CN116115596A - N-乙酰-l-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用 - Google Patents
N-乙酰-l-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用 Download PDFInfo
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Abstract
本发明提供N‑乙酰‑L‑天门冬氨酸的一种新用途——在制备预防或治疗肥胖药或食品中的应用,属于生物医药与保健技术领域。研究表明,N‑乙酰‑L‑天门冬氨酸可抑制脂肪细胞分化,降低脂质积累,从而抑制脂肪形成,因此具有抑制脂质积累的作用。因此,可以N‑乙酰‑L‑天门冬氨酸作为抑制细胞中脂肪积累的活性物质,用于制备预防或治疗减肥药物或保健制剂。即以N‑乙酰‑L‑天门冬氨酸作为活性组分,制备成减肥药物或减肥食品。或与其相适配的减肥活性成分复配,制备成复方减肥药物或保健制剂。
Description
技术领域
本发明涉及N-乙酰-L-天门冬氨酸的新用途——在抑制脂肪堆积中的应用,属于生物医药与保健技术领域。
技术背景
肥胖是一种慢性代谢性疾病,由遗传、生物行为和环境等多种因素引起,是目前人类面临的最容易被忽视的一种疾病。肥胖是体内脂肪尤其是甘油三酯积聚过多、皮下脂肪过度堆积而导致的一种状态。当人类由于食物摄入过多或机体代谢的改变而导致脂肪聚集过多时,就会造成体重过度增长并引起人体病理生理的改变,逐步演变为肥胖症。随着科技的发展和人们生活水平的提高,加上不健康的生活方式,肥胖在全球范围内已成为一种流行病。根据世界卫生组织统计,截止2022年全球有超过10亿人患有肥胖症,其中包括6.5亿成年人,3.4亿青少年和3900万儿童。在中国,肥胖更是一个值得注意的公共卫生问题,据《中国居民营养与慢性病状况报告(2020年)》数据显示,中国成人(≥18岁)的超重比例为34.3%,肥胖比例为16.4%。
肥胖主要分为两种类型,单纯性肥胖和病理性肥胖。单纯性肥胖通常无明显病因,具有明显病因者称为病理性肥胖。肥胖可引起人体生理、病理、神经、体液调节的一系列变化,使人体工作能力降低,严重肥胖者对疾病的抵抗能力下降,甚至显著缩短寿命。现代医学研究揭示,肥胖者比体重正常者寿命短5~20岁。另外肥胖会引起一系列并发症,包括糖尿病、冠心病、高血压、高血脂、动脉粥样硬化与斑块、脂肪肝、高尿酸血症等,不仅使患者自身受到影响,还会使家庭付出高昂的医疗费用。
目前对于肥胖的致病机理尚未完全明确,因此缺乏有效的治疗手段。常用的治疗手段有生活方式干预、药物治疗和手术治疗,其中药物治疗是临床主要治疗手段。目前市场上常用减肥药物包括奥利司他、利拉鲁肽等。肥胖者体内的脂肪酶含量相对较高,奥利司他能选择性地抑制胰脂酶活性,减少饮食中约30%脂肪的吸收,但其会引起肠道不良反应,抑制脂溶性维生素吸收,长期使用甚至可能含有潜在的心血管风险;利拉鲁肽胰高血糖素样肽-1(GLP-1)受体激动剂,能够刺激胰岛素的生成、抑制胰高血糖素分泌、降低食欲和食物摄入量。但注射利拉鲁肽后容易引发腹胀、腹泻、恶心、呕吐等胃肠道副作用。上述减肥药物药效低,副作用明显,因此急需研发出疗效好且副作用小的减肥药及保健产品。
N-乙酰-L-天门冬氨酸(N-Acetyl-L-aspartic acid,NAA)是重要的精细有机化工中间体,广泛应用于医药、农药、化学工业等领域。NAA是神经元损伤严重程度的一项生化指标。脑卒中后缺血脑组织NAA下降表明神经元代谢紊乱。现已证实,NAA和乳酸对脑卒中后缺血半暗带的判定,对急性脑卒中的治疗和预后的判断均有重要意义。N-乙酰-L-天门冬氨酸的结构式如下:
我们在研究中意外发现,N-乙酰-L-天门冬氨酸能够明显抑制细胞中的脂肪积累的作用,能够用于肥胖及其并发症的治疗或预防。
发明内容
本发明目的在于提供N-乙酰-L-天门冬氨酸的一种新用途——在制备预防或治疗肥胖药或食品中的应用。
下面通过实验对N-乙酰-L-天门冬氨酸抑制细胞脂肪积累的效果进行具体的研究。
1.实验材料及试剂
