pgc-1α基因的表达的图表。
图8为以β-丙氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了48小时处理时的共聚焦激光扫描显微镜照片。
图9为以β-丙氨酸对未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了72小时处理并测定线粒体红色荧光(Mito Tracker Red)的荧光而得到的图表。
图10为示出以β-丙氨酸对分化为肌管细胞的来自于小鼠骨骼肌的成肌细胞株C2C12细胞进行了处理时的Acaa1b基因或Acaa2基因的表达的图表。
具体实施方式
[1]线粒体功能活化剂
本发明的线粒体功能活化剂包含β-丙氨酸或甘氨酸、或者它们的盐。此外,本发明的线粒体功能活化剂还可以包含具有羧基及氨基的其他氨基酸或它们的盐等。线粒体功能活化剂可以单独包含β-丙氨酸、甘氨酸、或它们中的任一种的盐、或具有羧基及氨基的其他氨基酸或它们中的任一种的盐等,也可以包含其中两种以上的组合。
β-丙氨酸为下述式[1]所表示的化合物,其也被称作3-氨基丙酸(3-aminopropanoic acid)。作为本发明的线粒体功能活化剂中所含的β-丙氨酸,能够使用来自相对富含β-丙氨酸的食物或天然物质的提取物、浓缩物或提纯物等。此外,也可以使用合成的β-丙氨酸。β-丙氨酸能够通过例如来自β-丙内酯的β-丙氨酸合成法(Ford,Org.Sys.Coll.Vol.3,34(1955))而合成。作为其他合成方法,能够由丙烯腈及氨而合成。
[化学式1]
甘氨酸为下述式[2]所表示的化合物。作为本发明的线粒体功能活化剂中所含的甘氨酸,能够使用来自相对富含甘氨酸的食物或天然物质的提取物、浓缩物或提纯物等。此外,也可以使用合成的甘氨酸。作为甘氨酸的合成方法,可列举出斯特雷克法(Streckerreaction),该方法由甲醛、氢氰酸及氨合成氨基乙腈(甘氨腈),并将其以氢氧化钠等水解而制备甘氨酸的金属盐,然后以硫酸等酸进行中和。进一步,可列举出乙内酰脲法,该方法由甲醛与氢氰酸合成羟基乙腈,并使其在水的存在下与氨及二氧化碳进行反应从而制备乙内酰脲,然后通过水解而制备甘氨酸。
[化学式2]
作为β-丙氨酸或甘氨酸的盐,为与无机碱或有机碱等的盐、或与酸的盐,只要为医药或食物中允许的盐则没有限定。作为具体的与无机碱或有机碱等的盐,可列举出与无机碱、有机碱或金属醇盐的盐。可通过将β-丙氨酸或甘氨酸与无机碱、有机碱或金属醇盐混合而生成。
作为可形成盐的无机碱,可列举出碱金属(例如,锂、钠、或钾等)的氢氧化物、碳酸盐、碳酸氢盐、醋酸盐或氢化物;碱土类金属(例如,镁、钙、或钡)的氢氧化物或氢化物等。作为可形成盐的有机碱,可列举出二甲胺、三乙胺、哌嗪、四氢吡咯、哌啶、2-苯乙胺、苄胺、乙醇胺、二乙醇胺、吡啶、或三甲吡啶等。此外,作为金属醇盐,可列举出甲醇钠、叔丁醇钾、或甲醇镁等。作为β-丙氨酸或甘氨酸的盐,优选钠盐、钾盐、钙盐或它们的组合。
此外,作为具体的与酸的盐,可列举出与无机酸或有机酸的盐。作为可形成盐的无机酸,可列举出盐酸。
此外,作为线粒体的活化剂,还能够在本发明的β-丙氨酸或甘氨酸的基础上,使用具有羧基及氨基的其他氨基酸。具体而言,除了缬胺酸、亮氨酸、异亮氨酸、丙氨酸、精氨酸、谷氨酰胺、赖氨酸、天门冬氨酸、谷氨酸、脯氨酸、苏氨酸、组氨酸、苯丙氨酸、酪氨酸、色氨酸、天门冬酰胺、丝氨酸等构成蛋白质的氨基酸以外,还可列举出磷酸丝氨酸、乙醇胺磷酸酯、羟脯氨酸、肌氨酸、α-氨基己二酸、瓜氨酸、α-氨基正酪酸、β-氨基异酪酸、γ-氨基酪酸、3-甲基组氨酸、1-甲基组氨酸、肌肽、鹅肌肽、羟赖氨酸、鸟氨酸、乙醇胺、肉碱等生物游离氨基酸,但没有特别限定。
此外,还能够在本发明的β-丙氨酸或甘氨酸的基础上,使用β-丙氨酸或甘氨酸的衍生物。在本说明书中,β-丙氨酸或甘氨酸的衍生物是指,键合于主链的亚甲基碳的氢原子被取代而成的化合物。作为取代基,例如可列举出碳原子数为1~3的烷基。
<<线粒体>>
线粒体为真核生物的细胞器,其具有独自的线粒体DNA。其为进行有氧呼吸(好氧呼吸)的场所,且产生ATP。此外,已知线粒体在细胞凋亡中发挥重要的作用。
由于快肌纤维中线粒体少,因此容易通过糖分解而产生乳酸。另一方面,慢肌纤维及心肌中大量存在线粒体,通过摄取乳酸而用作能量源,产生ATP。
此外,线粒体在细胞凋亡中发挥重要的作用。通过DNA损伤等应激(stress),利用细胞凋亡诱导分子p53或调节细胞凋亡的Bcl-2家族蛋白质,线粒体的膜电位发生改变。其结果,细胞色素c从线粒体中泄漏从而诱导细胞凋亡。
<<提高有氧运动能力>>
通过本发明的线粒体功能活化剂,有氧运动能力升高。此外,通过本发明的线粒体功能活化剂,还能够提高脂肪的燃烧。作为有氧运动,可列举出跑步、行走、慢跑、骑行、越野滑雪、健身操(Aerobics dance)、登阶运动、游泳、或水中有氧锻炼。
