CN110996935A - 用于治疗线粒体功能障碍相关疾病的包含氨基酸的组合物 - Google Patents
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Abstract
用于在对象中促进线粒体生物发生并改善线粒体功能的组合物,所述组合物包含活性剂,所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸,以及柠檬酸、琥珀酸、苹果酸。
Description
技术领域
本说明书一般性地涉及包含氨基酸的组合物。更具体地,本说明书涉及包含氨基酸的组合物,其用于医药,特别是用于治疗与线粒体功能障碍(mitochondrialdysfunction)相关的疾病。
背景技术
线粒体是细胞器,其主要功能是氧化磷酸化,这是通过其将来源于葡萄糖或脂肪酸代谢的能量转化为三磷酸腺苷(adenosine triphosphate,ATP)的过程。然后,ATP用于驱动多种需要能量的生物合成反应和其他代谢活动。
线粒体功能障碍可能会影响任何组织,导致多种多样的症状,这取决于不同组织所被涉及的程度。
由线粒体功能障碍引起的疾病可包括例如:由于线粒体膜潜在的功能失常(malfunction)引起的线粒体肿胀、由于氧化应激(例如通过活性氧类(reactive oxygenspecies,ROS)或自由基的作用)引起的功能性障碍、由于遗传突变引起的功能性障碍,以及由于用于能量产生的氧化磷酸化机制的功能缺陷引起的疾病。
线粒体随着年龄的增长而劣化,失去呼吸活性,积累对其DNA(mtDNA)的损伤并产生过量的活性氧类(ROS)。
最近的证据表明,除主要的神经退行性疾病(例如,阿尔茨海默病(Alzheimer’sdisease)、帕金森病(Parkinson’s disease)和亨廷顿病(Huntington’s disease))以及慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD))之外,线粒体功能障碍还参与了数种疾病,包括与年龄相关的代谢和心血管障碍(动脉粥样硬化)。
线粒体功能障碍还在肥胖及相关病症,包括2型糖尿病、高血压、血脂异常、心力衰竭、肾疾病和骨质疏松症中被发现。
值得注意的是,肌少症(sarcopenia)被定义为由于骨骼肌质量和强度的非自愿丧失而导致老年人功能下降和独立性丧失的最重要原因之一以及所谓的衰弱综合征(frailty syndrome)的关键特征,其是由于线粒体质量和功能的降低。另外,恶病质(cachexia)或消耗综合征定义为体重的非故意损失、肌肉萎缩、疲劳和虚弱。恶病质见于患有癌症、AIDS、乳糜泻(coeliac disease)、COPD、多发性硬化、类风湿性关节炎、充血性心力衰竭、结核病和神经性厌食的人。尚未发现用于预防和/或治疗这种病症的药物或营养物。
因此,鉴于全球肥胖流行和增长的人口老龄化,在不久的将来,最常见的患者将是肌肉减少性肥胖的年长对象。
缓解线粒体生物发生和活动中与年龄相关的缺陷的策略包括促进哺乳动物存活的卡路里限制(calorie restriction,CR)和适度的体育锻炼。已发现,CR通过预防炎性病症、心血管病症、癌症病症和神经退行性病症延长身体健康的预期寿命(健康寿命(healthspan))。CR促进参与线粒体生物发生的基因的表达并且改善衰老或受损的细胞和组织中的线粒体功能(Nisoli et al.,2005)。
尽管CR对人具有有益作用,但这样的饮食方案不太可能在年长者中广泛采用。
作为在不减少热量摄取的情况下提供饮食限制的益处的替代方案,在哺乳动物中施用包含氨基酸的特定组合物,如例如在EP 2 196 203 B1中公开的。
发明内容
本说明书的目的是提供新的基于氨基酸的组合物,其在对象中促进线粒体生物发生并改善线粒体功能方面特别有效。
根据本说明书,由于在所附权利要求书中特别提到的主题而实现了以上目的,所附权利要求书被理解为构成本公开内容的组成部分。
本说明书的一个实施方案提供了用于在对象中促进线粒体生物发生并改善线粒体功能的组合物,所述组合物包含活性剂,所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸,以及柠檬酸、琥珀酸、苹果酸。
