CN115227706A - 5’-单磷酸核苷酸组合物在制备消脂减肥功能食品和药物中的应用 - Google Patents
5’-单磷酸核苷酸组合物在制备消脂减肥功能食品和药物中的应用 Download PDFInfo
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- CN115227706A CN115227706A CN202210663045.1A CN202210663045A CN115227706A CN 115227706 A CN115227706 A CN 115227706A CN 202210663045 A CN202210663045 A CN 202210663045A CN 115227706 A CN115227706 A CN 115227706A
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Abstract
本发明公开了5’‑单磷酸核苷酸组合物在制备消脂减肥功能食品和药物中的应用,属于医药和保健食品技术领域。本申请的组合物由5’‑单磷酸腺苷、5’‑单磷酸胞苷、5’‑鸟苷酸二钠、5’‑尿苷酸二钠和5’‑肌苷酸二钠组成,折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP 23‑78%、AMP 6‑44%、UMP 7‑40%、GMP 7‑51%、IMP为0、或大于0且不高于2.5%。本申请的5’‑单磷酸核苷酸组合物能够通过AMPK/Sirt‑1/PGC‑1α通路激活棕色脂肪组织内UCP‑1,改善棕色脂肪组织产热水平,显著增强棕色脂肪组织消耗能量的能力,具有用于制备新型的减脂减肥的药物或功能食品的潜力。
Description
技术领域
本发明属于医药和保健食品技术领域,具体涉及5’-单磷酸核苷酸组合物在制备消脂减肥功能食品和药物中的应用。
背景技术
肥胖是一种机体内脂肪过度累积以至威胁健康的慢性代谢性疾病,肥胖与饮食、遗传、精神状态及地域等多种因素有关,随着居民生活水平的提高,粗纤维类食物摄入量减少,高脂肪、高热量食物摄入增多,缺乏体育锻炼等因素导致超重和肥胖现象增多,并且呈现逐年增高和年轻化的倾向。随着肥胖发病率的迅速增长,与肥胖相关疾病也呈快速增长趋势,肥胖相关疾病主要包括高血压、糖尿病、动脉粥样硬化以及心脑血管疾病。
目前治疗肥胖的常规方法主要有饮食控制、运动疗法、药物疗法和手术治疗,饮食控制和运动疗法对肥胖患者来说多难以坚持且容易反弹;相关的药物大多存在着药物副作用及耐药性的问题;胃短路手术、胃成形术等手术治疗则存在并发吸收不良、贫血和管路狭窄的潜在危险,现有的治疗方法均无法从根源上解决肥胖问题的发生。
哺乳动物体内主要存在2种重要的脂肪组织:白色脂肪组织(white adiposetissue,WAT)和棕色脂肪组织(Brown adipose tissue,BAT),白色脂肪组织主要以甘油三酯形式存储摄入的富裕能量,细胞形态呈脂滴状,棕色脂肪组织主要通过氧化脂质来产生热量,被激活的BAT在全身能量消耗、葡萄糖平衡和人胰岛素敏感性方面具有重要作用,由于激活BAT可以消耗体内多余的营养物质,BAT已逐渐成为治疗肥胖及肥胖相关代谢障碍的全新靶点器官。
核苷酸(Nucleotides,NTs)是核酸的亚单位,由胞嘧啶、腺嘌呤、鸟嘌呤、胸腺嘧啶和尿嘧啶组成的碱基附着在核糖或带有磷酸基团的脱氧核糖部分上,除了参与构建DNA和RNA,NTs还参与各种细胞过程,包括细胞信号转导、参与酶促反应,调节细胞周期。现有研究发现NTs具有免疫调节、抗感染、促进婴幼儿生长发育、维持胃肠道健康、保护肝功能等多方面的功能,然而,将核苷酸及其组合物用于制备消脂减肥功能食品和药物的相关研究还未见报道。
发明内容
鉴于此,本发明的目的是提供5’-单磷酸核苷酸组合物在制备消脂减肥功能食品和药物中的应用。
本发明目的是通过以下方式实现:
本发明提供5’-单磷酸核苷酸或其钠盐形式的组合物在制备消脂减肥功能食品和/或药物中的应用。
进一步的,所述的组合物由5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2)组成。
