CN114681451A - 透明质酸或其盐和/或海藻糖的组合物及其在稳定麦角硫因中的用途 - Google Patents
透明质酸或其盐和/或海藻糖的组合物及其在稳定麦角硫因中的用途 Download PDFInfo
- Publication number
- CN114681451A CN114681451A CN202210452898.0A CN202210452898A CN114681451A CN 114681451 A CN114681451 A CN 114681451A CN 202210452898 A CN202210452898 A CN 202210452898A CN 114681451 A CN114681451 A CN 114681451A
- Authority
- CN
- China
- Prior art keywords
- ergothioneine
- salt
- trehalose
- hyaluronic acid
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229940093497 ergothioneine Drugs 0.000 title claims abstract description 74
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 title claims abstract description 62
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 title claims abstract description 61
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 59
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Abstract
本申请提供透明质酸或其盐和/或海藻糖在稳定麦角硫因中的用途,一种用于稳定麦角硫因的添加剂,所述添加剂包括透明质酸或其盐和/或海藻糖,以及一种组合物,所述组合物包括麦角硫因、透明质酸或其盐和海藻糖。本发明所提供的透明质酸或其盐和海藻糖相较其他辅料,可明显缓解高温对麦角硫因的破坏,提高麦角硫因粉末产品的收率。本发明得到的组合物具有较好的抗氧化作用和抗凋亡功效。同时使用透明质酸或其盐和海藻糖复合作辅料得到的组合物对细胞内活性氧自由基的抑制和清除作用明显高于单一的透明质酸或其盐或海藻糖作辅料得到的组合物。
Description
本案是申请日为2020年11月10日,发明名称为透明质酸或其盐和/或海藻糖的组合物及其在稳定麦角硫因中的用途,申请号为2020112495388的案件的分案申请。
技术领域
本申请涉及生物化工技术领域,特别涉及一种透明质酸或其盐和/或海藻糖在稳定麦角硫因中的用途,含有透明质酸或其盐和/或海藻糖的麦角硫因组合物。
背景技术
麦角硫因(Ergothioneine;2-mercaptohistidine trimethylbetaine)是一种稀有氨基酸,具有抗氧化、紫外防护和细胞修复之功效。麦角硫因存在于很多动植物体内,不能由动物机体自身合成,只能从食物中摄取。制备麦角硫因的方法有三种:化学合成法、提取法以及微生物发酵法。由于化学合成和提取法制备麦角硫因存在成本高、不安全等问题,因此微生物发酵法制备麦角硫因产品越来越受到关注。
使用微生物发酵法生产麦角硫因时,麦角硫因发酵液的干燥通常采用喷雾干燥法。喷雾干燥是用喷雾将料液喷成雾滴分散于高温中,使料液所含水分快速蒸发的一种干燥方法,具有传热快、水分蒸发迅速和干燥时间短的特点,且制品质量好,质地松脆,溶解性能也好,能改善某些制剂的溶出速率。常见的喷雾干燥辅料为糊精、β-环糊精、可溶性淀粉、微粉硅胶、微晶纤维素、乳糖、麦芽糊精。现有的喷雾干燥法干燥麦角硫因时,麦角硫因易于受到破坏,影响麦角硫因干燥得到的粉末产品的收率。