在一个或更多个实施方案中,组合物的活性剂还包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和酪氨酸的一种或更多种氨基酸。
在一个或更多个实施方案中,本文中公开的组合物可用于医药。
在一个优选实施方案中,该组合物旨在用于治疗和/或预防选自肌少症和心力衰竭的线粒体功能障碍相关疾病。
在另一个优选实施方案中,该组合物可用于治疗和/或预防线粒体功能障碍相关的神经退行性疾病,例如阿尔茨海默病、帕金森病和亨廷顿病。
在另一个实施方案中,该组合物可用于治疗和/或预防选自动脉粥样硬化、2型糖尿病、肾疾病、COPD和骨质疏松症的线粒体功能障碍相关疾病。
在一个或更多个实施方案中,该组合物可用于治疗和/或预防营养不良临床表现,尤其是用于治疗和/或预防蛋白质营养不良和恶病质。
附图说明
现在将参照附图仅以作为实例的方式描述本发明,其中:
-图1示出了在用不同的基于氨基酸的组合物处理48小时(48小时,2天)的HL-1心肌细胞中借助于定量PCR分析的线粒体DNA(mtDNA)的含量。定量PCR一式三份进行并归一化为编码GAPDH的基因组DNA(n=3,平均值±SEM)。将未经处理细胞(CT)的值取为1.0(*p<0.05,相对于未经处理细胞;#p<0.05,相对于BCAAem和B2)。
-图2示出了在用基于氨基酸的组合物处理24小时(1天)的HL-1心肌细胞中借助于定量PCR分析的线粒体生物发生标志物(Tfam、PGC-1α、Cyt c)的mRNA水平。定量PCR一式三份进行并归一化为GAPDH(n=3,平均值±SEM)。*p<0.05,相对于表示为1.0的未经处理细胞。#p<0.05,相对于BCAAem。
-图3示出了在用基于氨基酸的组合物处理48小时(2天)的HL-1心肌细胞中通过定量PCR分析的线粒体生物发生标志物(Tfam、PGC-1α、Cyt c)的水平。定量PCR一式三份进行并归一化为GAPDH(n=3,平均值±SEM)。*p<0.05,相对于表示为1.0的未经处理细胞。#p<0.05,相对于BCAAem。
-图4示出了Krüppel样因子15(Krüppel-like factor 15,KFL15)和靶向线粒体基质的蛋白磷酸酶2C家族成员(protein phosphatase 2C family member,PP2CM)的mRNA水平,KFL15和PP2CM是调节支链氨基酸(branched chain amino acid,BCAA)的分解代谢的蛋白质。通过定量PCR分析了在用基于氨基酸的组合物处理24小时(1天)或48小时(2天)的HL-1心肌细胞中的PP2CM和KFL15。定量PCR一式三份进行并归一化为GAPDH(n=3,平均值±SEM)。*p<0.05,相对于表示为1.0的未经处理细胞;#p<0.05,相对于BCAAem和B2。
-图5示出了氧消耗率(oxygen consumption rate,OCR)的评价。用基于氨基酸的组合物或DETA-NO处理48小时的HL-1心肌细胞中的氧消耗。****p<0.001,相对于未经处理细胞;####p<0.001,相对于BCAAem和B2。
具体实施方式
在以下描述中,给出了许多具体细节以提供对一些实施方案的透彻理解。可以在没有一个或更多个具体细节的情况下,或者在其他方法、组件、材料等的情况下实践一些实施方案。在其他情况下,未详细示出或描述公知的结构、材料或操作以避免使一些实施方案的一些方面模糊。
在本说明书通篇提及的“一个实施方案”意指与该实施方案相关描述的特定的特征、结构或特性包括在至少一个实施方案中。因此,在本说明书通篇多处出现的短语“在一个实施方案中”不一定均是指同一实施方案。此外,在一个或更多个实施方案中,可以任何合适的方式对特定的特征、结构或特性进行组合。本文中提供的标题仅是为了方便,并不解释一些实施方案的范围或含义。
本文中公开的组合物包含活性剂,该活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸,以及酸柠檬酸、琥珀酸、苹果酸。
