CN117304063A - 阿甘油神经酰胺及其合成方法与用途 - Google Patents
阿甘油神经酰胺及其合成方法与用途 Download PDFInfo
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- CN117304063A CN117304063A CN202310186335.6A CN202310186335A CN117304063A CN 117304063 A CN117304063 A CN 117304063A CN 202310186335 A CN202310186335 A CN 202310186335A CN 117304063 A CN117304063 A CN 117304063A
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- Prior art keywords
- ceramide
- acid
- arginin
- weight percent
- sphingosine
- Prior art date
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Abstract
本发明属于生物医药技术领域,公开了阿甘油神经酰胺,其由阿甘油脂肪酸与鞘氨醇类化合物反应得到,所述鞘氨醇类化合物选自鞘氨醇、植物鞘氨醇、二氢鞘氨醇,本方案还公开了阿甘油神经酰胺的合成方法与用途。阿甘油神经酰胺在皮肤天然屏障的修复、组织愈合、抗衰老等方面表现出优异性能,在化妆品、保健品、生物医药等领域有着广泛的应用前景。
Description
技术领域
本发明属于生物医药技术领域,具体涉及阿甘油神经酰胺及其合成方法与用途。
背景技术
神经酰胺(Ceramide,又称分子钉)天然存在于皮肤中,是皮肤屏障(角质层)非常重要的组成部分,含量高达40~50wt%,神经酰胺是一类由鞘氨醇类长链碱基与脂肪酸组成的神经鞘氨脂质,其中的鞘氨醇部分、脂肪酸部分的碳链长度、不饱和度和羟基数目都是可以变化的,神经酰胺代表了一类化合物。神经酰胺在调控皮肤屏障功能,恢复皮肤水分以及增强皮肤角质细胞之间的粘着力等方面表现出优异的性能。
由于神经酰胺的重要性,许多化妆品和制药公司正在研究、开发相应的产品。天然植物来源的神经酰胺因其更加可持续和更加环保的原料来源,以及与皮肤神经酰胺成分相近的特性,能形成有效的皮肤屏障防止水分流失,并对抗外部损坏,将可能成为下一代环境友好、安全可靠的神经酰胺产品。
阿甘油是由生长于摩洛哥的阿甘树上的坚果榨取而成。近些年来研究发现它的许多独特的化学成份,可以应对各种皮肤和头发问题,并成为一种可靠的纯天然护肤品。阿甘油虽然长得像油,但它的渗透性很好,抹到手上轻微摩擦,立即渗透,所以是保湿佳品。此外其去除皱纹、淡化疤纹的效果也很好。阿甘油含有大量的脂肪酸,这些都是不能在人内体合成、而必须从脂肪中获取的。脂肪酸维持人体健康的水合程度,亚油酸在对抗皮肤发炎,减少粉刺,保湿方面有明显效果;而必不可少的不饱和脂肪酸的缺乏可导致皮肤过早老化和皱纹。阿甘油含有2倍于橄榄油的维生素E,维生素E缺乏的症状包括头发干枯、脱发、伤口愈合缓慢等。阿甘油还含有稀有的植物甾醇,植物甾醇能帮助软化皮肤,刺激毛孔排毒,恢复天然脂质屏障。多酚则是众所周知的抗氧化剂,它不仅能延缓皮肤衰老,还可以延长人体内其它抗氧化剂,如维生素E、维生素C的作用时间。