进一步的,所述的组合物中各核苷酸折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP 23-78%、AMP 6-44%、UMP 7-40%、GMP 7-51%、IMP为0、或大于0且不高于2.5%。
进一步地,所述的组合物中的核苷酸是以发酵生产得到的核糖核酸为原料经过酶法降解生产的,纯度在99%以上。
进一步地,所述的组合物中各种核苷酸折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP23-45%、AMP 15-44%、UMP 20-40%、GMP 7-20%、IMP0-2%。
进一步地,所述的组合物中各种核苷酸折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP 40-45%、AMP 15-20%、UMP 20-25%、GMP 15-20%、IMP为0-2%。
进一步地,所述的药物的剂型包括片剂、胶囊剂、颗粒剂、丸剂和口服液体制剂。
进一步地,所述的片剂包括糖衣片、口腔崩解片、泡腾片、咀嚼片和缓释片。
进一步地,所述的功能食品包括粉剂、乳制品、烘焙制品和液体饮料。
进一步地,所述的功能食品和/或药物中包含有食品或药品中可接受的辅料。
进一步地,所述的辅料包括填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂和矫味剂。
进一步地,所述的功能食品和/或药物通过改善棕色脂肪组织产热能力来消脂减肥。
进一步地,所述的功能食品和/或药物能够显著升高棕色脂肪组织内UCP-1水平,增加AMPK活性,提高Sirt-1和PGC-1α表达量。
本发明相对于现有技术具有的有益效果如下:
1.本申请的5’-单磷酸核苷酸组合物中的核苷酸是核糖核酸及脱氧核糖核酸的基本组成单位,外源核苷酸在人体中使用的安全性已得到科学试验的充分证明,本发明的5’-单磷酸核苷酸组合物不仅安全还具有营养等功能。
2.本发明的5’-单磷酸核苷酸组合物能够显著升高棕色脂肪组织内UCP-1水平,增加AMPK活性,提高Sirt-1,PGC-1α表达量,能够显著增强棕色脂肪组织消耗能量的能力,维持棕色脂肪细胞形态和功能,达到消脂减肥的目的。
3.本发明的5’-单磷酸核苷酸组合物经志愿者人群试验表明,服用本发明的5’-单磷酸核苷酸组合物无需特意节食,没有厌食、腹泻等副作用,具有很好的瘦腰围减肥功效,具有用于制备新型的减脂减肥的药物或功能食品的潜力。
附图说明
为了更清楚地说明本发明实施例,下面将对实施例涉及的附图进行简单地介绍。
图1为本申请的5’-单磷酸核苷酸组合物对脂肪细胞中脂质含量的影响;图中#表示与一般对照比较有统计学差异,*表示与模型对照比较有统计学差异(P<0.05);
图2为饲喂本申请的5’-单磷酸核苷酸组合物的小鼠在冷刺激后体温变化情况;图中#表示与一般对照比较有统计学差异,*表示与模型对照比较有统计学差异(P<0.05);
图3为本申请的5’-单磷酸核苷酸组合物对各组SAMP8小鼠棕色脂肪组织功能的影响;A为Western Blot检测结果;B为5’-单磷酸核苷酸组合物对各组小鼠棕色脂肪组织UCP-1表达量的影响;C为5’-单磷酸核苷酸组合物对各组小鼠棕色脂肪组织AMPK活性的影响;D为5’-单磷酸核苷酸组合物对各组小鼠棕色脂肪组织Sirt-1表达量的影响;E为5’-单磷酸核苷酸组合物对各组小鼠棕色脂肪组织PGC-1α表达量的影响;图中#表示与一般对照比较有统计学差异,*表示与模型对照比较有统计学差异(P<0.05);
图4为本申请的5’-单磷酸核苷酸组合物对各组志愿者的减肥效果评价;图中#表示与一般对照比较有统计学差异,*表示与模型对照比较有统计学差异(P<0.05)。
具体实施方式
下面结合实施例对本发明进行详细的说明,但本发明的实施方式不限于此,显而易见地,下面描述中的实施例仅是本发明的部分实施例,对于本领域技术人员来讲,在不付出创造性劳动性的前提下,获得其他的类似的实施例均落入本发明的保护范围。下述实施例中的实验方法,如无特殊说明,均为常规方法,按照本领域内的文献所描述的实验方法或条件或者按照试剂盒说明书进行。下述实施例中所用的材料、试剂、仪器等均可从商业途径得到。
实施例1