发明内容
为解决现有技术中的问题,本发明提供一种透明质酸或其盐和/或海藻糖在稳定麦角硫因中的用途,用于稳定麦角硫因的添加剂,以及一种组合物。本发明技术方案如下:
1.透明质酸或其盐和/或海藻糖在稳定麦角硫因中的用途。
2.根据项1所述的用途,其特征在于,所述透明质酸或其盐和/或海藻糖用于提高麦角硫因的热稳定性。
3.根据项1所述的用途,其特征在于,所述透明质酸或其盐的分子量为3KDa-30KDa,优选为3KDa-10KDa。
4.一种用于稳定麦角硫因的添加剂,其特征在于,所述添加剂包括透明质酸或其盐和/或海藻糖。
5.根据项4所述的添加剂,其特征在于,所述添加剂包括透明质酸或其盐和海藻糖,所述透明质酸或其盐和海藻糖的质量比为1:99-50:50,优选为1:19-1:10。
6.根据项4所述的添加剂,其特征在于,所述透明质酸或其盐的分子量为3KDa-30KDa,优选为3KDa-10KDa。7.根据项4所述的添加剂,其特征在于,所述添加剂用作喷雾干燥处理麦角硫因发酵液的辅料。
8.一种组合物,其特征在于,所述组合物包括麦角硫因、透明质酸或其盐和海藻糖。
9.根据项8所述的组合物,其特征在于,按重量份计,麦角硫因为1重量份,透明质酸或其盐为20-1000重量份,优选为100-180重量份,海藻糖为1000-1980重量份,优选为1800-1900重量份。
10.根据项8所述的组合物,其特征在于,所述透明质酸或其盐的分子量为3KDa-30KDa,优选为3KDa-10KDa。
本发明所提供的透明质酸或其盐和海藻糖相较其他辅料,可明显缓解高温对麦角硫因的破坏,提高麦角硫因粉末产品的收率。本发明得到的组合物具有较好的抗氧化作用和抗凋亡功效。同时使用透明质酸或其盐和海藻糖复合作辅料得到的组合物对细胞内活性氧自由基的抑制和清除作用明显高于单一的透明质酸或其盐或海藻糖作辅料得到的组合物。
发明的具体实施方式
除非另外定义,本说明书中有关技术的和科学的术语与本领域内的技术人员所通常理解的意思相同。虽然在实验或实际应用中可以应用与此间所述相似或相同的方法和材料,本文还是在下文中对材料和方法做了描述。在相冲突的情况下,以本说明书包括其中定义为准,另外,材料、方法和例子仅供说明,而不具限制性。以下结合具体实施例对本申请作进一步的说明,但不用来限制本申请的范围。
下述所使用的实验方法如无特殊要求,均为常规方法。
下述所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
松蕈优选为松口蘑SR-LY(Tricholoma Matsutake SR-LY),已于2020年10月16日在中国武汉市武汉大学内的中国典型培养物保藏中心(简称CCTCC)保藏,保藏编号为CCTCCNo:M 2020587。
猴头菌优选为猴头菌(Hericium erinaceus)CCTCC No:M 2018567,已于2018年8月23日在中国典型培养物保藏中心(简称CCTCC)保藏。
喷雾干燥设备为离心式或压力式喷雾干燥机。
本发明提供透明质酸或其盐和/或海藻糖在稳定麦角硫因中的用途。
透明质酸(Hyaluronic Acid,HA)是一种天然粘多糖,其由呈直链的D-葡糖醛酸与N-乙酰葡糖胺的交替单元形成。透明质酸以其独特的分子结构和理化性质在机体内显示出多种重要的生理功能,尤为重要的是,它具有特殊的保水作用,是目前发现的自然界中保湿性最好的物质,被称为理想的天然保湿因子(NMF)。而且透明质酸分子在空间上呈刚性螺旋柱形,柱的内侧由于存在大量的羟基而产生强吸水性,另一方面由于羟基的连续定向排列,又在透明质酸分子链上形成憎水区,使得透明质酸能形成三维网状结构。