本发明的线粒体功能活化剂能够用于增强有氧运动时的能力。线粒体在细胞中主要担负使用氧来生产能量的作用。有氧性的能量代谢在该线粒体中进行。即,能够通过使线粒体活性化来提高有氧运动的能力。此外,普遍认为线粒体的活性化与耐力训练具有相同的效果,因此本发明的线粒体功能活化剂有助于增强有氧运动时的耐力,此外能够用于增强进行在有氧运动时需要耐力的运动比赛例如长跑、游泳比赛、竞走、铁人三项、公路自行车、足球时的能力。因此,通过向对象者给予本发明的线粒体功能活化剂,能够将其用于与有氧运动相关的运动训练方法。这些运动训练方法为非医疗行为。
进一步,通过以线粒体的活性化提高有氧运动能力,可得到脂肪燃烧的效果。
<<由线粒体功能障碍导致的疾病>>
通过本发明的线粒体功能活化剂,能够预防或治疗因线粒体功能障碍导致的疾病。作为因线粒体功能障碍导致的疾病,没有特别限定,可列举出线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病。所述线粒体病为因线粒体的变异而无法充分进行产生有氧能量的疾病。此外,已知线粒体的功能低下会阻碍能量需求性高的组织的活动,因此会引发除线粒体病以外的各种疾病,即引发神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病等,通过本发明的线粒体功能活化剂,能够增加线粒体数量,从而能够促进组织再生,进而能够进行治疗。
作为所述线粒体病,没有限定,可列举出Leigh氏脑病、脑卒中样发作综合征(MELAS)、慢性进行性眼外肌瘫痪综合征(CPEO)、Kearns-Sayre综合征(KSS)、肌阵挛性癫痫伴破碎红纤维综合征(MERRF)、皮尔逊病(Pearson病)、Leber遗传性视神经病(LHON)、线粒体脑肌病、Barth综合征或乳酸酸中毒等。
作为所述神经变性疾病,没有限定,可列举出肌肉萎缩性侧索硬化症(ALS)、帕金森病、阿尔茨海默病、亨廷顿病、佛莱德立希失调症、多系统萎缩症、进行性核上性麻痹、脊髓小脑变性症、脊髓性肌萎缩症、脊髓延髓肌萎缩症或腓骨肌萎缩症等。
作为所述免疫性神经疾病,没有限定,可列举出吉兰-巴雷综合征、多发性硬化症、Fisher综合征、慢性炎性脱髓鞘性多发性神经病或重症肌无力症等。
作为所述脑缺血性疾病,没有限定,可列举出脑梗塞。
作为所述肾脏疾病,没有限定,可列举出肾衰竭、淀粉样变肾病、膜性肾病、局灶节段性肾小球硬化症、IgA肾病、急性肾小管坏死、肾病综合征、糖尿病性肾病、痛风性肾病、肾性浮肿、肾肿瘤、肾缺血障碍、肾缺血再灌注损伤或多囊肾等。
作为所述肌肉疾病,没有限定,可列举出进行性肌营养不良、强直性肌营养不良、先天性肌病、代谢性肌病、远端型肌病、炎症性肌病、增龄性肌萎缩(肌少症、Sarcopenia)或废用性肌肉萎缩等。
作为所述心脏疾病,没有限定,可列举出心肌梗塞、心衰竭、缺血性心脏病或心肌病。
对于本发明的线粒体功能活化剂带来的“功能的活性化”,只要可提高线粒体的功能则没有特别限定,例如可列举出线粒体数量的增加或活性化的线粒体数量的增加。
此外,线粒体功能活化剂带来的“功能的活性化”还包括提高线粒体的功能的基因的活性化。例如,作为基因的活性化,可列举出参与线粒体的生物合成的基因Pgc-1α转录的增加。此外,可列举出与线粒体的脂肪酸β氧化螺旋的步骤相关的乙酰辅酶A酰基转移酶2(Acaa2)及乙酰辅酶A酰基转移酶1b(Acaa1b)转录的增加。
作为本发明的线粒体功能活化剂的给予剂型,没有特别限定,例如可列举出散剂、细粒剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳剂、糖浆、提取液、或药丸等口服剂;或注射剂、外用液剂、软膏、栓剂、局部给药的乳膏、或滴眼剂等非口服剂。
口服剂可使用例如明胶、海藻酸钠、淀粉、玉米淀粉、白砂糖、乳糖、葡萄糖、甘露醇、羧甲基纤维素、糊精、聚乙烯吡咯烷酮、结晶纤维素、大豆卵磷脂、蔗糖、脂肪酸酯、滑石、硬脂酸镁、聚乙二醇、硅酸镁、无水硅酸或合成硅酸铝等赋形剂、粘合剂、崩解剂、表面活性剂、润滑剂、流动性改进剂、稀释剂、保存剂、着色剂、香料、调味剂、稳定剂、保湿剂、防腐剂、或抗氧化剂等,并按照常规方法进行制造。
作为非口服剂,例如可列举出注射剂。在注射剂的制备中,除了有效成分以外,还能够任意使用例如生理盐水或林格氏液等水溶性溶剂;植物油或脂肪酸酯等非水溶性溶剂;葡萄糖或氯化钠等等渗剂(isotonicifier);助溶剂;稳定剂;防腐剂;悬浮剂或乳化剂等。
使用线粒体功能活化剂时的给予量,能够根据例如所使用的有效成分的种类、疾病的种类、患者的年龄、性别、体重、症状的程度或给予方法而适当确定,并可通过口服方式或非口服方式进行给予。例如,口服摄取本发明的线粒体功能活化剂时的摄取量,例如成人的情况下,以β-丙氨酸或甘氨酸计,优选每日0.01~100mg/kg。另外,上述的给予方法仅为一个例子,也可以采用其他给予方法。针对人体的线粒体功能活化剂的给予方法、给予量、给予期间及给予间隔等,可以通过管理下的临床试验而确定。