发明内容
本发明的目的是提供一种利用植物来源的阿甘油脂肪酸合成得到的神经酰胺。
本发明的另一目的是提供阿甘油神经酰胺的合成方法,其利用天然植物来源且易得的阿甘油油脂或者阿甘油脂肪酸作为原料。
本发明的另一目的是提供阿甘油神经酰胺的用途。
为达到上述目的之一,本发明采用以下技术方案:
本发明的第一方面,阿甘油神经酰胺,其由阿甘油脂肪酸与鞘氨醇类化合物反应得到,所述鞘氨醇类化合物选自鞘氨醇、植物鞘氨醇、二氢鞘氨醇。
反应即可以是化学合成反应(如下文详述),也可采用微生物发酵法,即应用雪氏毕赤酵母或酿酒酵母,在一定环境下发酵得到鞘氨醇类化合物,然后加入脂肪酸,最终得到神经酰胺;或者以阿甘油为原料,选用合适的菌株,进行发酵得到阿甘油神经酰胺。
鞘氨醇指2-氨基-4-十八烯-1,3-二醇,植物鞘氨醇指2-氨基-十八烷-1,3,4-三醇,二氢鞘氨醇指2-氨基-十八烷-1,3-二醇。
进一步地,所述阿甘油脂肪酸由阿甘油水解得到。
进一步地,所述阿甘油脂肪酸含有35~50wt%油酸。
进一步地,所述阿甘油脂肪酸含有30~50wt%亚油酸。
进一步地,所述阿甘油脂肪酸含有5~15wt%棕榈酸。
进一步地,所述阿甘油脂肪酸含有2~8wt%硬脂酸。
进一步地,所述阿甘油脂肪酸含有0.1~1wt%花生酸。
进一步地,所述阿甘油脂肪酸含有0.01~0.5wt%亚麻酸。
此外,阿甘油脂肪酸还含有0~0.5wt%山嵛酸、0~0.5wt%花生一烯酸。
阿甘油脂肪酸的组成为:35~50wt%油酸、30~50wt%亚油酸、5~15wt%棕榈酸、2~8wt%硬脂酸、0.1~1wt%花生酸、0.01~0.5wt%亚麻酸、0~0.5wt%山嵛酸、0~0.5wt%花生一烯酸。
阿甘油脂肪酸的主要成分为油酸和亚油酸,其他的脂肪酸包括棕榈酸、硬脂酸、花生酸和亚麻酸,是必要组分,受树种、土壤、气候、产地、采摘季节、提取过程的影响,各组分的含量会有所不同,而山嵛酸、花生一烯酸不一定含有,是可选组分或者非必要组分。
阿甘油神经酰胺,其组成包括:油酸神经酰胺,亚油酸神经酰胺,棕榈酸神经酰胺,硬脂酸神经酰胺,花生酸神经酰胺,亚麻酸神经酰胺;因为脂肪酸都会参与相同的反应,反应后神经酰胺的质量占比变化不大,所以与阿甘油脂肪酸的组成类似,阿甘油神经酰胺的组成为:35~50wt%油酸神经酰胺,30~50wt%亚油酸神经酰胺,5~15wt%棕榈酸神经酰胺,2~8wt%硬脂酸神经酰胺,0.1~1wt%花生酸神经酰胺,0.01~0.5wt%亚麻酸神经酰胺。各组分的含量因阿甘油脂肪酸或油脂中各脂肪酸的含量不同而存在差异。此外,阿甘油神经酰胺还包括山嵛酸、花生一烯酸中一种或多种与鞘氨醇类化合物反应得到的神经酰胺,即还包括0~0.5wt%山嵛酸神经酰胺、0~0.5wt%花生一烯酸神经酰胺。阿甘油神经酰胺还包括维生素E、甾醇、咖啡酸、香草酸、酪醇、间苯二酚等存在于阿甘油脂肪酸中但是不与鞘氨醇类化合物反应的化合物。
阿甘油神经酰胺,其组成包括:油酸神经酰胺、亚油酸神经酰胺、棕榈酸神经酰胺、硬脂酸神经酰胺;油酸神经酰胺占比35~50wt%,亚油酸神经酰胺占比30~50wt%,棕榈酸神经酰胺占比5~15wt%,硬脂酸神经酰胺占比2~8wt%。
进一步地,阿甘油神经酰胺包括花生酸神经酰胺,花生酸神经酰胺占比0.1~1wt%。