如EP 2 196 203 B1中所公开的,在哺乳动物中施用包含氨基酸的组合物作为提供卡路里限制(CR)的益处的替代方案。这样的基于氨基酸的组合物(在本公开内容中称为“BCAAem”)已显示出导致心肌和骨骼肌二者中线粒体生物发生提高(D’Antona et al.,2010)。这些作用是由内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的表达和随后一氧化氮(nitric oxide,NO)产生介导的(D’Antona et al.,2010)。
本申请的发明人出乎意料地发现,通过向包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸的类似组合的组合物添加特定酸,发生了细胞线粒体功能的显著提高。
本申请的发明人测试了在其中包含的酸方面不同的许多组合物,并且发现包含与亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸组合的柠檬酸、琥珀酸和苹果酸作为活性剂的组合物对于指定目的非常有效。事实上,包含上述活性剂的组合物以及包含含有另一些特定氨基酸(下表1中列出的)的上述活性剂的组合物在促进线粒体生物发生和功能方面比先前测试的基于氨基酸的组合物(BCAAm)更有效。
将组合物在心肌细胞系(HL-1)(即,代表心脏功能性的体外模型的细胞)上进行测试。从这些心肌细胞的分析获得的结果可用于验证新组合物在预防心力衰竭中的效力。
在一个或更多个实施方案中,本文中公开的组合物包含活性剂,所述活性剂包含与亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸组合的柠檬酸、琥珀酸和苹果酸,其中柠檬酸、琥珀酸和苹果酸的总量与氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸的总量的重量比为0.05至0.3,优选0.1至0.25。
在一个或更多个实施方案中,活性剂还可包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸、酪氨酸的一种或更多种氨基酸。
在另一个实施方案中,本文中公开的组合物的活性剂还可包含天冬氨酸和/或鸟氨酸L-α酮戊二酸(OKG)。
根据一个实施方案,该组合物包含活性剂,该活性剂由亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸、组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和任选地酪氨酸以及柠檬酸、琥珀酸和苹果酸组成,所述氨基酸是组合物中包含的唯一氨基酸。
在另一个实施方案中,该组合物可以相对于活性剂重量按重量计35%至65%,优选按重量计42%至56%的量包含氨基酸异亮氨酸、亮氨酸和缬氨酸。
在一个或更多个实施方案中,亮氨酸与柠檬酸的重量比为5至1,优选2.50至3.50。
在另一个实施方案中,柠檬酸的重量或摩尔量高于苹果酸和琥珀酸中每一个的重量或摩尔量。优选地,柠檬酸的重量或摩尔量高于苹果酸加上琥珀酸的重量或摩尔总量。在另一个实施方案中,柠檬酸与苹果酸和琥珀酸的总和的重量比为1.0至4.0,优选1.5至2.5。在一个优选实施方案中,柠檬酸:苹果酸:琥珀酸重量比为10:1:1至2:1.5:1.5,优选7:1:1至1.5:1:1,更优选5:1:1至3:1:1。在一个优选实施方案中,柠檬酸:苹果酸:琥珀酸重量比为4:1:1。
根据本公开内容的一些实施方案,优选的异亮氨酸:亮氨酸摩尔比为0.2至0.7,优选0.30至0.60,和/或优选的缬氨酸:亮氨酸重量比为0.2至0.70,优选0.30至0.65。
在另一个实施方案中,苏氨酸:亮氨酸摩尔比为0.10至0.90,优选0.20至0.70,和/或赖氨酸:亮氨酸重量比为0.20至1.00,优选0.40至0.90。
在一个优选实施方案中,柠檬酸、苹果酸、琥珀酸的总摩尔量与甲硫氨酸、苯丙氨酸、组氨酸和色氨酸的总摩尔量的比高于1.35。
在一个或更多个实施方案中,柠檬酸、苹果酸、琥珀酸的总和与支链氨基酸亮氨酸、异亮氨酸、缬氨酸的总和的重量比为0.1至0.4,优选0.15至0.35。
在另一个实施方案中,支链氨基酸亮氨酸、异亮氨酸、缬氨酸加上苏氨酸和赖氨酸的总重量量高于三种酸柠檬酸、苹果酸、琥珀酸的总重量量。优选地,单一酸(柠檬酸、琥珀酸或苹果酸)的重量量小于单一氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸和赖氨酸中的每一个的重量量。
