CN102784130A - 羟基酪醇用于改进线粒体功能的用途 - Google Patents
羟基酪醇用于改进线粒体功能的用途 Download PDFInfo
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- CN102784130A CN102784130A CN2012102034643A CN201210203464A CN102784130A CN 102784130 A CN102784130 A CN 102784130A CN 2012102034643 A CN2012102034643 A CN 2012102034643A CN 201210203464 A CN201210203464 A CN 201210203464A CN 102784130 A CN102784130 A CN 102784130A
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Abstract
本发明涉及羟基酪醇用于改进线粒体功能的用途。特别地,本发明涉及羟基酪醇(或包含羟基酪醇的组合物)作为抗衰老剂的用途。本发明还另外涉及的组合物基本上不包含白藜芦醇,并且经口施用给动物。本发明还涉及抗衰老方法。“抗衰老”在本发明的上下文中表示延迟所述动物中衰老的过程,改善所述动物中年龄相关的生理缺陷,和/或促进所述动物中健康的衰老。
Description
本申请是题目为“羟基酪醇作为抗衰老剂的用途”的中国专利申请200880012559.9(申请日:2008年4月17日)的分案申请。
发明领域
本发明涉及羟基酪醇和包含羟基酪醇的组合物改进线粒体功能、尤其是作为抗衰老剂的用途。本发明还涉及抗衰老方法。“抗衰老”在本发明的上下文中表示延迟动物中衰老的过程,改善动物中年龄相关的生理缺陷,和/或促进动物中健康的衰老。
发明背景
线粒体是细胞中负责能量产生的细胞器。线粒体内膜中埋有包含复合体I、II、III、IV和V的呼吸链,所述呼吸链通过一系列氧化还原反应传递电子并产生ATP,这是被称作氧化磷酸化的过程。
除了对细胞提供能量的公知功能以外,线粒体及其组件参与大量其他细胞活动。例如,线粒体还控制产热和凋亡过程,并因此涉及衰老过程。
线粒体含有高水平的氧化剂,因为呼吸链以降低的效率工作时或者在能量解偶联期间产生活性物质,例如超氧阴离子。超氧阴离子作为电子传递链若干步骤中的副产物产生,所述步骤例如复合体 III中辅酶Q的还原,其中形成作为中间体的高度活性的自由基(Q·-)。该不稳定的中间体会导致电子“泄漏”,其中电子直接跳跃至氧并形成超氧阴离子,而不是沿着正常的电子传递链的一系列受到良好控制的反应移动。
抗氧化剂是能够减缓或阻止其他分子氧化的分子。抗氧化剂通过去除自由基中间体来终止氧化链反应,并且通过氧化其自身抑制其他氧化反应。还原剂例如硫醇或多酚通常具有抗氧化特性。公知的抗氧化剂例如维生素A、C和E清除自由基并保护DNA、蛋白质和脂质免受损伤。抗氧化剂还保护线粒体远离ATP生产期间产生的活性氧物质和自由基。
尽管过去普遍接受施用抗氧化剂对于促进线粒体生物发生(biogenesis)是有益的,但是情况显示并非如此。Gomez-Carbera et al.2008 Am.J Clin.Nutr.87(1):142-149在双盲的随机化临床研究中证明,每天口服施用1g维生素C降低骨骼肌中线粒体的生物发生。
过去羟基酪醇被描述为具有积极的心血管作用(见例如Gonzalez-Santiago et al 2006 Atherosclerosis 188:35-42;或 Mitro et al 2003 NMCD.Nutritional Metabolism and Cardiovascular Diseases 13(5):306),但是这些涉及羟基酪醇的抗动脉粥样硬化作用和/或其作为抗氧化剂的状态。