进一步,给予方式也并非限定于药品,还能够以各种的方式而给与,例如,作为功能性食品或健康食品(包括饮料)或饲料的饮料食物的方式。
对于含有β-丙氨酸或甘氨酸的线粒体功能活化剂的制造方法,除了包含β-丙氨酸或甘氨酸型磷脂作为有效成分以外,能够利用公知的药品的制造方法而制造。
本发明的线粒体功能活化剂能够含有其他成分。作为所述其他成分,例如可列举出食用油脂、水、甘油脂肪酸酯、蔗糖脂肪酸酯、山梨糖醇酐脂肪酸酯、丙二醇脂肪酸酯、甘油有机酸脂肪酸酯、聚甘油脂肪酸酯、硬脂酰乳酸钙、硬脂酰乳酸钠、聚氧乙烯山梨糖醇酐脂肪酸酯等乳化剂;角豆胶、卡拉胶、海藻酸类、果胶、黄原胶、结晶纤维素、羧甲基纤维素、甲基纤维素、琼脂、葡甘露聚糖、明胶、淀粉或化工淀粉等增粘稳定剂;食盐或盐化钾等咸味剂;醋酸、乳酸或葡萄糖酸等酸味剂;糖类或糖醇类、甜菊糖或阿斯巴甜等甜味剂;β-胡萝卜素、焦糖、或红曲色素等着色剂;生育酚或茶提取物等抗氧化剂;香料、pH调节剂、食品保存剂或保质期延长剂等食品原料或食品添加剂。此外,还能够含有各种维生素或辅酶Q、植物固醇或乳脂球膜等功能原料。在本发明的线粒体功能活化剂中,这些其他成分的含量优选合计为80质量%以下,更优选为40质量%以下,进一步优选为20质量%以下。
本发明的线粒体功能活化剂能够对人进行给予,但其给予对象也可以为除了人以外的动物,可列举出狗、猫、兔、仓鼠、豚鼠、及松鼠等宠物;牛、马及猪等家畜;小鼠、大鼠等实验动物;以及动物园等中饲养的动物等。
[2]线粒体功能活化方法
本发明的线粒体功能的活化方法,包括向对象给予所述线粒体功能活化剂的工序。即,所述β-丙氨酸或甘氨酸能够用于线粒体的功能活化方法。通过向人或动物给予有效量的所述线粒体功能活化剂,能够使线粒体的功能活性化。此外,当所述对象患有因线粒体功能障碍导致的疾病时,也可以实施本发明的线粒体的功能活化方法。此外,本发明的线粒体的功能活化方法也可以用于提高对象的脂肪燃烧或提高有氧运动能力。
此外,β-丙氨酸或甘氨酸能够利用线粒体的功能活性化而用于提高有氧运动能力的方法、或用于增强慢肌的运动训练方法。
进一步,β-丙氨酸或甘氨酸能够利用线粒体的功能活性化而用于预防或治疗因线粒体功能障碍导致的疾病的方法。即,本发明的预防或治疗因线粒体功能障碍导致的疾病的方法,包括向因线粒体功能障碍导致的疾病患者给予治疗有效量的β-丙氨酸或甘氨酸或者它们的盐的工序。作为所述因线粒体功能障碍导致的疾病,例如可列举出线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病、心脏疾病、阿尔茨海默病或肌少症等。
<<线粒体的功能活化方法中所使用的β-丙氨酸或甘氨酸>>
所述β-丙氨酸或甘氨酸能够用于线粒体的功能活化方法。即,本说明书公开使用于线粒体的功能活化方法的β-丙氨酸或甘氨酸。
此外,β-丙氨酸或甘氨酸为使用于提高有氧运动能力的方法、或用于增强慢肌的运动训练方法的β-丙氨酸或甘氨酸。进一步,β-丙氨酸或甘氨酸为使用于预防或治疗因线粒体功能障碍导致的疾病的方法的β-丙氨酸或甘氨酸。
<<β-丙氨酸或甘氨酸在制造线粒体功能活化剂中的应用>>
所述β-丙氨酸或甘氨酸能够用于线粒体的功能活化剂的制造。即,本说明书公开β-丙氨酸或甘氨酸在制造线粒体的功能活化剂中的应用。
此外,β-丙氨酸或甘氨酸能够用于在制造有氧运动能力提高剂、脂肪燃烧剂、或因线粒体功能障碍导致的疾病的预防或治疗剂中的应用。
[3]线粒体功能活化用食品组合物
本发明的线粒体功能活化用食品组合物包含β-丙氨酸或甘氨酸、或者它们的盐。线粒体功能活化用食品组合物可以单独包含β-丙氨酸、甘氨酸或它们中任意一种的盐,也可以包含其中两种以上的组合。
本发明的线粒体功能活化用食品组合物只要为能够以口服方式进行给予,则可以包含所述线粒体功能活化剂。即,本发明的线粒体功能活化用食品组合物只要能够以口服方式进行使用,则能够使用所述线粒体功能活化剂的项中所记载的条件等,且能够获得相同的效果。
本发明的线粒体功能活化用食品组合物中的食品为饮料食品,包括饮料。作为本发明中的食品,没有特别限定,例如可列举出味噌、酱油、面酱、酱汁、汤头、意面酱、沙拉酱、蛋黄酱、番茄酱、辣酱油、猪排酱、或拌饭调料(ふりかけ)等调料;清汤汤料、咖喱块、白酱、茶泡饭汤料、或汤底等方便食品;味噌汤、清汤、法式清汤、或浓汤等汤类;烤肉、火腿、或香肠等畜牧加工品;鱼糕、海鲜干、腌制海鲜、佃煮、或珍味食品等水产加工品;腌菜等蔬菜加工品;薯片或米饼等零食类;面包、甜点、或曲奇等烘焙食品类;水煮菜、油炸食品、烧烤、咖喱、炖菜、焗烤菜、米饭、粥、或饭团等熟食;意大利面、乌冬面、或拉面等面类食品;人造黄油、起酥油、人造奶油(fat spread)或风味人造奶油等油脂加工食品;鲜花膏或馅料等甜点面包制作用原料;面包用混合粉、蛋糕用混合粉或油炸食品用混合粉等混合粉;巧克力、糖果、果冻、冰淇淋或口香糖等甜点类;豆沙包或蜂蜜蛋糕等日式点心类;咖啡、咖啡牛奶、红茶、奶茶、豆浆、营养饮品、蔬菜饮料、醋饮料、果汁、可乐、矿泉水或运动饮料等饮料;啤酒、葡萄酒、鸡尾酒或酸味鸡尾酒(SOUR)等酒精饮料类;牛奶、酸奶、或奶酪等奶或奶制品等。