在另一个实施方案中,赖氨酸和苏氨酸的总摩尔量高于三种酸柠檬酸、琥珀酸、苹果酸的总摩尔量。优选地,三种酸柠檬酸、琥珀酸、苹果酸的总摩尔量与赖氨酸和苏氨酸的总摩尔量的比为0.1至0.7,优选0.15至0.55。
在一个或更多个实施方案中,本文中公开的组合物还包含维生素,其优选地选自维生素B,例如维生素B1和/或维生素B6。
在本公开内容的另一个实施方案中,组合物可包含碳水化合物、添加剂和/或矫味物质。
此外,特别是在制备根据本公开内容的组合物时,并且特别是在制备活性剂时,优选地避免氨基酸精氨酸。
另外,本文中公开的组合物优选地排除的另一些氨基酸是丝氨酸、脯氨酸、丙氨酸。
这样的氨基酸在组合物内以一些浓度或化学计量比存在可能适得其反或者甚至有害。
本说明书中公开的氨基酸可被相应的可药用衍生物(即,盐)替代。
在一个或更多个实施方案中,本文中公开的组合物旨在用于医药。
如在下文中将清楚地显现的,根据本公开内容的组合物的施用在促进线粒体生物发生和线粒体功能方面特别有效。
在一个优选实施方案中,公开的组合物可用于治疗和/或预防选自肌少症和心力衰竭的线粒体功能障碍相关疾病。
在另一个优选实施方案中,本文中公开的组合物可用于治疗和/或预防线粒体功能障碍相关的神经退行性疾病,所述疾病优选地选自阿尔茨海默病、帕金森病和亨廷顿病。
在另一个实施方案中,该组合物可用于治疗和/或预防选自动脉粥样硬化、2型糖尿病、肾疾病、COPD和骨质疏松症的线粒体功能障碍相关疾病。
在一个或更多个实施方案中,该组合物可用于治疗和/或预防营养不良临床表现,尤其是用于治疗和/或预防蛋白质营养不良和恶病质。
根据另一个实施方案,氨基酸组合物可包含可药用赋形剂,如例如蛋白质、维生素、碳水化合物、天然和人工甜味剂和/或矫味物质。在一个优选实施方案中,可药用赋形剂可选自乳清蛋白、麦芽糊精、果糖、酪蛋白钙、鱼油、柠檬酸或其盐、三氯蔗糖、蔗糖酯、维生素D3、维生素B。
对于经口使用,根据说明书的组合物可以为片剂、胶囊剂、颗粒剂、凝胶剂、可凝胶化散剂(gelable powder)、散剂的形式。
在组合物提供的多种氨基酸之间的量和比方面的进一步说明包含在所附权利要求书中,其构成与本发明有关的本文中提供的技术教导的组成部分。
实施例
如下所公开的,表1示出了在HL-1细胞上进行测试的不同的基于氨基酸的组合物。
特别地,BCAAem组合物是EP 2 196 203 B1中公开的组合物。
命名为“B2”的组合物具有与BCAAem组合物类似的氨基酸的组合作为活性剂,但B2还包含柠檬酸。这样的组合物还包含维生素B1和B6。
命名为alpha 5(α5)、alpha 6(α6)、alpha 7(α7)的组合物包含含有氨基酸和柠檬酸、琥珀酸和苹果酸的活性剂。另外,alpha 7组合物的活性剂还包含OKG(鸟氨酸L-α酮戊二酸)和氨基酸天冬氨酸(L-天冬氨酸)。
表1
上表1的组合物可首先通过用0.8目筛选所有组分来制备。为了获得预混合物,将每种成分(量为总量的按重量计<10%)与一部分L-赖氨酸HCl一起放入聚乙烯袋中,以获得总组合物的10%重量。然后将袋手动摇动5分钟。然后将预混合物与成分的其余部分一起加载在混合器(Planetaria)中并在120rpm下混合15分钟的时间以获得均匀的最终组合物。
将表1中列出的组合物施用于HL-1心肌细胞,并且如下文中公开的评价线粒体功能。
方法
细胞和处理
将HL-1心肌细胞(来自WC Claycomb,New Orleans,School of Medicine的馈赠)平板接种在纤连蛋白/明胶包被的烧瓶中,在补充有100μM去甲肾上腺素(来自溶解在30mML-抗坏血酸[Sigma-Aldrich]中的10mM去甲肾上腺素[Sigma-Aldrich]储备溶液)、2mM L-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素和10%FBS(JRH Biosciences)的Claycomb培养基(JRH Biosciences)中培养至70%至80%汇合,如Claycomb et al.,1998中公开的。