本发明涉及羟基酪醇的抗衰老特性,这与其作为抗氧化剂起作用的能力不同。
发明详述
本发明涉及包含羟基酪醇的组合物作为抗衰老剂的用途,其中所述组合物基本不含白藜芦醇且其中所述组合物被经口施用给动物。
衰老的特征是生理功能的逐渐损失,这可能是由多种细胞组件中积累的损伤引起的。线粒体是通过转化三磷酸腺苷(ATP)分子中的营养物而在细胞中产生能量的普遍存在的细胞器,所述能量被用于正常的细胞功能和维持。线粒体还涉及调节细胞存活。最近有人提出,线粒体功能的损失不仅促成疾病,而且在衰老过程中起重要作用。某些器官中线粒体数量的降低和线粒体呼吸链的损伤常常伴随着衰老过程,并且被认为是衰老的一个主要原因。年龄在65-75岁的健康受试者显示改变的线粒体特性的征兆,其特征是氧化酶活性和组织线粒体含量的损失。另外,得自衰老动物的组织显示线粒体结构的改变,伴随着降低的能量产生。衰老的人和动物器官在组织中具有提高的线粒体DNA(mtDNA)突变水平,并且mtDNA损伤与最大生命期成反比。无营养不良的热量限制(这是提高生命期的公认的最好方法)还增加编码下述蛋白质的基因并减少指示细胞衰老的DNA损伤,所述蛋白质涉及人骨骼肌中的线粒体功能。因此,衰老伴随着降低的线粒体生物发生和线粒体损伤的累积。
“线粒体生物发生”是指线粒体生长、扩增和健康维持的过程。线粒体生物发生是涉及核参与者和线粒体参与者二者的复杂过程。线粒体DNA编码小量蛋白质,所述蛋白质在线粒体核糖体上被翻译。这些蛋白质中的大部分是位于线粒体内膜上的呼吸链的高度疏水的亚基。核编码的蛋白质在胞质核糖体上被翻译,并被输入线粒体中。这些蛋白质包括结构蛋白质,酶或酶亚基,输入机制、复制机制、转录机制和翻译机制的组件,和陪伴分子。
过氧化物酶体增殖子活化的受体-γ共同活化子-1(PGC-1)是细胞能量代谢的共同转录调节因子,其涉及线粒体功能的控制并诱导线粒体生物发生。衰老组织中PGC-1的减少是线粒体功能障碍的一个关键因素,所述线粒体功能障碍可以通过PGC1的增加来预防,所述PGC1的增加导致提高的线粒体生物发生。
羟基酪醇通过线粒体呼吸链复合物的活化和线粒体生物发生的提高改进线粒体功能。由此,线粒体功能的改进能够预防细胞衰老,并因此预防身体的衰老。因此,羟基酪醇可以被认为是预防衰老和年龄相关疾病的一种有用的药剂。
附图简述
图1显示PGC-1α的表达。A)PGC-1α脂肪细胞中的Western印迹分析。B)用光密度法针对PGC-la:α-微管蛋白比例计算的定量值。数值为五个试验的均值±SE。*与对照相比p<0.05;**与对照相比P<0.01。
图2显示线粒体蛋白质的表达。用羟基酪醇将3T3-L1脂肪细胞处理48小时。随后将细胞溶于SDS样品缓冲液中,并通过Western印迹用针对α-微管蛋白、线粒体电子传递复合物I、复合物II、复合物III和复合物V的抗体进行分析。稳态水平蛋白质的代表性免疫印迹在顶部(A)显示。通过光密度法对条带的定量分析在B、C、D和E中分别针对线粒体复合物I、复合物II、复合物III和复合物V显示。所示结果是来自4个独立实验的对照与对照细胞相比的提高倍数。*与对照相比p<0.05。**与对照相比p<0.01。
图3显示线粒体DNA的表达。用羟基酪醇将3T3-L1脂肪细胞处理48小时。使用SYBR绿,用荧光对PCR产物定量。针对D-环:18sRNA比例计算定量值。结果被表述为对照的提高倍数。数据是均值±SE(n=5)。*与对照相比P<0.05;**与对照相比p<0.01。
图4显示3T3-L1脂肪细胞中的氧消耗。将等体积的细胞在96-孔 BDOxygen Biosensor平板的孔中分成等分试样。覆盖平板,用荧光微板分光光度计随时间记录每孔中的荧光。A)代表性氧消耗曲线。B)通过测定动力学测量结果计算每种条件下脂肪细胞呼吸速率的定量改变。数值为均值±SE;显示的结果是来自3个独立实验的对照与对照细胞相比。*与对照相比p<0.05。