进一步地,阿甘油神经酰胺包括亚麻酸神经酰胺,亚麻酸神经酰胺占比0.01~0.5wt%。
进一步地,阿甘油神经酰胺包括不超过0.5wt%的山嵛酸神经酰胺和不超过0.5wt%的花生一烯酸神经酰胺,尤其是0.1~0.5wt%山嵛酸神经酰胺和0.1~0.5wt%花生一烯酸神经酰胺。
油酸神经酰胺是油酸与鞘氨醇类化合物缩合反应得到,包括油酸植物鞘氨醇神经酰胺、油酸鞘氨醇神经酰胺、油酸二氢鞘氨醇神经酰胺;亚油酸神经酰胺是亚油酸与鞘氨醇类化合物缩合反应得到,包括亚油酸植物鞘氨醇神经酰胺、亚油酸鞘氨醇神经酰胺、亚油酸二氢鞘氨醇神经酰胺;棕榈酸神经酰胺是棕榈酸与鞘氨醇类化合物缩合反应得到,包括棕榈酸植物鞘氨醇神经酰胺、棕榈酸鞘氨醇神经酰胺、棕榈酸二氢鞘氨醇神经酰胺;硬脂酸神经酰胺、花生酸神经酰胺、亚麻酸神经酰胺、山嵛酸神经酰胺、花生一烯酸神经酰胺等以此类推。
本发明的第二方面,阿甘油神经酰胺的合成方法,包括以下步骤:
在缩合剂、有机碱条件下,阿甘油脂肪酸与鞘氨醇类化合物反应,所述缩合剂为EDCI,所述有机碱为Et3N。
进一步地,所述阿甘油脂肪酸、鞘氨醇类化合物、EDCI、Et3N的摩尔比为1:(1~1.5):(1~2):(1~2),所述反应的溶剂为二氯甲烷、四氢呋喃、乙酸乙酯、乙腈中的至少一种。
在市场上购买的阿甘油一般是油脂形态,需要水解成阿甘油脂肪酸,因此还包括以下步骤:
阿甘油油脂通过皂化反应水解得到阿甘油脂肪酸。
进一步地,所述皂化反应是阿甘油油脂在氢氧化钾溶液中水解。
进一步地,所述阿甘油油脂与氢氧化钾的质量比为1:(1~2)。
本发明的第三方面,阿甘油神经酰胺在化妆品、药品、膳食品或保健品中的用途。
进一步地,所述阿甘油神经酰胺具有皮肤屏障修复、组织愈合、抗衰老、抗光老化、抗氧化、促进胶原合成、维持弹性蛋白活力、美白功效中的至少一种。
一种组合物,包括阿甘油神经酰胺,所述组合物具有皮肤屏障修复、组织愈合、抗衰老、抗光老化、抗氧化、促进胶原合成、维持弹性蛋白活力、美白功效中的至少一种。
该组合物含有可接受的辅料,包括增溶剂、防腐剂、抗氧剂、pH调节剂、促渗剂、脂质体、保湿剂、增稠剂、螯合剂、肤感调节剂、表面活性剂、乳化剂、香精及色素中的一种或多种;该组合物为霜剂、乳剂、溶液剂、膜剂、气雾或喷雾形式。
本发明具有以下有益效果:
阿甘油脂肪酸属于天然形成的脂肪酸,最主要的成分是单不饱和脂肪酸——油酸和亚油酸,此外还含有棕榈酸、硬脂酸等,其与天然存在于皮肤中的鞘氨醇类化合物,经温和反应制备得到阿甘油神经酰胺,在皮肤天然屏障的修复、抗氧化、抗衰老等方面表现出优异性能,在化妆品、保健品、生物医药等领域有着广泛的应用前景。
1、与单一的神经酰胺相比效果更好。不同的神经酰胺,因其结构的差异,功效也会存在差异,单一结构的神经酰胺一般难以具备全面的效果。本方案基于仿生的思路,利用天然来源的阿甘油油脂或脂肪酸作为原料,合成复合的神经酰胺,以弥补不同神经酰胺功效的差异,阿甘油中的微量脂肪酸可以形成微量神经酰胺,起到功效补充的作用。
2、与复配的神经酰胺相比效果更好。除了脂肪酸(或油脂),阿甘油还含有人体所需的营养素维生素、甾醇、咖啡酸、香草酸、酪醇、间苯二酚等,这些营养物质有滋润皮肤、过滤紫外线、为皮肤提供屏障等效果,用阿甘油合成的神经酰胺,与阿甘油中含有的其它活性成分具有协同增效的作用,相比按照类似比例复配的神经酰胺,具有更好的效果。