用1%(w/v)的表1中所示组合物(溶解在Claycomb培养基中)处理细胞24小时或48小时。
在这些时期结束时,从细胞中提取mRNA和DNA,或者将细胞用于评价氧消耗。对照细胞仅用Claycomb培养基处理。
基因表达和线粒体生物发生方法
使用RNeasy Mini试剂盒(Qiagen)从HL-1心肌细胞分离总RNA;使用iScript cDNA合成试剂盒(Bio-Rad Laboratories)将1微克的总RNA反转录成cDNA,如D’Antona et al.(2010)中所述。
将基因相对水平计算为2-DDCT,其中DDCT对应于使用GAPDH作为内控(internalcontrol)的任一处理组的DCT与未经处理组的DCT之间的差异。Delta-Delta-CT(DDCT)算法是用定量实时PCR(quantitative real-time PCR,qRT-PCR)实验确定相对基因表达的近似方法(参见Livak和Schmittgen,2001)。
使用Beacon Designer 2.6软件(Premier Biosoft International)设计引物(下表2中报道的序列)。用甘油醛3-磷酸脱氢酶(Glyceraldehyde 3-phosphatedehydrogenase,GAPDH)的表达对值进行归一化。
表2
Ta退火温度(℃);登录号GAPDH:NM_008084.3;登录号Cyt c:NM_007808;登录号PGC-1α:AF049330;登录号Tfam:NM_009360.4;登录号KFL15:NM_023184.4;登录号PP2CM:NM_175523.4;小家鼠(Mus musculus)线粒体,完整基因组:NC_005089.1;gDNA(GAPDH):NC_000072.6;12S线粒体rRNA的引物编码(NC_005098.1)。GAPDH用于使线粒体DNA归一化。
对于线粒体DNA(mtDNA)分析,用QIAamp DNA提取试剂盒(QIAGEN)提取总DNA。
使用对线粒体DNA(mtDNA)基因具有特异性的引物扩增mtDNA,并通过扩增GAPDH基因DNA将其归一化为基因组DNA。表2中示出了使用Beacon Designer 2.6软件(PremierBiosoft International;Palo Alto,CA)设计的gDNA引物。
统计分析
对于所有基因表达数据,使用双侧配对样本t检验(two-sided paired-sample ttest)比较对照细胞与经处理细胞之间的值。p值<0.05被认为具有统计学显著性。
氧消耗
将用表1中所示组合物处理的1ml的量的HL-1心肌细胞重悬于Hank’s平衡盐溶液(Hank’s balanced salt solution)(Sigma)中,并离心以沉淀细胞。许多HL-1细胞还补充有一氧化氮(NO)供体,特别是补充有二亚乙基三胺-NO(还称为DETA-NO;Sigma-Aldrich,Milan,Italy)作为阳性对照。
然后,将细胞以3.0×106/ml的密度重悬于呼吸缓冲液(respiration buffer)(0.3M甘露醇、10mM KCl、5mM MgCl2、10mM K2PO4,pH 7.4)中。
在配备有连接至图表记录器的Clark型氧电极(Rank Brothers Ltd.)的气密容器中,在37℃下对样品进行分析。
对氧电极进行校准,假定在37℃下孵育培养基中的氧浓度为200μmol/l。
通过连续混合约十分钟来评估氧消耗。然后将示踪记录器(trace recorder)的斜率用于计算氧消耗。氧含量可根据细胞的量而变化。因此,已将与细胞含量直接相关的蛋白质含量用于对细胞样品中的氧消耗进行归一化。通过使用二辛可宁酸蛋白质(bicinchoninic acid protein,BCA)测定确定蛋白质含量。
结果
线粒体DNA(mtDNA)
首先在用不同的氨基酸组合物处理的细胞中评价线粒体DNA(mtDNA),以验证其对线粒体质量的作用。
如图1中所示,相对于在对照细胞(CT)中、在经B2处理的细胞中以及非常有趣地在用BCAAem组合物处理的细胞中评价的mtDNA,用α5组合物处理的HL-1心肌细胞表现出mtDNA最显著提高。
PGC-1α、Tfam和Cyt
c