本发明的线粒体功能活化用食品组合物除了包含β-丙氨酸或甘氨酸等以外,能够使用公知的食品饮料的制造方法而制造。
本发明的线粒体功能活化用食品组合物表现出与所述线粒体功能活化剂相同的效果。因此,本发明的线粒体功能活化用食品组合物可提高有氧运动能力。此外,通过本发明的线粒体功能活化剂能够提高脂肪燃烧。因此,通过使对象摄取本发明的线粒体功能活化用食品组合物的饮食方法,能够获得增强有氧运动时的能力或增强慢肌等效果。
[4]运动训练方法
本发明的运动训练方法包括使对象摄取所述线粒体功能活化剂的工序。本发明的运动训练方法尤其对于增强有氧运动时的能力或增强慢肌有效。
作为有氧运动,可列举出跑步、行走、慢跑、骑行、越野滑雪、健身操、登阶运动、游泳、或水中有氧锻炼。
本发明的运动训练方法对于耐力锻炼有用。即,有助于增强有氧运动时的耐力,并且能够用于增强进行在有氧运动时需要耐力的运动比赛,例如增强长跑、游泳比赛、竞走、铁人三项、公路自行车、足球时的能力。这些运动训练方法为非医疗行为。
[5]饮食方法
本发明的饮食方法包括使对象摄取所述线粒体功能活化剂的工序。本发明的饮食方法对于增强有氧运动时的能力或增强慢肌有效。另外,所述饮食方法为非医疗行为。
<<作用>>
本发明的线粒体功能活化剂等中所含的β-丙氨酸或甘氨酸可使线粒体数量增加或使线粒体的功能活性化的机理并未完全明确,但推断β-丙氨酸或甘氨酸直接作用于细胞及其线粒体的活性化。此外,除了主链的亚甲基碳原子数为2个和1个以外,β-丙氨酸或甘氨酸的化学结构完全相同,可以认为具有羧基及氨基对线粒体功能活性化起到了重要的作用。因此,虽然大多的氨基酸均能够用作本发明的线粒体功能活化剂的有效成分,但特别优选β-丙氨酸、甘氨酸或γ-氨基酪酸。
实施例
以下,通过实施例对本发明进行具体的说明,但本发明的范围并不限定于这些实施例。
<<实施例1>>
在本实施例中,使用未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞,研究β-丙氨酸的线粒体功能的活性化。
使用包含10%灭活FBS、青霉素(10万U/L;Meiji,Tokyo,Japan)、链霉素(100mg/L:Meiji)、NaHCO3(2.0g/L:Wako,Osaka,Japan)、L-谷氨酰胺(L-glutamine)(Wako)的达尔伯克改良伊格尔培养基(Dulbecco’s Modified Eagle Medium)(DMEM)培养基(Nissui,Tokyo,Japan)于37℃、5%的CO2存在下对C2C12细胞进行传代培养。
对于β-丙氨酸,将0.0089g的β-丙氨酸粉末(Wako)溶解于1×PBS(1mL)中并利用0.22μM×13mm的过滤器(Merck Millipore,Billerica,MA,USA)进行过滤灭菌,将该经过滤灭菌的溶液制成100mM母液(stock solution)。
通过以下方式测定C2C12细胞内的线粒体数量。以4.0×105个细胞/孔的方式将C2C12细胞接种到6孔板中,24小时后,以成为500μM或1mM的方式添加β-丙氨酸。此外,对照组中添加1×PBS。从添加起经过2小时后,吸除培养基,以2mL/孔的的方式添加用含10%FBS的DMEM培养基稀释至200nM的Mito Tracker Green FM(Invitrogen),在遮光下,于37℃、5%的CO2存在下培养30分钟。然后,吸除稀释液,以1mL/孔添加1×PBS,从而对细胞进行洗涤。吸除1×PBS,以500μL/孔的方式添加胰蛋白酶后,吸除胰蛋白酶,在遮光下,于37℃、5%的CO2存在下培养5分钟。培养后,将细胞悬浮于1mL的含10%FBS的DMEM培养基中并回收至1.5mL试管。使该细胞悬浮液通过尼龙网(共进理工公司,Tokyo,Japan)后,利用流式细胞计数仪(EPICS XL System II-JK,贝克曼库尔特,CA,USA;细胞分析仪EC800 C5C,Sony,Tokyo,Japan)进行测定。通过FCM分析软件FlowJo(TOMY Digital Biology,Tokyo,Japan)进行分析。
此外,接种细胞,24小时后以成为100μM或1mM的方式添加β-丙氨酸,24小时后第二次添加β-丙氨酸,在第二次添加的24小时后吸除培养基,将添加Mito Tracker Green FM(Invitrogen)的稀释液的细胞作为以β-丙氨酸处理48小时的细胞,进行与以β-丙氨酸处理2小时的细胞相同的操作。