实施例中所使用的5’-单磷酸核苷酸组合物包括5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)各种核苷酸有效百分含量以CMP、AMP、UMP、GMP计分别为:CMP 43%、AMP 17%、UMP 22%、GMP 18%。
上述四种5’-单磷酸核苷酸或者其钠盐分别进行检测,合格后分别过60目筛备用;按上述比例称取所需的各单磷酸核苷酸样品量,进行总混,混合时间不低于40分钟,所得混匀样品常温保存。
实施例2
实施例中所使用的5’-单磷酸核苷酸组合物包括5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2),各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP计分别为:CMP23.5%、AMP 44%、UMP 25%、GMP 7%、IMP为0.5%。上述五种5’-单磷酸核苷酸或者其钠盐分别进行检测,合格后分别过60目筛备用;按上述比例称取所需的各单磷酸核苷酸样品量,进行总混,混合时间不低于40分钟,所得混匀样品常温保存。
实施例3
实施例中所使用的5’-单磷酸核苷酸组合物包括5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2),各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP计分别为:CMP 78%、AMP 6%、UMP 8%、GMP 7%、IMP为1%。上述五种5’-单磷酸核苷酸或者其钠盐分别进行检测,合格后分别过60目筛备用;按上述比例称取所需的各单磷酸核苷酸样品量,进行总混,混合时间不低于40分钟,所得混匀样品常温保存。
实施例4
实施例中所使用的5’-单磷酸核苷酸组合物包括5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2),各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP计分别为:CMP 23%、AMP 17%、UMP 40%、GMP18%、IMP为2%。上述五种5’-单磷酸核苷酸或者其钠盐分别进行检测,合格后分别过60目筛备用;按上述比例称取所需的各单磷酸核苷酸样品量,进行总混,混合时间不低于40分钟,所得混匀样品常温保存。
实施例5
实施例中所使用的5’-单磷酸核苷酸组合物包括5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2),各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP计分别为:CMP 24%、AMP 15.5%、UMP7%、GMP 51%、IMP为2.5%。上述五种5’-单磷酸核苷酸或者其钠盐分别进行检测,合格后分别过60目筛备用;按上述比例称取所需的各单磷酸核苷酸样品量,进行总混,混合时间不低于40分钟,所得混匀样品常温保存。
实施例6
本实施例考察实施例1-5的5’-单磷酸核苷酸组合物对脂肪细胞中脂质含量的影响,以3T3-L1细胞分化的脂肪细胞为模型,对实施例1-5的5’-单磷酸核苷酸组合物的减脂效果进行评价实验,设置实验组1(实施例1的5’-单磷酸核苷酸组合物)、实验组2(实施例2的5’-单磷酸核苷酸组合物)、实验组3(实施例3的5’-单磷酸核苷酸组合物)、实验组4(实施例4的5’-单磷酸核苷酸组合物)、实验组5(实施例5的5’-单磷酸核苷酸组合物),并以仅含有5’-单磷酸胞苷作为对照组1,以仅含有5’-单磷酸腺苷作为对照组2,以仅含有5’-尿苷酸二钠作为对照组3,以仅5’-鸟苷酸二钠作为对照组4,以仅含有5'-肌苷酸二钠(5’-IMPNa2)作为对照组5。
3T3-L1细胞的培养和分化:
将3T3-L1脂肪细胞在DMEM培养基(包含4.5g/l的葡萄糖、2mM的谷氨酰胺和10%的胎牛血清)中培养,在细胞铺满孔板90%以上呈接触抑制状态2天后,更换为培养基中添加有终浓度为0.5mM的4,3-异丁基-1-甲基黄嘌呤溶液(IBMX)、终浓度为1μM的***和终浓度为10μg/ml的胰岛素的培养液,培养两天后,更换为终浓度为10μg/ml的胰岛素的培养液继续培养,2天更换一次培养液,继续培养6天,显微镜下观察细胞基本成圆形,即诱导3T3-L1细胞分化成脂肪细胞。