海藻糖是由两个葡萄糖分子通过半缩醛羟基缩合而成,由于不存在游离的醛基,故为一种非还原型双糖,分子式是C12H22O11(含两个结晶水)。由于两个葡萄糖分子可以形成α-吡喃葡萄糖和β-吡喃葡萄糖,通过α-1,1糖苷键连接可以得到三种异构体:海藻糖(α,α)、异海藻糖(β,β)和新海藻糖(α,β)。因为海藻糖具有独特的生物学功能,能在逆境中有效地维持细胞内生物膜和蛋白质、活性肽的稳定性和完整性,被赞誉为生命之糖,可广泛用于生物制剂、医药、食品、保健品、精细化工、化妆品、饲料及农业科学等各个行业。
在一个具体的实施方式中,所述透明质酸或其盐和/或海藻糖用于提高麦角硫因的热稳定性。其中,所述透明质酸盐选自钠盐、钾盐、镁盐、锌盐、钙盐或季铵盐中的至少一种。
麦角硫因(Ergothioneine;2-mercaptohistidine trimethylbetaine)是一种稀有氨基酸,具有抗氧化、紫外防护和细胞修复之功效。麦角硫因存在于很多动植物体内,不能由动物机体自身合成,只能从食物中摄取。
麦角硫因通过微生物发酵法生产时,麦角硫因发酵液的干燥通常采用喷雾干燥法。其中,喷雾干燥是用喷雾将料液喷成雾滴分散于高温中,使料液所含水分快速蒸发的一种干燥方法,具有传热快、水分蒸发迅速和干燥时间短的特点,且制品质量好,质地松脆,溶解性能也好,能改善某些制剂的溶出速率。但是麦角硫因在高温容易受到破坏,影响最终干燥得到的麦角硫因粉末的收率。
本发明提供一种用于稳定麦角硫因的添加剂,所述添加剂包括透明质酸或其盐和/或海藻糖。即所述添加剂可以为透明质酸或其盐,可以为海藻糖,也可以为任意配比的透明质酸或其盐和海藻糖。其中,所述透明质酸盐选自钠盐、钾盐、镁盐、锌盐、钙盐或季铵盐中的至少一种。
在一个具体的实施方式中,所述添加剂包括透明质酸或其盐和海藻糖。所述透明质酸或其盐和海藻糖的质量比为1:99-50:50,例如可以为1:99、1:90、1:80、1:70、1:60、1:50、1:40、1:30、1:20、1:19、1:10,优选为1:19-1:10。
在一个具体的实施方式中,所述添加剂中透明质酸或其盐的分子量为3KDa-30KDa,例如可以为3KDa、5KDa、10KDa、15KDa、20KDa、25KDa、30KDa,优选为3KDa-10KDa。
在一个具体的实施方式中,所述添加剂用作喷雾干燥处理麦角硫因发酵液的辅料。其中,麦角硫因发酵液可以是任何现有技术中已有的微生物的发酵液。例如松蕈、猴头菌等的麦角硫因发酵液。
优选的,所述喷雾为离心式或压力式喷雾干燥,进风温度为150℃-200℃,出风温度为50℃-100℃。
优选的,在所述含麦角硫因的发酵液中加入1-30%(w/v,g/ml)辅料。
本发明还提供一种组合物,所述组合物包括麦角硫因、透明质酸或其盐和海藻糖。所述组合物具有较好的抗氧化作用和抗凋亡功效。同时使用透明质酸或其盐和海藻糖复合作辅料得到的组合物对细胞内活性氧自由基的抑制和清除作用明显高于单一的透明质酸或其盐或海藻糖作辅料得到的组合物。其中,所述透明质酸盐选自钠盐、钾盐、镁盐、锌盐、钙盐或季铵盐中的至少一种。
在一个具体的实施方式中,所述组合物中,麦角硫因、透明质酸或其盐和海藻糖的质量比为1:(20-1000):(1000-1980)。例如可以为1:20:1000、1:20:1500、1:20:1980、1:100:1000、1:100:1500、1:100:1980、1:500:1000、1:500:1500、1:500:1980、1:1000:1000、1:1000:1500、1:1000:1980。按重量份计,麦角硫因为1重量份,透明质酸或其盐为20-1000重量份,例如可以为20重量份、50重量份、100重量份、300重量份、500重量份、700重量份、1000重量份,优选为100-180重量份。海藻糖为1000-1980重量份,例如可以为1000重量份、1100重量份、1200重量份、1300重量份、1500重量份、1700重量份、1800重量份、1980重量份,优选为1800-1900重量份。在一个具体的实施方式中,所述组合物中透明质酸或其盐的分子量为3KDa-30KDa,例如可以为3KDa、5KDa、10KDa、15KDa、20KDa、25KDa、30KDa,优选为3KDa-10KDa。