通过以下方式测定C2C12细胞内的活性化的线粒体数量。以4.0×105个细胞/孔的方式将C2C12细胞接种到6孔板中,24小时后,以成为500μM或1mM的方式添加β-丙氨酸。此外,对照组中添加1×PBS。从添加起经过2小时后,吸除培养基,以2mL/孔的方式添加利用含10%FBS的DMEM培养基稀释至250nM的Mito Tracker Red CMXRos(Invitrogen),在遮光下,于37℃、5%的CO2存在下培养30分钟。然后,吸除稀释液,以1mL/孔的方式添加1×PBS,从而对细胞进行洗涤。吸除1×PBS,以500μL/孔添加胰蛋白酶后,吸除胰蛋白酶,在遮光下,于37℃、5%的CO2存在下培养5分钟。培养后,将细胞悬浮在1mL的含10%FBS的DMEM培养基中并回收至1.5mL的试管。使该细胞悬浮液通过尼龙网(共进理工公司)后,利用流式细胞计数仪(EPICS XL System II-JK,贝克曼库尔特;细胞分析仪EC800 C5C,Sony)进行测定。通过FCM分析软件FlowJo(TOMY Digital Biology)进行分析。
此外,接种细胞,24小时后,以成为100μM或1mM的方式添加β-丙氨酸,24小时后第二次添加β-丙氨酸,在第二次添加β-丙氨酸24小时后吸除培养基,将添加Mito TrackerRed CMXRos(Invitrogen)的稀释液的细胞作为处理48小时的细胞,进行与以β-丙氨酸处理2小时的细胞相同的操作。
Mito Tracker Green FM(Invitrogen)为以不依赖于膜电位的方式对线粒体进行染色的荧光试剂。因此,通过添加β-丙氨酸,流式细胞计数仪的直方图的谱峰向右发生位移这一现象表示线粒体数量增加。如图1所示,不论处理时间为2小时或48小时中的哪一种,均确认到了通过向未分化细胞中添加β-丙氨酸,线粒体数量以浓度依赖性方式增加。
另一方面,Mito Tracker Red CMXRos(Invitrogen)为以膜电位依赖性方式对线粒体进行染色的荧光试剂。因此,通过添加β-丙氨酸,流式细胞计数仪的直方图的谱峰向右发生位移这一现象表示线粒体的活性增强。如图2所示,通过向未分化细胞中添加β-丙氨酸,2小时及48小时的任一处理时间,均确认到了线粒体浓度依赖性的活性化。
<<实施例2>>
在本实施例中,使用未分化的来自于小鼠骨骼肌的成肌细胞株C2C12细胞,研究甘氨酸的线粒体功能的活性化。
除了使用甘氨酸以代替β-丙氨酸以外,重复进行实施例1的操作。以如下方式制备甘氨酸溶液。将0.0075g的甘氨酸粉末(Wako)溶解于1×PBS(1mL)中并利用0.22μM×13mm的过滤器(Merck Millipore)进行过滤灭菌,将该经过滤灭菌的溶液制成100mM母液。
如图3所示,通过向未分化细胞中添加甘氨酸,2小时及48小时的任一处理时间,均确认到了线粒体数量浓度依赖性的增加。此外,如图4所示,通过向未分化细胞中添加甘氨酸,2小时及48小时的任一处理时间,均确认到了线粒体浓度依赖性的的活性化。
<<实施例3>>
在本实施例中,使用分化为肌管细胞的来自于小鼠骨骼肌的成肌细胞株C2C12细胞,研究甘氨酸的线粒体功能的活性化。除了使用分化为肌管细胞的C2C12细胞以代替未分化的C2C12细胞以外,重复进行实施例2的操作。按照以下方式进行将C2C12细胞分化诱导为肌管细胞。
接种C2C12细胞,在细胞达到约90%汇合度后,将培养基更换为含2%马血清(HS)(Invitrogen,Tokyo,Japan)的DMEM培养基,从而进行分化诱导。此后,每隔48小时进行培养基更换,并同时于37℃、5%的CO2存在下培养一周左右,将以该方式培养的细胞作为肌管细胞而用于实验。此外,对Mito Tracker Green FM(Invitrogen)及Mito Tracker RedCMXRos(Invitrogen)以含2%HS的DMEM培养基进行稀释,并将染色后的细胞以含2%HS的DMEM培养基回收。
如图5所示,通过向分化细胞中添加甘氨酸,2小时及48小时的任一处理时间,均确认到了线粒体数量浓度依赖性的增加。此外,如图6所示,通过向分化细胞中添加甘氨酸,2小时及48小时的任一处理时间,均确认到了线粒体的浓度依赖性活性化。
<<实施例4>>
在本实施例中,测定以β-丙氨酸或甘氨酸进行了处理的来自于小鼠骨骼肌的成肌细胞株C2C12细胞中的Pgc-1α基因的转录。
首先,使用High Pure RNAIsolation Kit(Roche,Basel,Switzerland)制备细胞中的总RNA。