还测试了不同的氨基酸组合物对线粒体生物发生的作用。特别地,评价了HL-1心肌细胞的以下标志物的表达:
-过氧化物酶体增殖物激活受体γ辅激活物1-α(PGC-1α),线粒体生物发生的主要调节物,
-线粒体DNA转录因子A(Tfam),调节mtDNA复制的mtDNA转录因子,
-细胞色素复合物(Cyt c),呼吸复合物蛋白质。
在施用BCAAem组合物、B2组合物(即,与BCAAem组合物类似但还包含柠檬酸的组合物)、α5(即,除氨基酸之外还包含酸柠檬酸、琥珀酸、苹果酸作为活性剂的组合物)之后获得的结果的比较表明,α5组合物在促进HL-1心肌细胞中的以上标志物的表达方面最有效。
此外,观察到时间进程效应:在用包含表1中列出的氨基酸以及三种指定的羧酸的α5组合物补充48小时之后,事实上,与基本值相比,这种提高仍然更加明显。
与24小时处理的Tfam(图2),以及48小时处理之后的PGC-1α和Cyt c(图3)相比,关于BCAAem组合物的值的提高也具有统计学显著性。
KFL15和PP2CM
Krüppel样因子15(KFL15)和线粒体基质靶向的蛋白质磷酸酶2C家族成员(PP2CM)是调节支链氨基酸(BCAA)的分解代谢的蛋白质。
BCAA分解代谢的第一步骤是这三种BCAA共有的步骤,并且需要线粒体酶BCAA氨基转移酶(BCAA aminotransferase,BCAT)和支链α-酮酸脱氢酶复合物(branched-chainα-keto acid dehydrogenase complex,BCKDC)。
在降解的第一且完全可逆的步骤中,线粒体BCAT将氨基从BCAA转移到α-酮戊二酸以形成相应的支链α-酮酸(branched-chainα-keto acid,BCKA)和谷氨酸。
此后,BCKDC催化BCKA的羧基脱羧,以形成相应的支链酰基辅酶A酯(acyl-CoAester)。
该反应是不可逆的,并因此使BCAA降解。
BCKDC活性受NADH、α-酮异己酸和支链酰基辅酶A酯的终产物变构抑制作用的调节。
BCKDC活性由其调节亚基E1a的磷酸化状态确定。
当BCAA水平低时,E1a被BCKD激酶过度磷酸化,导致BCKDC活性的抑制和游离BCAA的保存。
当BCAA水平高时,E1a被线粒体靶向的2C型Ser/Thr蛋白磷酸酶(命名为线粒体中的PP2C(PP2C in mitochondria,PP2CM)),或蛋白磷酸酶Mg2+/Mn2+依赖性1K(proteinphosphatase,Mg2+/Mn2+dependent1K,PPM1K))去磷酸化,导致BCKDC活化和总BCAA减少(Bifari和Nisoli,2016)。
另外,发现KLF15提高心脏中的BCAT、BCKDC和PP2CM基因表达(Sun et al.,2016)。
对PP2CM和KFL15的mRNA水平的评价表明,与基本值相比,α5组合物提高了HL-1心肌细胞中PP2CM和KLF15的mRNA水平。即使与BCAAem组合物相比,这种提高也是显著的(图4)。
这些结果表明,包含活性剂的组合物(所述活性剂包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸以及柠檬酸、琥珀酸和苹果酸),在代谢活跃细胞中在促进线粒体功能方面非常有效,并且甚至相对于BCAAem组合物,更有效地激活线粒体生物发生。
氧消耗(OCR)
测试了补充有不同组合物的HL-1细胞的氧消耗。还测试了补充有二亚乙基三胺-NO(DETA-NO)的细胞作为阳性对照。已示出了DETA-NO对提高细胞氧消耗的作用(Nisoli etal.,2003)。在多种细胞如棕色脂肪细胞和3T3-L1、U937以及HeLa细胞中发现NO引起线粒体生物发生。一氧化氮的这种作用取决于环鸟苷3’,5’-单磷酸(cyclic guanosine 3’,5’-monophosphate,cGMP),并通过诱导线粒体生物发生的主要调节物PGC-1α来介导(Nisoliet al.,2003)。
正如预期的,在48小时的DETA-NO处理之后,观察到氧消耗提高。
最值得注意的是,当HL-1细胞用α5组合物补充48小时之后,观察到氧消耗显著提高,从而表明线粒体活性上升(图5)。
这种提高显著高于B2和BCAAem组合物施用之后观察到的提高。