本发明采用透明质酸或其盐和/或海藻糖能显著提高麦角硫因的稳定性,尤其是在麦角硫因发酵液进行喷雾干燥过程中能显著缓解高温对麦角硫因的破坏。当采用一定比例的透明质酸或其盐和海藻糖作为喷雾干燥的辅料对麦角硫因发酵液进行处理时,得到的含有麦角硫因、透明质酸或其盐和海藻糖的组合物具有优异的抗氧化作用和抗凋亡功效。尤其是组合物中透明质酸或其盐和海藻糖的质量比例1:19-1:10时,抑制和清除活性氧自由基的作用最优。
本申请的以下实施例仅用来说明实现本申请的具体实施方式,这些实施方式不能理解为是对本申请的限制。其他的任何在未背离本申请的精神实质与原理下所作的改变、修饰、替代、组合、简化,均视为等效的置换方式,落在本申请的保护范围之内。
实施例
下面结合实施例进一步说明本发明,应当理解,实施例仅用于进一步说明和阐释本发明,并非用于限制本发明。
下述实施例中所使用的实验方法如无特殊要求,均为常规方法。
下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1麦角硫因组合物制备的优化(松蕈发酵)
液体种子培养基:3.0%(w/v)的乳糖、2.0%(w/v)的马铃薯浸出粉、0.1%(w/v)的磷酸氢二钾,0.1%(w/v)的硫酸钠,其余为水,pH 4.0~4.5,于121℃灭菌20min;
发酵培养基:3.0%(w/v)的葡萄糖、2.0%(w/v)的麦芽糖、1.0%(w/v)的牛肉膏、1.5%(w/v)的胰蛋白胨、0.06%(w/v)的磷酸二氢钠,0.0003%(w/v)的氯化锌,0.0005%(w/v)的烟酸,0.0001%(w/v)的维生素B1,其余为水,pH 4.0~4.5,于121℃灭菌20min。
将松蕈即松口蘑SR-LY(Tricholoma Matsutake SR-LY)CCTCC No:M 2020587菌丝体斜面菌种接种至液体种子培养基中,在23℃、200rpm振荡条件下,培养25天,获得松蕈种子液。将种子液按体积比5%的接种量接入发酵培养基,在23℃、200rpm振荡条件下,培养25天,在培养进行的第20天补充前体物质半胱氨酸、甲硫氨酸和甜菜碱各5mM,得到发酵液。在发酵结束后,使用均质乳化机将菌丝体发酵液8000rpm均质30min。再经过1.2μm精细过滤纸板、0.22μm聚醚砜滤芯过滤除菌即可得到含麦角硫因的溶液。
分别加入发酵液5%(w/v,g/ml)的麦芽糊精、微晶纤维素、3KDa透明质酸钠、5KDa透明质酸钠、10KDa透明质酸钠、15KDa透明质酸钠、30KDa透明质酸钠、50KDa聚谷氨酸钠、岩藻糖、甘露醇、β-环糊精、乳糖、海藻糖以及糊精,混匀,使用离心式喷雾干燥机喷雾。喷雾干燥中采用的进风温度为180℃,出风温度为90℃,得到的粉末即为含麦角硫因的组合物,各组合物中麦角硫因含量结果如表1所示。
表1松蕈发酵时使用不同辅料得到麦角硫因含量
麦角硫因在高温喷雾时不可避免的遭到一些破坏,从表1结果中可以看出,透明质酸钠和海藻糖作辅料得到的组合物中,麦角硫因的含量分别为0.167%、0.168%、0.169%、0.165%、0.167%和0.168%,明显高于其他几种常用喷雾辅料得到的粉末。这说明透明质酸钠和海藻糖相较其他辅料,可明显缓解高温对麦角硫因的破坏。
实施例2麦角硫因组合物制备的优化(猴头菌发酵)
液体种子培养基:4.0%(w/v)的蔗糖、1.5%(w/v)的豆饼粉、0.2%(w/v)的磷酸二氢钠,0.1%(w/v)的硫酸钠,其余为水,pH 4.0~4.5,于121℃灭菌20min;