3、成本更低。本发明的方法快速得到多种神经酰胺复配的组合物,植物源的阿甘油油脂或其脂肪酸来源广泛、易于商业化获取、成本较低,更加环保经济,有别于将不同的单一神经酰胺混合复配的思路,单一成分的脂肪酸不仅原料价格高,而且需要分别生产不同的神经酰胺,然后再进行复配,增加了制备成本。
4、合成方法简单。本发明的方法可以采用化学合成,实现一步制备多种神经酰胺,也可以使用微生物发酵法。
附图说明
图1为实施例4细胞迁移能力测试结果;
图2、3为实施例5弹性蛋白酶抑制率柱形图;
图4、5为实施例6抗光老化测试MMP1表达量柱形图;
图6、7为实施例7抗氧化性测试DPPH自由基清除率柱形图;
图8为实施例8美白活性测试黑色素含量柱形图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
EDCI指1-乙基-(3-二甲基氨基丙基)碳二亚胺,Et3N指三乙胺。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。薄层色谱分析(TLC)使用60F254硅胶板,TLC显色采用UV光(254nm)或碘。
实施例1
阿甘油脂肪酸和植物鞘氨醇合成神经酰胺
第一步:将50g阿甘油油脂溶于60mL四氢呋喃,冰浴下冷却,滴加110mL氢氧化钾(25wt%)溶液,滴加完毕后升至室温反应,至TLC检测反应完毕。
后处理:加入稀盐酸(3N)调节反应体系的pH值到3,加入120mL乙酸乙酯萃取水相,加入80mL饱和食盐水洗一次,有机相加入无水Na2SO4干燥,过滤并真空浓缩,得到38g阿甘油脂肪酸。
第二步:将阿甘油脂肪酸(50mmol,以主成分脂肪酸计)、EDCI(70mmol)、Et3N(70mmol)加入250mL圆底烧瓶中,再加入80mL二氯甲烷,随后在室温条件下搅拌1小时,随后将植物鞘氨醇(55mmol)加入到反应体系中,在室温条件下搅拌,至TLC检测反应完毕。
后处理:加入水淬灭反应,分离有机层,干燥,过滤并真空浓缩后经溶剂洗涤得到阿甘油神经酰胺,产物经HPLC分析,HPLC色谱条件:使用岛津高效液相色谱仪(LC-2030C 3DPlus),用Innoval ODS-2 4.6*250mm,5μm色谱柱,柱温:30℃,进样体积:10μL,流速:1.0mL/min,蒸发温度:40℃,载气流速:2.5L/min,流动相:100%甲醇。
各成分HPLC的保留时间为:亚麻酸-植物鞘氨醇神经酰胺8.3min,亚油酸-植物鞘氨醇神经酰胺9.5min,棕榈酸-植物鞘氨醇神经酰胺10.7min,油酸-植物鞘氨醇神经酰胺11.3min,花生一烯酸-植物鞘氨醇神经酰胺12.9min,硬脂酸-植物鞘氨醇神经酰胺13.9min,花生酸-植物鞘氨醇神经酰胺16.5min,山嵛酸-植物鞘氨醇神经酰胺18.3min。
所得产物经高效液相色谱分析,油酸-植物鞘氨醇神经酰胺、亚油酸-植物鞘氨醇神经酰胺、棕榈酸-植物鞘氨醇神经酰胺、硬脂酸-植物鞘氨醇神经酰胺、花生酸-植物鞘氨醇神经酰胺、亚麻酸-植物鞘氨醇神经酰胺、山嵛酸-植物鞘氨醇神经酰胺、花生一烯酸-植物鞘氨醇神经酰胺的含量比依次为50%、33%、5%、6%、0.5%、0.5%、0.5%、0.5%,其余为其他成分,含量较少。
实施例2
阿甘油脂肪酸和鞘氨醇合成神经酰胺