一并考虑,这些结果表明,包含亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸、柠檬酸、琥珀酸和苹果酸的组合作为活性剂的一些组合物在促进HL-1心肌细胞中的线粒体生物发生、线粒体功能和BCAA分解代谢方面显著更有活性。
认为,提供包含BCAA、苏氨酸和赖氨酸,以及柠檬酸、琥珀酸和苹果酸的活性成分的组合物alpha 6(α6)和alpha 7(α7)具有类似的优点。
值得注意的是,混合物中富含的BCAA的分解代谢除乙酰辅酶A之外还提供了琥珀酰辅酶A。后者可激活琥珀酰辅酶A合成酶反应,其继而产生琥珀酸作为底物用于后续的琥珀酸脱氢酶反应。
因此,在混合物中提供琥珀酸连同BCAA也会刺激琥珀酸脱氢酶反应,从而进一步促进循环。值得注意的是,通过直接提供FADH2,琥珀酸脱氢酶也是线粒体电子传递链(复合体II)的一部分。因此,琥珀酸对其的刺激可直接激活线粒体氧化还原载体并提高膜电位,从而提高质子梯度、氧消耗和ATP合成。
同时,苹果酸补充剂可激活苹果酸脱氢酶反应并提高NADH水平;这也将为复合物I提供底物,并因此以与来源于琥珀酸的FADH2相同的方式提高ATP水平。另一方面,苹果酸可刺激苹果酸-天冬氨酸穿梭的活性。这将有利于胞质NADH也进入到线粒体中,否则胞质NADH将不可经由线粒体膜而透过,从而使其可用于线粒体氧化。这将进一步提高线粒体活性和氧消耗。
从前述内容清楚地显现根据本公开内容的组合物如何可用于治疗以人中和动物中线粒体功能不足进行区分的病理状态。
参考文献
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Claims (15)
1.用于在对象中促进线粒体生物发生并改善线粒体功能的组合物,所述组合物包含活性剂,所述活性剂包含氨基酸亮氨酸、异亮氨酸、缬氨酸、苏氨酸、赖氨酸,以及柠檬酸、琥珀酸、苹果酸。
2.根据权利要求1所述的组合物,其中柠檬酸、苹果酸、琥珀酸的总和与支链氨基酸亮氨酸、异亮氨酸、缬氨酸加上赖氨酸和苏氨酸的总和的重量比为0.05至0.3,优选0.1至0.25。
3.根据前述权利要求中任一项所述的组合物,其中柠檬酸、苹果酸、琥珀酸的总量与所述支链氨基酸亮氨酸、异亮氨酸、缬氨酸的总量的重量比为0.1至0.4,优选0.15至0.35。
4.根据前述权利要求中任一项所述的组合物,其中柠檬酸与苹果酸和琥珀酸的总和的重量比为1.0至4.0,优选1.5至2.5。
5.根据前述权利要求中任一项所述的组合物,其中柠檬酸:苹果酸:琥珀酸重量比为10:1:1至2:1.5:1.5,优选7:1:1至1.5:1:1,更优选5:1:1至3:1:1。
6.根据前述权利要求中任一项所述的组合物,其中所述活性剂还包含选自组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、酪氨酸、半胱氨酸的至少一种氨基酸。
7.根据前述权利要求中任一项所述的组合物,其中所述活性剂还包含组氨酸、苯丙氨酸、甲硫氨酸、色氨酸、半胱氨酸和任选的酪氨酸。
8.根据前述权利要求中任一项所述的组合物,其中柠檬酸、苹果酸、琥珀酸的总摩尔量与甲硫氨酸、苯丙氨酸、组氨酸和色氨酸的总摩尔量的比高于1.35。
9.根据前述权利要求中任一项所述的组合物,其中三种酸柠檬酸、琥珀酸、苹果酸的总摩尔量与赖氨酸和苏氨酸的总摩尔量的比为0.10至0.70,优选0.15至0.55。
10.根据前述权利要求中任一项所述的组合物,其中柠檬酸的重量或摩尔量高于苹果酸和琥珀酸二者的总重量或总摩尔量。
11.根据前述权利要求中任一项所述的组合物,其中亮氨酸与柠檬酸的重量比为5至1,优选2.50至3.50。
12.根据前述权利要求中任一项所述的组合物,其中所述活性剂不含精氨酸。
13.根据前述权利要求中任一项所述的组合物,其中所述组合物还包含一种或更多种维生素,所述维生素优选地选自维生素B,更优选维生素B1和/或维生素B6。
14.根据权利要求1至13中任一项所述的组合物,用于医药。
15.根据权利要求1至14中任一项所述的组合物,用于治疗和/或预防选自肌少症和心力衰竭的线粒体功能障碍相关疾病。
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