5’-单磷酸核苷酸组合物处理脂肪细胞:
将诱导获得脂肪细胞接种于96孔板中,5×104cells/孔,待24h细胞贴壁后,分别设置实验组1、实验组2、实验组3、实验组4、实验组5、对照组1、对照组2、对照组3、对照组4、对照组5和阳性对照(未处理),每组6个复孔,每日向对应的脂肪细胞的培养液中添加终浓度为2.0mg/mL的药物,每日更换培养液,持续4天,使用1×PBS缓冲液清洗细胞,然后更换为终浓度为100nM尼罗红的PBS缓冲液,标记10分钟,最后更换为新的PBS缓冲液,将孔板避光放于荧光光谱仪的托架上,于540nm激发,600nm发射条件下进行荧光信号的检测,实验数据以均值±标准偏差表示。
实验结果如图1所示,与阳性对照以及对照组1-5的5’-单磷酸核苷酸相比,实施例1-5的5’-单磷酸核苷酸组合物能够显著降低脂肪细胞内的脂质含量,可用于清除脂肪细胞内的脂质。
实施例7
根据实施例6的结果可知,实施例1制备的5’-单磷酸核苷酸组合物的减脂效果最优,本次实验使用实施例1制备的5’-单磷酸核苷酸组合物进行小鼠实验,下述实施例中所提到的一般对照组、低剂量组、中剂量组棕色脂肪组织均为老年SAMP8小鼠肩胛间棕色脂肪,模型对照组棕色脂肪组织为老年SAMR1小鼠肩胛间棕色脂肪。
本实施例所用的小鼠为3月龄的雄性SAMP8、SAMR1小鼠,饲养于SPF级动物房中,饲养环境温度22±2℃,相对湿度50%-60%,以12h/12h(8:00-20:00)光照模式模拟正常昼夜变化节律。适应喂养一周后,将SAMP8小鼠随机分为一般对照组、低剂量组(NTs-L)和中剂量组(NTs-M),SAMR1小鼠为模型对照组,每组8只,给予正常对照组、模型对照组小鼠基础饲料,低剂量组小鼠给予0.3g/kg实施例1制备的5’-单磷酸核苷酸组合物+基础饲料、中剂量组给予0.6g/kg实施例1制备的5’-单磷酸核苷酸组合物+基础饲料喂养9个月。实验最后一天早上8:00在喂养5’-单磷酸核苷酸组合物2h后,分别将一般对照组、低剂量组、中剂量组和模型对照组的小鼠持续暴露在4℃环境中,在冷刺激开始后0min,30min,60min,90min,120min和150min时,将石蜡油润滑的小鼠肛温计***小鼠直肠约1.5-2cm,测定各组小鼠直肠温度;12月龄时处死小鼠,分离小鼠的肩胛间棕色脂肪组织,使用Western Blot检测小鼠棕色脂肪UCP-1、tAMPK、pAMPK、Sirt-1、PGC-1α的表达情况。以UCP-1/β-actin、pAMPK/tAMPK、Sirt-1/β-actin、PGC-1α/β-actin的相对光密度值表示蛋白相对表达量。数据采用均数±标准差表示。
各组小鼠在冷刺激后体温变化情况如图2所示,在冷刺激30min时,低剂量组和中剂量组的小鼠的体温已明显高于一般对照组和模型对照组的小鼠,在冷刺激60min时低剂量组和中剂量组的小鼠的体温与一般对照组和模型对照组的差距进一步拉大,说明本申请制备的5’-单磷酸核苷酸组合物能够明显促进小鼠进行适应性产热;当低剂量组和中剂量组的小鼠暴露于冷环境中,体温保持在较高温度是由棕色脂肪组织通过氧化脂质产生热量来维持的。
本申请的5’-单磷酸核苷酸组合物对小鼠棕色脂肪组织功能的影响的结果如图3所示,可以看出,低剂量组小鼠的棕色脂肪组织内的UCP-1表达量较一般对照组明显升高,低剂量组小鼠的棕色脂肪组织内的AMPK活性显著高于模型对照组(P<0.05);中剂量组小鼠的棕色脂肪组织内的的Sirt-1表达量显著高于一般对照组(P<0.05),中剂量组小鼠的棕色脂肪组织内的PGC-1α表达量显著高于一般对照组(P<0.05)。