图5显示用羟基酪醇处理对脂肪细胞中复合物活性的影响。(A)复合物I,(B)复合物II,和(C)复合物III。用不同浓度的羟基酪醇将脂肪细胞处理48小时。数值对于复合物I而言是来自三个独立实验的数据的均值±SE,对复合物II和III而言是来自六个独立实验的数据的均值±SE,并且每个实验一式两份进行。*与对照相比p<0.05,**与对照相比p<0.01。
PGC1α,过氧化物酶体活化子受体(PPAR)γ-共同活化子1α,是一种转录共同活化子,其作为大范围代谢和生理学过程的主要调节子发挥作用,并且是线粒体生物发生过程中的关键因素。PGC-1α过表达刺激3T3细胞中线粒体的生物发生,如提高的线粒体量和活性所示。
优选地,羟基酪醇是组合物中唯一的活性抗衰老成分。
由此,根据本发明的组合物和羟基酪醇自身使人年轻和/或健康,带来了抗衰老的解决方案,并且预防衰老过程和/或使人在衰老时快乐或更满足。
本发明的另一方面是包含羟基酪醇的组合物用于制造下述组合物的用途,所述组合物用于降低动物中给定年龄处年龄相关疾病的发病率,进而提高生存更久的可能性;用于推迟动物中衰老过程的视觉征兆,例如但不限于头发泛灰、皱纹、听觉功能损失、肌肉量损失、骨密度损失和固有心脏功能的损失;和/或用于降低动物中加速衰老过程的生活方式疾病的风险;其中所述组合物基本不含白藜芦醇。
本发明的一个目的是包含羟基酪醇的组合物作为抗衰老剂的用途,其中所述组合物基本不含白藜芦醇且其中所述组合物经口施用给动物。
羟基酪醇(3,4-二羟基苯乙醇)可以是合成来源或其可以从橄榄叶、橄榄果实的提取物和橄榄油生产的植被水(vegetation water)中被分离。
因此,术语“羟基酪醇”还包括含有羟基酪醇的植物的任何材料或提取物或植物部分的任何材料或提取物或植物(例如橄榄)果实的任何提取物/浓缩物/果汁,特别是以植物材料或提取物的总重为基础,以至少30重量%的量,优选地以至少40重量%的量,更优选地以至少50、55、60、65、70、75、80、85、90重量%的量,最优选地以至少50重量%的量含有羟基酪醇。本发明上下文中使用的术语“植物材料”表示植物的任何部分,还表示果实。
在本发明的其他实施方案中,除了羟基酪醇外还可以使用羟基酪醇衍生物例如酯和生理学/药学可接受的盐,或者使用它们代替羟基酪醇。合适的衍生物是本领域技术人员已知的。优选的羟基酪醇酯为例如乙酸酯或葡糖苷酸缀合物;最优选的是橄榄苦苷。
“基本不含白藜芦醇”是指组合物中白藜芦醇的量以组合物的总重为基础≤1重量%,优选地<0.5重量%,更优选地<0.1重量%。其还表示不有意地向组合物中添加白藜芦醇。白藜芦醇仅可作为从植物或植物果实(例如橄榄)中获得的羟基酪醇提取物/浓缩物的副产物存在于组合物中。如果存在,则其处于生物活性不显著的浓度下。
“组合物被经口施用给动物”,这表示组合物是可以被动物食用或饮用或通过口/颌(jaw)放入动物胃中的任何形式。
因此,组合物优选地选自饮食补剂、食物添加剂、功能性食物、饲料添加剂、功能性饲料、食物预混物、饲料预混物和饮料。饮食补剂形式的例子是片剂、丸剂、颗粒剂、锭剂、胶囊、即食饮品和泡腾配制物。
食物/饲料添加剂的例子是为用于消耗在食物/饲料的制造期间或其制备期间添加进食物/饲料中的任何组合物/配制物。
功能性食物的例子是乳制品(酸乳)、谷物棒和烘焙物品例如蛋糕、曲奇和面包。也包括临床营养品。
功能性饲料(包括宠物食品组合物)的例子包括旨在提供必需饮食需求的饲料,以及所有的零食(例如狗饼干)或其他饲料补剂。包含根据本发明的组合物的动物饲料可以是干燥组合物(例如粗粉(kibble))、半湿润组合物、湿润组合物或其任何组合的形式。替代地或额外地,动物饲料是补剂例如肉汁(gravy)、饮用水、酸乳、粉末、悬浮液、咀嚼物、调剂物(例如饼干)或任何其他递送形式。