第一步:将50g阿甘油油脂溶于60mL四氢呋喃,冰浴下冷却,滴加110mL氢氧化钾(25wt%)溶液,滴加完毕后升至室温反应,至TLC检测反应完毕。
后处理:加入稀盐酸(3N)调节反应体系的pH值到3,加入120mL乙酸乙酯萃取水相,加入80mL饱和食盐水洗一次,有机相加入无水Na2SO4干燥,过滤并真空浓缩,得到39.8g阿甘油脂肪酸。
第二步:将阿甘油脂肪酸(50mmol,以主成分脂肪酸计)、EDCI(60mmol)、Et3N(65mmol)加入250mL圆底烧瓶中,再加入100mL二氯甲烷,随后在室温条件下搅拌1小时,随后将鞘氨醇(70mmol)加入到反应体系中,在室温条件下搅拌,至TLC检测反应完毕。
后处理:加入水淬灭反应,分离有机层,干燥,过滤并真空浓缩后经溶剂洗涤得到阿甘油神经酰胺,产物经HPLC分析,HPLC色谱条件:使用岛津高效液相色谱仪(LC-2030C 3DPlus),用Innoval ODS-2 4.6*250mm,5μm色谱柱,柱温:30℃,进样体积:10μL,流速:1.0mL/min,蒸发温度:40℃,载气流速:2.5L/min,流动相:100%甲醇。
各成分HPLC的保留时间为:亚麻酸-鞘氨醇神经酰胺7.9min,亚油酸-鞘氨醇神经酰胺8.7min,油酸-鞘氨醇神经酰胺10.2min,棕榈酸-鞘氨醇神经酰胺10.4min,花生一烯酸-鞘氨醇神经酰胺12.8min,硬脂酸-鞘氨醇神经酰胺13.6min,花生酸-鞘氨醇神经酰胺17.8min。
所得产物经高效液相色谱分析,油酸-鞘氨醇神经酰胺、亚油酸-鞘氨醇神经酰胺、棕榈酸-鞘氨醇神经酰胺、硬脂酸-鞘氨醇神经酰胺、花生酸-鞘氨醇神经酰胺、亚麻酸-鞘氨醇神经酰胺、花生一烯酸-鞘氨醇神经酰胺的含量依次为43%、41%、9%、3.5%、1%、0.5%、0.5%,其余为其他成分,含量较少。
实施例3
阿甘油脂肪酸和二氢鞘氨醇合成神经酰胺
第一步:将50g阿甘油油脂溶于60mL四氢呋喃,冰浴下冷却,滴加110mL氢氧化钾(25wt%)溶液,滴加完毕后升至室温反应,至TLC检测反应完毕。
后处理:加入稀盐酸(3N)调节反应体系的pH值到3,加入120mL乙酸乙酯萃取水相,加入80mL饱和食盐水洗一次,有机相加入无水Na2SO4干燥,过滤并真空浓缩,得到39.5g阿甘油脂肪酸。
第二步:将阿甘油脂肪酸(50mmol,以主成分脂肪酸计)、EDCI(65mmol)、Et3N(70mmol)加入250mL圆底烧瓶中,再加入100mL二氯甲烷,随后在室温条件下搅拌1小时,随后将二氢鞘氨醇(60mmol)加入到反应体系中,在室温条件下搅拌,至TLC检测反应完毕。
后处理:加入水淬灭反应,分离有机层,干燥,过滤并真空浓缩后经溶剂洗涤得到阿甘油神经酰胺,产物经HPLC分析,HPLC色谱条件:使用岛津高效液相色谱仪(LC-2030C 3DPlus),用Innoval ODS-2 4.6*250mm,5μm色谱柱,柱温:30℃,进样体积:10μL,流速:1.0mL/min,蒸发温度:40℃,载气流速:2.5L/min,流动相:100%甲醇。
各成分HPLC的保留时间为:亚麻酸-二氢鞘氨醇神经酰胺8.3min,亚油酸-二氢鞘氨醇神经酰胺9.5min,棕榈酸-二氢鞘氨醇神经酰胺10.6min,油酸-二氢鞘氨醇神经酰胺11.1min,硬脂酸-二氢鞘氨醇神经酰胺13.5min,花生酸-二氢鞘氨醇神经酰胺16.0min,山嵛酸-二氢鞘氨醇神经酰胺21.9min。