以4.0×105个细胞/孔的方式将C2C12细胞接种到6孔板中,细胞达到约90%汇合度后,将培养基更换为含2%HS的DMEM培养基,从而进行分化诱导。此后,每隔48小时更换培养基,并同时于37℃、5%的CO2存在下培养一周左右,将以该方法培养的细胞用于实验。对分化后的细胞添加β-丙氨酸及甘氨酸,在对照组中添加1×PBS。从添加起经24小时后,进行第二次样本添加,在第二次添加样本的24小时后吸除培养基,以1mL/孔添加1×PBS,从而对细胞进行洗涤。洗涤进行两次。然后,添加1×PBS(200μL/孔)及裂解/结合缓冲液(Lysis/-binding buffer)(400μL/孔)并使其遍布整盘后,将其全部回收到1.5mL试管中。利用旋涡混合器将回收的样本悬浮60秒。组装过滤器试管与回收用试管,将样本溶液添加到过滤器试管中,以10000rpm于4℃离心分离15秒。舍弃排出到回收用试管中的液体,再次组装过滤器试管与回收用试管。利用1.5mL试管,将相对于每份样本为90μL的DNase IncubationBuffer及相对于每份样本为10μL的DNase I进行混合。将该混合液添加到过滤器试管中,在室温下培养15分钟。培养后,将Wash buffer I(500μL)添加到过滤器试管中,以10000rpm于4℃离心分离15秒。舍弃排出到回收用试管中的液体,再次组装过滤器试管与回收用试管。将Wash buffer II(500μL)添加到过滤器试管中,以10000rpm于4℃离心分离15秒。舍弃排出到回收用试管中的液体,再次组装过滤器试管与回收用试管。将Wash buffer II(200μL)添加到过滤器试管中,以13000×g于4℃离心分离2分钟。将过滤器试管插入到新的1.5mL试管中,向过滤器试管中添加Elution buffer(70μL),在室温下静置3分钟后,以10000rpm于4℃离心分离1分钟。将通过以上的操作得到的洗脱液作为RNA溶液。使用NanoDrop 2000/2000c分光光度计(Thermo Scientific,Waltham,MA,USA)根据260nm时的吸光值算出溶液中的RNA浓度,并用于以后的实验。
以如下方法合成cDNA。向1.0μg提取自细胞的总RNA添加0.5μL的Oligo(dT)20引物(10pmoles/μL),以使总液量为13.5μL的方式添加RNase Free水。进行叩击使其悬浮,快速离心(spin down)后利用Thermal Cycler PTC-200(MJ Research,Waltham,MA,USA)于65℃进行5分钟热处理反应,立即移至冰中静置5分钟。在0.2mL试管中对每份样本添加4μL的5×RT Buffer(TOYOBO,Osaka,Japan)、2μL的10mM dNTPs(GE Healthcare,Amersham Place,UK)、0.5μL的逆转录酶ReverTra Ace(100units/μL)(TOYOBO),通过移液操作(pipetting)进行混合。将6.5μL该混合液添加到静置了5分钟的试管中,在冰中移液后快速离心。然后于42℃反应20分钟、于99℃反应5分钟,由此合成cDNA,将其用作后续实时定量PCR的模板。
将所制作的cDNA用作模板进行定量RT-PCR。在冰上,向PCR试管(0.2mL)中添加49μL灭菌水、各3.5μL的稀释至10μM的引物(正向/反向两种)、7.0μL模板cDNA(Pgc-1α的引物稀释为1/5、β-肌动蛋白的引物稀释为1/50),快速离心后添加24.5μL的THUNDERBIRD SYBRqPCR Mix(TOYOBO),在冰上充分悬浮。在阴性对照组中,向0.2mL PCR试管中添加17μL灭菌、两者各0.5μL均稀释成10μM的引物正向/反向,快速离心后添加7μL的THUNDERBIRD SYBRqPCR Mix,在冰上充分混合。然后,向96孔PCR板(NIPPON Genetics,Tokyo,Japan)的3孔中各添加25μL,使用Thermal Cycle Dicer Real Time System(Takara,Shiga,Japan)进行定量RT-PCR。以如下方式进行PCR反应:进行95℃下30秒的1个循环、95℃下5秒且60℃下60秒的40个循环,并通过FAM进行检测。使用ΔΔCt法,将作为管家基因之一的β-肌动蛋白的Ct值与Pgc-1α的Ct值进行比较,相对地对Pgc-1α的表达量进行定量。另外,委托Sigma公司进行引物的合成,所使用的引物的序列如下所示。
β-肌动蛋白正向:5’-GGCCAGGTCATCACTATTG-3’(序列号1)
β-肌动蛋白反向:5’-GAGGTCTTTACGGATGTCAAC-3’(序列号2)
Pgc-1α正向:5’-AATGCAGCGGTCTTAGCACT-3’(序列号3)
Pgc-1α反向:5’-TGTTGACAAATGCTCTTCGC-3’(序列号4)