食物预混物的例子是用于制造乳制品、谷物棒和烘焙物(例如蛋糕和曲奇)和汤的预混物。
本发明的另一方面涉及饲料添加剂或添加剂组合物,例如要被添加进一种或多种可食用饲料物质或成分中,例如用于制备饲料组合物或用于补充现存的饲料以形成饲料组合物。
所谓的预混物是本发明的动物饲料添加剂的例子。预混物表示一种或多种微量成分(micro-ingredient)与稀释剂和/或载体的优选地均一的混合物。预混物被用于促进微量成分在更大混合物中的均一分散。预混物可以是颗粒或团粒的形式。
在一个具体的实施方案中,羟基酪醇在被添加进饲料中的形式下或被包含在饲料添加剂中时,是充分确定的。术语“充分确定的”表示羟基酪醇制剂至少为40%纯净。在另一具体的实施方案中,充分确定的羟基酪醇制剂为至少60%、65%、70%、75%、80%、85%、88%、90%、92%、94%或至少95%纯净。
通常,脂溶性和水溶性维生素,以及痕量矿物质形成用于添加进饲料中的所谓预混物的部分,而主要矿物质则通常被独立地添加进饲料中。
另外,任选的饲料添加剂成分是着色剂,例如类胡萝卜素如β-胡萝卜素、虾青素和叶黄素;芳香化合物;稳定剂;抗微生物肽;产活性氧的物类;和/或至少一种选自以下的酶:植酸酶(EC 3.1.3.8或3.1.3.26);木聚糖酶(EC 3.2.1.8);半乳聚糖酶(EC 3.2.1.89);α-半乳糖苷酶(EC 3.2.1.22);蛋白酶(EC 3.4.)、磷脂酶A1(EC 3.1.1.32);磷脂酶A2(EC 3.1.1.4);溶血磷脂酶(EC 3.1.1.5);磷脂酶C(EC 3.1.4.3);磷脂酶D(EC 3.1.4.4);淀粉酶,例如α-淀粉酶(EC 3.2.1.1);和/或β-葡聚糖酶(EC 3.2.1.4或EC3.2.1.6)。
饮料包括无醇饮品和含酒精的饮品,以及要添加进饮用水和液体食品中的液体制剂。无醇饮品为例如方便饮品、软饮、运动饮品或一般性运动饮料、果汁(如例如橙汁、苹果汁和葡萄汁);蔬菜汁(如番茄汁);思慕雪、柠檬水、功能性水、接近水的饮品(即具有低卡路里含量的基于水的饮品)、茶和基于乳的饮品。含酒精的饮品特别是啤酒。液体食品为例如汤和乳制品(例如麦芯饮品)。
根据本发明的饮食组合物可还含有保护性水胶体、粘合剂、成膜剂、包封剂/材料、壁/壳材料、基质化合物、包衣、乳化剂、表面活性剂、增溶剂(油、脂肪、蜡、卵磷脂等等)、吸附剂、载体、填充剂、辅助化合物、分散剂、湿润剂、加工助剂(溶剂)、流动剂、遮味剂、增重剂、啫喱化剂(jellyfying agents)、凝胶形成剂、抗氧化剂和抗微生物剂。
也可以替代饮食补剂使用并被本发明涵盖的是药物组合物。
除了可药用的载体和具有上文给出的优选的纯度(和其他优选级)的羟基酪醇(衍生物)以外,根据本发明的药物组合物可还含有常规的药物添加剂和佐剂、赋形剂或稀释剂,包括但不限于水、任何来源的明胶、植物胶、硫酸木质素、滑石、糖、淀粉、阿拉伯胶、植物油、聚亚烷基二醇、调味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、湿润剂、填充剂等等。载体材料可以是适用于口施用的有机或无机惰性载体。
根据本发明的饮食补剂和药物组合物可以是适用于对动物体(优选地对人体)口施用的任何盖仑形式(galenic form),例如固体形式如片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制物如粉末和片剂,或液体形式如溶液、乳液或悬浮液,如例如饮料、糊剂和油悬浮液。糊剂可以被填充进硬壳或软壳胶囊中。饮食和药物组合物可以是受控(延迟)释放配制物的形式。
根据本发明,这类组合物被用于延迟动物(优选人)中的衰老过程,用于改善动物(优选人)中年龄相关的生理缺陷,和/或用于促进动物(优选人)中的健康衰老。