所得产物经高效液相色谱分析,油酸-二氢鞘氨醇神经酰胺、亚油酸-二氢鞘氨醇神经酰胺、棕榈酸-二氢鞘氨醇神经酰胺、硬脂酸-二氢鞘氨醇神经酰胺、花生酸-二氢鞘氨醇神经酰胺、亚麻酸-二氢鞘氨醇神经酰胺、山嵛酸-二氢鞘氨醇神经酰胺的含量依次为39%、37%、13%、7%、0.5%、0.5%、0.5%,其余为其他成分,含量较少。
实施例4
细胞迁移评估皮肤屏障修复作用
原理:当细胞长到融合成单层状态时,在融合的单层细胞上划痕工具制造一个空白区域,空白区域的细胞被机械力去除掉了,通过一段时间的培养,观察细胞向无细胞区域迁移的情况,通过测量细胞的迁移距离反映细胞的迁移能力。
操作步骤:
1、培养板划线。首先使用Marker笔在6孔板背后,用直尺比着,均匀的划横线,大约每隔0.5~1cm一道,横穿过孔,每孔至少穿过5条线,划线时注意线不要太粗。
2、铺细胞。在孔中加入约5×105个细胞(不同的细胞数量有所不同,根据细胞的生长快慢调整),接种原则为过夜后融合率达到100%。
3、细胞划线。第二天用枪头,垂直于细胞平面,沿着第一天划在平板背面的线在细胞层上进行划痕(不同孔之间最好使用同一只枪头)。
4、洗细胞。划痕完成后,使用无菌PBS洗细胞3次,洗去不贴壁的细胞,即划线时划线的细胞,划线后留下的间隙清晰可见,然后更换新鲜无血清培养基。
5、细胞培养、观察。样品(实施例1产物、神经酰胺3B)用培养基稀释后(实施例1产物浓度为100mg/L,神经酰胺3B浓度为100mg/L)加入细胞培养皿,将细胞放入37℃、5wt%CO2培养箱培养,在24h后取出细胞,显微镜观察并测量划痕的宽度,并拍照,用Image J软件计算愈合率。
结果如图1所示,相比溶剂对照组,实验组的划痕宽度更窄,说明阿甘油神经酰胺具有更好的组织愈合能力。溶剂对照组在24h后的愈合率为28.92%,阿甘油神经酰胺在24h后的愈合率为95.71%,神经酰胺3B在24h后的愈合率为59.32%。本发明的化合物明显提升了细胞愈合速率,具备良好的皮肤组织修复活性,而且效果比神经酰胺3B更好。
实施例5
弹性蛋白酶抑制实验测试抗衰老作用
弹性蛋白酶抑制方法:取2mg/mL弹性蛋白酶溶液2mL,加入不同浓度样品(实施例1产物),充分涡旋混匀,在37℃、400r/min摇床振荡20min,立即加入pH6.0的0.5mol/L磷酸盐缓冲液5mL,涡旋混匀,取适量混匀液至2mL离心管内,在9 391×g下离心10min,精密吸取上清液200μL至96孔板内,在波长495nm处酶标仪测定吸光度,同时进行400~800nm光谱扫描。
以底物加酶溶液为空白对照组,底物加酶和样品溶液为酶抑制组,底物加样品不加酶溶液作扣背景用。每组均设3复孔。抑制率(%)=[1–(An–An′)/(A0–A0′)]×100%,式中,A0为加酶不加样品的吸光度,A0′为仅加底物不加样品和酶的吸光度,An为仅加样品溶液的吸光度,An′为加样品不加酶的吸光度。若An′>An,则表现为促进作用,促进率(%)=[1–(An′–An)/(A0–A0′)]×100%。
结果如图2所示,阿甘油神经酰胺在不同浓度下对弹性蛋白酶均具有较好的抑制效果,具体而言,在0.25g/L的浓度时对弹性蛋白酶的抑制率为10.47%,在0.5g/L的浓度时对弹性蛋白酶的抑制率为22.27%,在1.0g/L的浓度时对弹性蛋白酶的抑制率为35.00%,在2.0g/L的浓度时对弹性蛋白酶的抑制率为30.00%。