3T3-L1小鼠胚胎成纤维细胞(普诺赛,CL0006);Dulbecco’s Modified EagleMedium(DMEM,Biological Industries,01-052-1A);Fetal Bovine Serum(FBS,Biological Industries,04-001-1A);Penicillin-streptomycin(PS,BiologicalIndustries,03-031-1B);3-isobytyl-1-methylxanthine(IBMX,Sigma Aldrich,I7018);地塞米松(阿拉丁,D392303);胰岛素(罗恩,R008974);N-乙酰-L-天门冬氨酸(阿拉丁,N305071)。
2.实验分组
将所培养的细胞分为三组:空白对照组MDI(-)+N-Acetyl-L-aspartic acid(-),模型对照组MDI(+)+N-Acetyl-L-aspartic acid(-),实验组MDI(+)+N-Acetyl-L-asparticacid(+)。
3.实验方法
3.1细胞分化
(1)在6孔板上接种3T3-L1细胞,用10% FBS/1% PS/DMEM在5% CO2、37℃下孵化至细胞接触抑制;
(2)将3T3-L1细胞用含10%小牛血清(BCS)的1% PS/DMEM培养液5% CO2,37℃孵育2天;
(3)MDI(+)+N-Acetyl-L-aspartic acid(-),MDI(+)+N-Acetyl-L-aspartic acid(+)两组加入分化诱导剂(1 μM 地塞米松,0.5 mM IBMX,10 μg/mL 胰岛素,MDI),10% FBS/1% PS/DMEM,5% CO2,37℃孵育2天。MDI(+)+N-Acetyl-L-aspartic acid(+)组加N-Acetyl-L-aspartic acid,以后此组换液都要加入N-Acetyl-L-aspartic acid。N-Acetyl-L-aspartic acid浓度为100 nM;
(4)将培养液换成含有10 μg/mL胰岛素的10% FBS/1% PS/DMEM,5% CO2,37℃条件下再次孵育2天;
(5)将培养液换成10% FBS/1% PS/DMEM,在5% CO2,37℃条件下继续孵育,两天换一次培养液。在实验的10-14天左右分化成功,脂滴积累,呈现脂肪细胞表型,开展后续实验。
3.2油红染色
将细胞进行油红染色,具体如下:
(1)小心轻缓倒除培养液,用1 mL PBS清洗细胞2-3次;
(2)加1 mL 4%多聚甲醛溶液,固定30 min;
(3)吸除多聚甲醛溶液,用1 mL PBS洗2-3次;
(4)加入1 mL 60%异丙醇浸润1分钟左右其目的是使脂粒更好的着色;加入1 mL0.3%的油红,放至37℃烘箱里染色30分钟;
(5)染色完成后用蒸馏水洗一遍,再用1 mL 60%异丙醇快速洗一遍,随后用蒸馏水洗2-3次。加入1 mL PBS,放到显微镜下观察结果。
4.实验结果
图1 为本发明各组细胞油红染色结果图:其中MDI为分化诱导剂,N-Acetyl-L-aspartic acid为N-乙酰-L-天门冬氨酸。“MDI(-)+N-Acetyl-L-aspartic acid(-)”为未加入分化诱导剂和N-乙酰-L-天门冬氨酸的空白对照组,“MDI(+)+N-Acetyl-L-asparticacid(-)”为加入分化诱导剂且未加入N-乙酰-L-天门冬氨酸的模型对照组,“MDI(+)+N-Acetyl-L-aspartic acid(+)”为加入分化诱导剂和N-乙酰-L-天门冬氨酸的实验组。如图1所示,3T3-L1细胞在分化诱导剂的作用下,胞内脂质不断积累,模型对照组“MDI(+)+N-Acetyl-L-aspartic acid(-)”细胞中脂质积累明显高于空白对照组“MDI(-)+N-Acetyl-L-aspartic acid(-)”,而加入N-乙酰-L-天门冬氨酸的实验组“MDI(+)+N-Acetyl-L-aspartic acid(+)”与模型对照组“MDI(+)+N-Acetyl-L-aspartic acid(-)”相比,细胞内脂质积累明显减少,且接近空白对照组“MDI(-)+N-Acetyl-L-aspartic acid(-)”水平。由此可见,N-乙酰-L-天门冬氨酸可抑制脂肪细胞分化,从而抑制脂肪形成,因此具有抑制脂质积累的作用。