因此,本发明还涉及(具有上文给出的形式和优选级的)被经口施用给动物(优选人)的包含羟基酪醇组合物,所述组合物用于延迟动物(优选人)中的衰老过程,用于改善动物(优选人)中年龄相关的生理缺陷,和/或用于促进动物(优选人)中的健康衰老,其中所述组合物基本不包含白藜芦醇。
另外,本发明涉及通过对动物施用有效量羟基酪醇或有效量包含羟基酪醇的组合物而延迟动物中的衰老过程,改善动物中年龄相关的生理缺陷,和/或促进动物中健康衰老的方法,其中所述组合物基本不含白藜芦醇。
动物在本发明的上下文中包括人并包括哺乳动物、鱼和鸟。优选的“动物”是人、宠物动物和农业动物。特别优选的动物是人。
宠物动物的例子是狗、猫、鸟、观赏鱼(aquarium fish)、荷兰猪、(jack)兔子、野兔和雪貂。农业动物的例子是观赏鱼、猪、马、反刍动物(牛、绵羊和山羊)和家禽。
“延迟动物中的衰老过程”在本发明的上下文中表示以下任何一种:
降低动物中给定年龄处年龄相关疾病的发病率,进而提高生存更久的可能性;
推迟动物中衰老过程的视觉征兆,例如但不限于头发泛灰、皱纹、听觉功能损失、肌肉量损失、骨密度损失和固有心脏功能的损失;和/或
降低动物中加速衰老过程的生活方式疾病的风险。
“改善动物中年龄相关的生理缺陷”在本发明的上下文中表示降低(在给定年龄下)发生年龄相关疾病的(平均)风险。
“促进动物中健康的衰老”在本发明的上下文中表示提高健康的生命预期,即提高保持健康更久的概率。
这类效果最好在介入试验中研究,将经处理的个体与未经处理的对照组中平均衰老状态/疾病发病率进行比较。
用于人(70kg人)的羟基酪醇每日剂量可以为至少0.1mg。其可从5到500mg变化,优选地从10到100mg变化。
对哺乳动物而言,羟基酪醇的优选的剂量从0.28到1.9mg/kg代谢体重变化,其中对哺乳动物而言
“代谢体重”[以kg计]=(体重[以kg计])0.75
这表示例如对70kg的人而言,优选的每日剂量应在6.77和45.98mg之间变化,对20kg的狗而言,优选的每日剂量应在2.23和15.1mg之间变化。
本发明接着通过以下的非限制性实施例进一步阐述。
实施例
实施例1
软明胶胶囊
通过常规工序来制备提供下述剂量的软明胶胶囊,所述剂量为每粒胶囊50mg羟基酪醇。合适的每日剂量为1到5粒胶囊。
其它成分:甘油。水、明胶、植物油
实施例2
硬明胶胶囊
通过常规工序来制备提供下述剂量的硬明胶胶囊,所述剂量为每粒胶囊75mg羟基酪醇。合适的每日剂量为1到5粒胶囊。
其它成分:
填料:适量的乳糖或纤维素或纤维素衍生物
润滑剂:如果需要的话,硬脂酸镁(0.5%)
实施例3
片剂
通过常规工序来制备片剂,每片提供100mg羟基酪醇作为活性成分,和微晶纤维素、二氧化硅(SiO2)、硬脂酸镁、交羧甲基纤维素钠总计500mg作为赋形剂。
实施例4
软饮
可如下制备含有羟基酪醇的软饮:
混合果汁浓缩物和水溶性香料而不掺入空气。将色素溶于去离子水中。将抗坏血酸和柠檬酸溶于水中。将苯甲酸钠溶于水中。果胶在搅拌下被添加并在煮沸时溶解。冷却溶液。预混合橙油和油溶性香料。将“F”下提到的活性成分搅拌进A的果汁浓缩物混合物中。
为了制备软饮,将所有的组分A-F混合在一起后使用Turrax和随后使用高压匀化器(p1=200bar,p2=50bar)匀化。
实施例5
线粒体生物发生
抗兔PGC-1α和抗兔PPAR-γ购自Santa Cruz(California,美国);抗-α-微管蛋白来自Sigma(St.Louis,MO,美国);Mito-Tracker GreenFM、抗氧化的复合体I、II、III和V来自Invitrogen(Carlsbad,美国);GREEN PCR Master Mix来自ABI(Warrington,英国);BDOxygen Biosensor System平板来自BD Biosciences (California,美国);羟基酪醇(DSM Nutritional Products);线粒体D-环和18SRNA引物由Bioasia Biotech(上海,中国)合成,用于细胞培养的其他试剂来自Invitrogen(Carlsbad,美国)。