如图7所示,通过500μM及1mM的β-丙氨酸处理,此外,通过500μM的甘氨酸处理,在分化C2C12细胞中,Pgc-1α的表达得到了增强。
<<实施例5>>
在本实施例中,制备包含β-丙氨酸及甘氨酸的胶囊形态的线粒体功能活化剂。
将1.0重量份的β-丙氨酸、1.0重量份的甘氨酸及0.5重量份的糊精混合均匀后,填充于硬胶囊中,从而制备内容量为250mg的胶囊剂(β-丙氨酸100mg/个胶囊、甘氨酸100mg/个胶囊)。
<<实施例6>>
在本实施例中,制备包含β-丙氨酸及甘氨酸的饮料形态的线粒体功能活化用食品组合物。
向35.5g的运动饮料粉末、0.5g的β-丙氨酸、0.5g的甘氨酸中添加水,制造总量为500mL的饮料。
<<实施例7>>
在本实施例中,制备凝胶形态的线粒体功能活化剂,所述凝胶形态的线粒体功能活化剂包含含有β-丙氨酸及甘氨酸的胶囊。
添加7.1重量份的运动饮料粉末、2重量份的明胶水解物及适量的水并加热溶解。然后,添加0.1重量份的β-丙氨酸、0.1重量份的甘氨酸与适量的水从而使总量为100重量份,制备每份150g的凝胶状制剂。
<<实施例8>>
在本实施例中,使用共聚焦激光扫描显微镜研究线粒体的活性化。
以与实施例1相同的操作,制备以β-丙氨酸处理48小时小时的细胞。另外,以3.0×104个细胞/mL或5.0×104个细胞/mL的浓度接种C2C12细胞,一同添加Mito Tracker GreenFM(Invitrogen)及Mito Tracker Red CMXRos(Invitrogen)。用共聚焦激光扫描显微镜(Olympus Corporation)观察所得到的细胞。
如图8所示,通过添加500μM的β-丙氨酸,Mito Tracker Red CMXRos的红色荧光尤其变强,通过添加1mM的β-丙氨酸,红色荧光进一步变强。
<<实施例9>>
在本实施例中,使用流式细胞仪测定Mito Tracker Red CMXRos的荧光。
除了将β-丙氨酸处理设为72小时以外,重复进行实施例1的Mito Tracker RedCMXRos的操作,从而制备细胞。
通过流式细胞仪(贝克曼库尔特公司)对所得到的细胞进行分析。如图9所示,通过添加β-丙氨酸,Mito Tracker Red的荧光增强。因此,通过添加β-丙氨酸,线粒体发生了活性化。
<<实施例10>>
在本实施例中,测定进行了β-丙氨酸处理的来自于小鼠骨骼肌的成肌细胞株C2C12细胞中的Acaa1b及Acaa2的基因的转录。
除了使用Acaa1b正向引物及Acaa1b反向引物、或Acaa2正向引物及Acaa2反向引物以代替Pgc-1α正向引物及Pgc-1α反向引物以外,重复进行实施例4的操作。
Acaa1b正向:5’-TGAGCGGTTTGGCGTTT-3’(序列号5)
Acaa1b反向:5’-CTTGTCACCCTTGTCATTCAGG-3’(序列号6)
Acaa2正向:5’-TGCCCCTCAGTTCTTGTCTGT-3’(序列号7)
Acaa2反向:5’-AGGTGTGCGGTGATTCTGG-3’(序列号8)
如图10所示,通过500μM的β-丙氨酸处理,在分化C2C12细胞中,Acaa1b及Acaa2的表达增强。
工业实用性
本发明的线粒体功能活化剂及线粒体功能活化用食品组合物能够用于预防或治疗因线粒体功能障碍导致的疾病,或能够用于增强慢肌、增强运动训练或促进脂肪代谢等。
<110> 有机合成药品工业株式会社
国立大学法人九州大学
<120> 线粒体功能活化剂
<130> YGK-046
<150> JP 2019-121874
<151> 2019-06-28
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> β-肌动蛋白正向引物
<400> 1
ggccaggtca tcactattg 19
<210> 2
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> β-激动蛋白反向引物
<400> 2
gaggtcttta cggatgtcaa c 21
<210> 3
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> Pgc-1alfa 正向引物
<400> 3
aatgcagcgg tcttagcact 20
<210> 4
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> Pgc-1alfa 反向引物
<400> 4
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<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> Acaa1b 正向引物
<400> 5