按照相同的方法测试神经酰胺2对弹性蛋白酶的抑制活性,结果如图3所示,在浓度为0.25、0.5、1.0、2.0g/L时的弹性蛋白酶抑制率分别为10.12%、18.06%、28.84%和19.78%,其抑制效果不如相同浓度的阿甘油神经酰胺。
实施例6
MMP1又称间质性胶原酶、基质金属蛋白酶,属基质金属蛋白酶家族,其主要作用底物为纤维性胶原,可降解细胞外基质中的胶原纤维和明胶及改变细胞的微环境。MMP1在弹性蛋白中起着重要作用,抑制MMP1可提高成纤维细胞胶原蛋白和弹性蛋白合成,MMP活性降低可增加胶原合成速度。
将HaCaT细胞以1×105个/孔的密度种于96孔板,培养箱内过夜。24h后弃去上清液,加入含不同浓度的样品(实施例1产物)的培养基100μL,模型组不加入样品,阴性对照组为不含样品的DMEM培养基,每组3个复孔,在质量分数5% CO2、37℃环境中孵育2h后,辐射UVA或UVB紫外线。紫外线辐射光源与细胞之间的距离为15cm,UVA强度为200mJ/cm2,辐射时间为2h,UVB强度为50mJ/cm2,辐射时间为1h。结束辐射后,在培养箱内继续孵育12h。使用MMP-1ELISA试剂盒检测细胞内MMP-1基因表达。抑制率=1-(实验组MMP1表达量/模型组MMP1表达量)×100%。
结果如图4、5所示,对于UVA,阴性对照组的MMP1表达量设为1,模型组的表达量为1.90,阿甘油神经酰胺在125、250、400mg/L的浓度时,相对模型组MMP1表达的抑制率为34%、44%、56%;对于UVB,阴性对照组的MMP1表达量设为1,模型组的表达量为2.33,阿甘油神经酰胺在125、250、400mg/L的浓度时,相对模型组MMP1表达的抑制率为40%、52%、67%。
UVA紫外线辐射后,角质形成细胞促进成纤维细胞MMP1表达升高,从而引起皮肤细胞外基质和皮肤胶原降解,导致皮肤光老化。上述结果表明,阿甘油神经酰胺可以抑制紫外线辐射导致的成纤维细胞产生MMP1,对防止皮肤光老化有一定作用。
实施例7
DPPH自由基清除检测抗氧化性能
DPPH是1,1-二苯-2-三硝苯肼,可以用于抗氧化实验。
将对应浓度(50、100、200、400、800mg/L)样品(实施例1产物)分别与0.1mol/LDPPH、无水乙醇溶液按1:1的体积比例混合均匀,DPPH与无水乙醇1:1等体积混合,室温避光反应30min,于517nm处测吸光值。样品与DPPH反应液的吸光度记作A1,样品与无水乙醇反应液的吸光度记作A2,DPPH与无水乙醇反应液的吸光度记作A3,样品的DPPH清除率=[1-(A1-A2)/A3]×100%。
结果如图6所示,在浓度为50、100、200、400、800mg/L时的DPPH自由基清除率分别为15.43%、23.91%、35.85%、41.93%、47.56%,表现出优异的抗氧化效果。按照相同的方法测试神经酰胺3B(即油酸神经酰胺)的抗氧化效果,结果如图7所示,在浓度为50、100、200、400、800mg/L时的DPPH自由基清除率为7.76%、12.82%、24.10%、29.60%、33.16%。阿甘油神经酰胺对DPPH的清除率高于神经酰胺3B,具有更好的抗氧化效果。