细胞培养和脂肪细胞分化
在补充有10%胎牛血清的Dulbecco′s改良的Eagle′s培养基(DMEM)中培养鼠3T3-L1前脂肪细胞(American Type Culture Collection),并允许其达到汇合。用补充有10%胎牛血清的DMEM中1μM胰岛素、0.25μM地塞米松和0.5mM3-异丁基-1-甲基黄嘌呤起始前脂肪细胞的分化。48小时后,用补充有10%胎牛血清和1μM胰岛素的DMEM替换培养基。每隔一天用含10%胎牛血清的DMEM替换培养基。分化诱导后9-10天,当显示90%脂肪细胞表型时使用细胞。
线粒体量的测定
用胰蛋白酶消化脂肪细胞并于4℃下在1000rpm离心5分钟,重悬于用HEPES和0.1% BSA缓冲的Kreb′s Ringer溶液中,然后在DMEM中于37℃下用0.1μM MitoTracker Green FM孵育30分钟。将细胞在4℃下以1000rpm离心5分钟,并重悬于用HEPES缓冲的400μl新鲜的Kreb′sRinger溶液中。为了检查级分中的相对线粒体染色,将来自每种级分的200μl PBS中20×103个Mitotracker-标记的细胞上样在96-孔板中,并使用荧光微量培养板分光光度计(Molecular probe)对相对荧光强度进行读数(激发485±25nm;发射538±25nm)。结果被表述为荧光强度超过未处理的对照细胞的提高倍数。数值是来自四个独立试验结果的均值±SE。
Western印迹分析
处理后,用冰冷的PBS将细胞洗涤两次,于室温下在样品缓冲液(62.5mM Tris-Cl pH6.8,2% SDS,5mM DTT)中裂解,并振荡。然后将细胞裂解物煮沸5分钟并通过离心(13000rpm,4℃下10分钟)澄清。使用Bio-Rad DC蛋白质试验测定蛋白质浓度。对可溶的裂解产物进行10%SDS-PAGE(每条泳道10μg),然后将蛋白质转移至硝酸纤维素膜上,并用5%脱脂乳/TBST在室温下封闭1小时。在5%奶/TBST中于4℃下将膜与针对以下的初级抗体孵育过夜:PPAR-γ(1∶1000)、PGC-1α(1∶1000)、α-微管蛋白(1∶10 000)、复合体I(1∶2000)、复合体II(1∶2000)、复合体III(1∶2000)和复合体V(1∶2000)。用TBST将膜洗涤三次后,在室温下将膜与结合了辣根过氧化物酶的二级抗体孵育1小时。使用ECL(RocheManheim,德国)使Western印迹显影,并通过扫描密度测定法定量。
测量脂肪细胞中的呼吸
测量完整细胞的氧消耗,作为线粒体呼吸活性的指标。BDTM OxygenBiosensor System(BD Biosciences,Franklin Lakes,NJ,美国)是包埋在可透气且疏水基质中的对氧敏感的荧光化合物(三1,7-联苯-1,10二氮杂菲钌(II)氯化物),所述基质永久性附着于多孔板的底部。染料附近的氧浓度与液体培养基中的氧浓度处于平衡中。氧以可预测的浓度依赖性方式淬灭染料。荧光的量与孔中氧消耗的速率相关,这进而可以涉及能够与氧消耗相关联的任何种类的反应。这一特有的技术允许氧水平的同质同时检测。处理后,在添加了1% BSA的KRH缓冲液中洗涤脂肪细胞。在BD OxygenBiosensor System平板(BD Biosciences)中一式三份将来自每一条件下的细胞分为等分试样。将平板密封,在Fluorescence分光光度计(Molecularprobes)上485nm的激发波长和630nm的发射波长下,以1分钟的间隔读数60分钟。多个条件之间等体积中含有的细胞数不是统计学显著的(Wilson-Fritch et al.,2004 J Clin Invest 114:1281-1289)。