图2为本发明各组积累脂肪细胞油红染色后所占面积比柱状图。其中MDI为分化诱导剂,N-Acetyl-L-aspartic acid为N-乙酰-L-天门冬氨酸。“MDI(-)+N-Acetyl-L-aspartic acid(-)”为未加入分化诱导剂和N-乙酰-L-天门冬氨酸的空白对照组,“MDI(+)+N-Acetyl-L-aspartic acid(-)”为加入分化诱导剂且未加入N-乙酰-L-天门冬氨酸的模型对照组,“MDI(+)+N-Acetyl-L-aspartic acid(+)”为加入分化诱导剂和N-乙酰-L-天门冬氨酸的实验组。如图2所示,模型对照组“MDI(+)+N-Acetyl-L-aspartic acid(-)”与空白对照组“MDI(-)+N-Acetyl-L-aspartic acid(-)”相比,###p<0.001,表明3T3-L1脂肪细胞分化成功;实验组“MDI(+)+N-Acetyl-L-aspartic acid(+)”与模型对照组“MDI(+)+N-Acetyl-L-aspartic acid(-)”相比,***p<0.001,说明N-乙酰-L-天门冬氨酸具有很好的抑制脂肪细胞分化,降低脂质积累的作用。
基于上述研究,本发明可将N-乙酰-L-天门冬氨酸作为抑制细胞中脂肪积累的活性物质,用于制备预防或治疗减肥药物或保健制剂。即以N-乙酰-L-天门冬氨酸作为活性组分,制备成减肥药物或减肥食品。或与其相适配的减肥活性成分复配,制备成复方减肥药物或保健制剂。制剂的剂型包括散剂、注射剂、片剂、胶囊剂、颗粒剂、丸剂、口服液等。
附图说明
图1为本发明各组细胞油红染色结果图。
图2为本发明各组积累脂肪细胞油红染色后所占面积比柱状图。
具体实施方式
实施例1:以N-乙酰-L-天门冬氨酸作为活性组分,以药学或生理学可接受的辅料及常规药物制剂的制备工艺制成减肥药物制剂。药物制剂为散剂、颗粒剂、胶囊剂、软胶囊、粉剂、丸剂、片剂、口服液。
实施例2:以N-乙酰-L-天门冬氨酸与其相适配的减肥试剂的复配物作为活性组分,制备成复方减肥药物制剂。药物制剂内服药物制剂为散剂、颗粒剂、胶囊剂、软胶囊、粉剂、丸剂、片剂、口服液。
实施例3:以N-乙酰-L-天门冬氨酸作为活性组分,制备成减肥食品。
实施例4:以N-乙酰-L-天门冬氨酸与其相适配的减肥活性成分的复配物作为活性组分,制备成减肥食品。
Claims (5)
1.N-乙酰-L-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用,其特征在于:所述N-乙酰-L-天门冬氨酸的结构式如下:
。
2.如权利要求1所述N-乙酰-L-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用,其特征在于:以N-乙酰-L-天门冬氨酸为活性组分,以药学或生理学可接受的辅料及常规药物制剂的制备工艺制成减肥药物制剂。
3.如权利要求1所述N-乙酰-L-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用,其特征在于:以N-乙酰-L-天门冬氨酸与相适配的减肥活性成分的复配物为活性组分,以药学或生理学可接受的辅料及常规药物制剂的制备工艺制成减肥药物制剂。
4.如权利要求1所述N-乙酰-L-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用,其特征在于:以N-乙酰-L-天门冬氨酸为活性组分,制备成减肥食品。
5.如权利要求1所述N-乙酰-L-天门冬氨酸在制备预防或治疗肥胖药品或食品中的应用,其特征在于:以N-乙酰-L-天门冬氨酸与相适配的减肥活性成分的复配物为活性组分,制备成减肥食品。
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