Uncoupling protein 1(UCP-1)是唯一在BAT细胞中表达的解偶联蛋白,主要参与BAT的产热调节和能量代谢,在寒冷、去甲肾上腺素刺激作用下可以完成非震颤性产热,是用来反映BAT细胞产热功能的标志蛋白;腺苷酸活化蛋白激酶(AMP-activated proteinkinase,AMPK)是细胞代谢和能量平衡的关键调节剂;沉默信息调节因子-1(Sirtuin-1,Sirt-1)参与调节机体糖脂代谢、氧化应激等,具有重要的生理功能;过氧化物酶体增殖物激活受体-γ共激活因子-1α(Peroxlsome proliferator-activated receptor-γcoactlvator-1α,PGC-1α)在BAT中可以诱导UCP-1和其他产热成分的表达,对产热基因激活表达具有重要作用,是产热脂肪细胞肾上腺素能激活的中心转录效应物。AMPK/Sirt-1/PGC-1α通路在维持BAT正常生理功能中发挥着重要作用。激活AMPK/Sirt-1/PGC-1α信号可以刺激UCP-1蛋白表达,从而维持老年小鼠棕色脂肪的产热功能,减少小鼠体内白色脂肪的生成。综上可知,低剂量(0.3g/kg)5’-单磷酸核苷酸组合物可以显著升高棕色脂肪组织内UCP-1水平,可能是通过AMPK/Sirt-1/PGC-1α通路诱导增高,可以显著增强棕色脂肪组织消耗能量的能力,具有潜在减脂减肥作用。
实施例8
本实施例选择300名年龄40~60周岁、身体质量指数(BIM值)大于25的志愿者参加本申请的5’-单磷酸核苷酸组合物的减肥效果评价实验,并随机分为6组,每组50人,6组志愿者分别对应空白组(木糖醇)、实验组1(实施例1的5’-单磷酸核苷酸组合物)、实验组2(实施例2的5’-单磷酸核苷酸组合物)、实验组3(实施例3的5’-单磷酸核苷酸组合物)、实验组4(实施例4的5’-单磷酸核苷酸组合物)、实验组5(实施例5的5’-单磷酸核苷酸组合物),且每组志愿者均使用对应试验产品作为唯一减脂减肥产品,志愿者按正常习惯进行饮食,每人每天服用对应的核苷酸组合物0.6g,连续服用30天,试验结束后参加试验的志愿者反馈服用前后的体重差值和腰围差值,评价本申请的5’-单磷酸核苷酸组合物的减肥效果。
本申请的5’-单磷酸核苷酸组合物的减肥效果评价结果如图4所示,结果表明本发明的5’-单磷酸核苷酸组合物的减肥效果具有较好的减重和瘦腰功效,主要是由于本申请的5’-单磷酸核苷酸组合物可以通过激活AMPK/Sirt-1/PGC-1α通路改善棕色脂肪组织产热水平,减少脂肪囤积,从而使体重和腰围减少。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.5’-单磷酸核苷酸或其钠盐形式的组合物在制备消脂减肥功能食品和/或药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述的组合物由5’-单磷酸腺苷(5’-AMP)、5’-单磷酸胞苷(5’-CMP)、5’-鸟苷酸二钠(5’-GMPNa2)、5’-尿苷酸二钠(5’-UMPNa2)和5'-肌苷酸二钠(5’-IMPNa2)组成。
3.根据权利要求2所述的应用,其特征在于,所述的组合物中各核苷酸折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP 23-78%、AMP 6-44%、UMP 7-40%、GMP 7-51%、IMP为0、或大于0且不高于2.5%。
4.根据权利要求3所述的应用,其特征在于,所述的组合物中各种核苷酸折合为CMP、AMP、UMP、GMP、IMP酸型的质量比分别为:CMP 23-45%、AMP 15-44%、UMP 20-40%、GMP 7-20%、IMP 0-2%。
5.根据权利要求2所述的应用,其特征在于,所述的药物的剂型包括片剂、胶囊剂、颗粒剂、丸剂和口服液体制剂。
6.根据权利要求5所述的应用,其特征在于,所述的片剂包括糖衣片、口腔崩解片、泡腾片、咀嚼片和缓释片。
7.根据权利要求2所述的应用,其特征在于,所述的功能食品包括粉剂、乳制品、烘焙制品和液体饮料。
8.根据权利要求2所述的应用,其特征在于,所述的功能食品和/或药物中包含有食品或药品中可接受的辅料。
9.根据权利要求8所述的应用,其特征在于,所述的辅料包括填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂和矫味剂。
10.根据权利要求2所述的应用,其特征在于,所述的功能食品和/或药物通过改善棕色脂肪组织产热能力来消脂减肥。
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