线粒体DNA的测量
在Mx3000P Real-Time PCR体系(Stratagene)中进行定量PCR。用12.5μl SYBR-Green Master Mix(ABI)、0.5μl每种引物(10μM)、100ng模板(DNA)或无模板(NTC)进行反应,并添加无RNase的水达到25μl的终体积。循环条件如下:50℃ 2分钟,在95℃下初始变性10分钟,然后在95℃下30秒、55℃下1分钟、72℃下30秒进行40个循环。每个定量PCR一式三份进行。使用以下的引物:线粒体D-环正向,
5′-AATCTACCATCCTCCGTG-3’(SEQ.ID.NO:1)
反向5’-GACTAATGATTCTTCACCGT(SEQ.ID.NO:2)
18SRNA正向:5′-CATTCGAACGTCTGCCCTATC-3′(SEQ.ID.NO:3)和
反向:5′-CCTGCTGCCTTCCTTGGA-3′(SEQ.ID.NO:4)
小鼠18S rRNA基因发挥内源参照基因的作用。制作解链曲线以确保特异性扩增。使用标准曲线方法用于相对定量。然后计算线粒体D-环与18S rRNA的比例。最后的结果表示为对照的百分比。
线粒体复合物I、II和III的活性测定
在100mm平板中培养脂肪细胞,在PBS中洗涤,重悬于适当的等渗缓冲液(0.25M蔗糖、5mM Tris-HCl,pH 7.5和0.1mM苯甲磺酰氟化物)中,并且匀化。通过细胞匀化物的差速离心分离线粒体。使用略微修改的常规实验(Picklo and Montine,2001 Biochim Biophys Acta 1535:145-152;Humphries,K.M.,and Szweda,L I.1998 Biochemistry 37:15835-15841),通过光谱测定法测定NADH-CoQ氧化还原酶(复合物I)、琥珀酸盐-CoQ氧化还原酶(复合物II)、CoQ-细胞色素c还原酶(复合物III)。
统计学分析
所有定性数据代表至少三个独立实验。数据被表示为均值±SE。通过使用两组之间的单通道ANOVA Bonferroni’s事后检验,测定统计学显著性。显著性标准设定为p<0.05。
结果:
羟基酪醇对脂肪细胞中PGC-1α蛋白质水平的影响
如图1中所示,羟基酪醇对从0.1到10.0μM递增的PGC-1α显示钟形影响,在1.0μM下具有最大蛋白质表达(205±52%,与对照相比p,0.05)。
羟基酪醇对脂肪细胞中复合物I、II、III和V蛋白质表达的影响
通过Western印迹测定线粒体复合物(图2)。在0.1μM(131±16%,与对照相比p<0.05)、1.0μM(163±31%,与对照相比p<0.01)和10.0μM(138±21%,与对照相比p<0.05)的羟基酪醇处理下观察到线粒体电子传递复合物I蛋白质的增加。
羟基酪醇对线粒体DNA的影响
因为已知D-环是mtDNA重链和轻链二者上主要的转录起始位点,所以我们体外检查了羟基酪醇是否能够提高mtDNA表达。如图3中所示,在用1.0μM羟基酪醇处理的脂肪细胞中,mt D-环/18SRNA的比例显著提高。
羟基酪醇对脂肪细胞中氧消耗的影响
为了确定提高的线粒体生物发生是否伴随着氧消耗的改变,用0.1-10μM的羟基酪醇处理细胞。如图4中所示,在用1.0-5.0μM羟基酪醇处理的脂肪细胞中氧消耗的基底速率显著提高。
线粒体复合物I、II和III活性的测定
相对于对照,分别在0.1μM和1.0μM下的羟基酪醇显示脂肪细胞中线粒体复合物I和II活性的显著提高(图5A和5B)。在0.1μM-10μM下,羟基酪醇还显示脂肪细胞中线粒体复合物III活性的显著提高。