实施例8
美白活性测试
取指数生长期B16细胞,用质量分数0.25%胰蛋白酶-EDTA消化并吹打均匀,将细胞按3×105个/孔的密度接种于12孔板。于37℃、质量分数5%CO2环境中培养过夜。弃去上清液,加入含不同质量浓度样品(实施例1产物)的培养液,以不加样品的RPMI-1640培养基孵育为空白组,加DMEM培养基孵育为造模组,每组3个复孔,在质量分数5%CO2、37℃环境中孵育24h。将孔板中培养基弃去,用磷酸盐缓冲液(PBS)清洗一到两次后,加入1mL含质量分数10%DMSO的NaOH溶液(1mol/L)裂解细胞,置于80℃或100℃下恒温2h至细胞完全溶解。置于酶标仪中,于405nm下测吸光值。计算出黑色素抑制率=1-(各孔OD值/模型组OD值)×100%。
结果如图8所示,空白对照组的黑色素含量设为1,造模组的黑色素表达为1.54,在浓度为10、20、40、80、100mg/L时,阿甘油神经酰胺的黑色素抑制率分别为17.91%、18.95%、22.16%、30.87%、39.66%,表现出很好的美白效果。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.阿甘油神经酰胺,其由阿甘油脂肪酸与鞘氨醇类化合物反应得到,所述鞘氨醇类化合物选自鞘氨醇、植物鞘氨醇、二氢鞘氨醇。
2.根据权利要求1所述的阿甘油神经酰胺,其特征在于,所述阿甘油脂肪酸由阿甘油水解得到。
3.根据权利要求1或2所述的阿甘油神经酰胺,其特征在于,所述阿甘油脂肪酸含有35~50wt%油酸、30~50wt%亚油酸、5~15wt%棕榈酸、2~8wt%硬脂酸、0.1~1wt%花生酸、0.01~0.5wt%亚麻酸。
4.阿甘油神经酰胺,其组成包括:油酸神经酰胺,亚油酸神经酰胺,棕榈酸神经酰胺,硬脂酸神经酰胺,花生酸神经酰胺,亚麻酸神经酰胺。
5.根据权利要求4所述的阿甘油神经酰胺,其组成包括:35~50wt%油酸神经酰胺,30~50wt%亚油酸神经酰胺,5~15wt%棕榈酸神经酰胺,2~8wt%硬脂酸神经酰胺,0.1~1wt%花生酸神经酰胺,0.01~0.5wt%亚麻酸神经酰胺。
6.根据权利要求4或5所述的阿甘油神经酰胺,其组成还包括:0~0.5wt%山嵛酸神经酰胺、0~0.5wt%花生一烯酸神经酰胺。
7.权利要求1~6任意一项所述的阿甘油神经酰胺的合成方法,包括以下步骤:
在缩合剂、有机碱条件下,阿甘油脂肪酸与鞘氨醇类化合物反应,所述缩合剂为EDCI,所述有机碱为Et3N;
所述阿甘油脂肪酸、鞘氨醇类化合物、EDCI、Et3N的摩尔比为1:(1~1.5):(1~2):(1~2),所述反应的溶剂为二氯甲烷、四氢呋喃、乙酸乙酯、乙腈中的至少一种。
8.权利要求1~6任意一项所述的阿甘油神经酰胺在化妆品、药品、膳食品或保健品中的用途。
9.根据权利要求8所述的用途,其特征在于,所述阿甘油神经酰胺具有皮肤屏障修复、组织愈合、抗衰老、抗光老化、抗氧化、促进胶原合成、维持弹性蛋白活力、美白功效中的至少一种。
10.一种组合物,包括权利要求1~6任意一项所述的阿甘油神经酰胺,所述组合物具有皮肤屏障修复、组织愈合、抗衰老、抗光老化、抗氧化、促进胶原合成、维持弹性蛋白活力、美白功效中的至少一种。
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