tgagcggttt ggcgttt 17
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<211> 22
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<213> 人工序列(Artificial Sequence)
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<213> 人工序列(Artificial Sequence)
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Claims (19)
1.一种线粒体功能活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐。
2.根据权利要求1所述的线粒体功能活化剂,其用于提高脂肪燃烧或提高有氧运动能力。
3.根据权利要求1所述的线粒体功能活化剂,其用于预防或治疗因线粒体功能障碍导致的疾病。
4.根据权利要求3所述的线粒体功能活化剂,其中,所述因线粒体功能障碍导致的疾病为线粒体病、神经变性疾病、免疫性神经疾病、脑缺血性疾病、肾脏疾病、肌肉疾病或心脏疾病。
5.根据权利要求4所述的线粒体功能活化剂,其中,所述线粒体病为Leigh氏脑病、脑卒中样发作综合征(MELAS)、慢性进行性眼外肌瘫痪综合征(CPEO)、Kearns-Sayre综合征(KSS)、肌阵挛性癫痫伴破碎红纤维综合征(MERRF)、皮尔逊病、Leber遗传性视神经病(LHON)、线粒体脑肌病、Barth综合征或乳酸酸中毒。
6.根据权利要求4所述的线粒体功能活化剂,其中,所述神经变性疾病为肌肉萎缩性侧索硬化症(ALS)、帕金森病、阿尔茨海默病、亨廷顿病、佛莱德立希失调症、多系统萎缩症、进行性核上性麻痹、脊髓小脑变性症、脊髓性肌萎缩症、脊髓延髓肌萎缩症或腓骨肌萎缩症。
7.根据权利要求4所述的线粒体功能活化剂,其中,所述免疫性神经疾病为吉兰-巴雷综合征、多发性硬化症、Fisher综合征、慢性炎性脱髓鞘性多发性神经病或重症肌无力症。
8.根据权利要求4所述的线粒体功能活化剂,其中,所述脑缺血性疾病为脑梗塞。
9.根据权利要求4所述的线粒体功能活化剂,其中,所述肾脏疾病为肾衰竭、淀粉样变肾病、膜性肾病、局灶节段性肾小球硬化症、IgA肾病、急性肾小管坏死、肾病综合征、糖尿病性肾病、痛风性肾病、肾性浮肿、肾肿瘤、肾缺血障碍、肾缺血再灌注损伤或多囊肾。
10.根据权利要求4所述的线粒体功能活化剂,其中,所述肌肉疾病为进行性肌营养不良、强直性肌营养不良、先天性肌病、代谢性肌病、远端型肌病、炎症性肌病、增龄性肌萎缩(肌少症)或废用性肌肉萎缩。
11.根据权利要求4所述的线粒体功能活化剂,其中,所述心脏疾病为心肌梗塞、心衰竭、缺血性心脏病或心肌病。
12.一种线粒体功能活化用食品组合物,其包含β-丙氨酸或甘氨酸、或者它们的盐。
13.一种线粒体功能的活化方法,其包括向对象给予权利要求1所述的线粒体功能活化剂的工序。
14.根据权利要求13所述的线粒体功能的活化方法,其用于提高所述对象的脂肪燃烧或提高有氧运动能力。
15.一种用于增强有氧运动时的能力或增强慢肌的运动训练方法,其包括使对象摄取权利要求1所述的线粒体功能活化剂的工序。
16.一种用于增强有氧运动时的能力或增强慢肌的饮食方法,其包括使对象摄取权利要求1所述的线粒体功能活化剂的工序。
17.一种Pgc-1α基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐。
18.一种Acaa1b基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐。
19.一种Acaa2基因活化剂,其包含β-丙氨酸或甘氨酸、或者它们的盐。
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CN107847475A (zh) * | 2015-05-28 | 2018-03-27 | 贝勒医学院 | 补充n‑乙酰半胱氨酸和甘氨酸以改善谷胱甘肽水平的有益效果 |
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JP2015097507A (ja) * | 2013-11-19 | 2015-05-28 | 国立大学法人九州大学 | ミトコンドリア活性化剤 |
CN107847475A (zh) * | 2015-05-28 | 2018-03-27 | 贝勒医学院 | 补充n‑乙酰半胱氨酸和甘氨酸以改善谷胱甘肽水平的有益效果 |
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