数据显示羟基酪醇提高mtDNA-编码的多肽和线粒体电子传递复合物I的表达。另外,复合物II和V的活性和氧消耗被提高,进而导致线粒体呼吸活性的提高。最后,羟基酪醇提高过氧化物酶体增殖子活化的受体-γ共同活化子1(PGC-1)的表达,所述PGC-1涉及线粒体活性和线粒体生物发生的控制。PGC-1的该增加导致提高的线粒体生物发生。
总之,羟基酪醇促进线粒体活性,并可用于预防或治疗衰老过程。
Claims (9)
1.羟基酪醇用于制造改进线粒体功能的组合物的用途,其中所述组合物基本不含白藜芦醇,并且其中所述组合物经口施用给动物。
2.根据权利要求1所述的用途,其特征是所述线粒体功能改进通过线粒体呼吸链复合物的活化和线粒体生物发生的提高来获得。
3.根据权利要求1到2中任一项的用途,其特征是羟基酪醇是所述组合物中唯一的活性抗衰老成分。
4.根据权利要求1到3中任一项的用途,其中所述组合物选自膳食补剂、食物添加剂、功能性食物、食物预混物、饲料添加剂、功能性饲料、饲料预混物和饮料。
5.根据权利要求1-4中任一项的用途,其特征是所述动物是人。
6.根据权利要求1-5中任一项的用途,其特征是所述改进导致推迟动物中的衰老过程。
7.根据权利要求1-6中任一项的用途,其特征是所述改进导致推迟衰老过程的视觉征兆。
8.根据权利要求1-7中任一项的用途,其特征是所述改进导致预防细胞衰老。
9.根据权利要求1-8中任一项的用途,其特征是所述改进导致预防身体衰老。
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US20120302645A1 (en) * | 2009-10-07 | 2012-11-29 | Jiankang Liu | Use of hydroxytyrosol for improving muscle differentiation |
US8465939B2 (en) * | 2010-03-02 | 2013-06-18 | Nox Technologies, Inc. | Aging-related circulating particle-associated lipoprotein B oxidase (apoBNOX) and inhibitors thereof |
BR112013006232A2 (pt) * | 2010-09-22 | 2019-09-24 | L´Oreal | processo de tratamento cosmético, composto e composição cosmética |
EP2813221A1 (en) | 2013-06-13 | 2014-12-17 | Natac Biotech, S.L. | Combination of pentacyclic triterpenes and hydroxytyrosol and derivatives thereof |
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TW201733619A (zh) * | 2015-12-16 | 2017-10-01 | Suntory Holdings Ltd | 肌肽二肽酶阻礙用組成物 |
CN112245413A (zh) * | 2020-10-22 | 2021-01-22 | 潍坊医学院 | 一种羟基酪醇对小鼠急性心肺损伤保护作用的方法 |
CN115154339B (zh) * | 2022-04-28 | 2023-11-28 | 上海曙雅生物科技有限公司 | 一种羟基酸护肤组合物及其应用 |
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