发酵培养基:3.0%(w/v)的葡萄糖、1.5%(w/v)的牛肉膏、0.05%(w/v)的磷酸二氢钠,0.03%(w/v)硫酸钠、0.0003%(w/v)的氯化锌,0.0006%(w/v)的烟酸,0.0001%(w/v)的维生素B1,其余为水,pH 4.0~4.5,于121℃灭菌20min。
将猴头菌(Hericium erinaceus)CCTCC No:M 2018567菌丝体斜面菌种接种至液体种子培养基中,在23℃、200rpm振荡条件下,培养7天,获得猴头菌种子液。将种子液按体积比5%的接种量接入发酵培养基,在23℃、200rpm振荡条件下,培养10天,其中在培养进行的第5天补充前体物质半胱氨酸、甲硫氨酸和甜菜碱各5mM,得到发酵液。在发酵结束后,使用均质乳化机将菌丝体发酵液8000rpm均质30min。再经过1.2μm精细过滤纸板、0.22μm聚醚砜滤芯过滤除菌即可得到含麦角硫因的溶液。分别加入发酵液5%(w/v,g/ml)的麦芽糊精、微晶纤维素、3KDa透明质酸钠、5KDa透明质酸钠、10KDa透明质酸钠、15KDa透明质酸钠、30KDa透明质酸钠、50KDa聚谷氨酸钠、岩藻糖、甘露醇、β-环糊精、乳糖、海藻糖以及糊精,混匀,使用离心式喷雾干燥机喷雾。喷雾干燥中采用的进风温度为180℃,出风温度为90℃,得到的粉末即为含麦角硫因的组合物,各组合物中麦角硫因含量结果如表2所示。
表2猴头菌发酵时使用不同辅料得到麦角硫因含量
样品 | 辅料 | 组合物中麦角硫因含量 |
样品D1 | 麦芽糊精 | 0.365% |
样品D2 | 微晶纤维素 | 0.353% |
样品D3 | 透明质酸钠(5KDa) | 0.392% |
样品D4 | 聚谷氨酸钠 | 0.362% |
样品D5 | 岩藻糖 | 0.361% |
样品D6 | 甘露醇 | 0.364% |
样品D7 | β-环糊精 | 0.359% |
样品D8 | 乳糖 | 0.355% |
样品D9 | 海藻糖 | 0.395% |
样品D10 | 糊精 | 0.360% |
样品D11 | 透明质酸钠(3KDa) | 0.394% |
样品D12 | 透明质酸钠(10KDa) | 0.394% |
样品D13 | 透明质酸钠(15KDa) | 0.395% |
样品D14 | 透明质酸钠(30KDa) | 0.392% |
从表2结果中可以看出,采用猴头菌发酵,使用透明质酸钠和海藻糖作辅料得到的组合物中,麦角硫因的含量也明显高于其他几种常用喷雾辅料得到的粉末,这说明透明质酸钠和海藻糖可以明显缓解喷雾时高温对麦角硫因的破坏。
实施例3透明质酸和海藻糖配比的优化
由实施例1和实施例2的结果可知,透明质酸钠和海藻糖对麦角硫因均具有良好的稳定作用。其中,透明质酸钠具有良好的保湿、抗炎等功效,但是价格较高,因此,为了降低成本,且同时获得一种保湿、抗炎等效果较好的组合物,故考虑将透明质酸钠(5KDa)和海藻糖不同比例复配使用作为喷雾辅料。其中,采用实施例1的发酵液,在对发酵液进行喷雾干燥时,将透明质酸钠和海藻糖的混合物作为辅料,其中将透明质酸钠和海藻糖的质量比在1:99-50:50之间进行调节。同样按照发酵液5%(w/v,g/ml)的辅料加入量,使用上述的同样的喷雾干燥操作的条件,得到的组合物中麦角硫因含量如表3所示。
表3
从上述表格中可以看出,使用质量比为1:99-50:50的透明质酸钠和海藻糖复配作为辅料,均可以有效缓解喷雾时高温对麦角硫因的破坏。但是透明质酸钠分子量大于10KDa时,由于分子量大,黏度高,喷雾得到的粉末收率略有降低,因此透明质酸钠分子量优选3KDa-10KDa。
实施例4组合物的抗氧化活性
1.对活性氧自由基生成的影响
样品溶液的配制:分别以无血清DMEM培养液将上述实施例中制备的样品C3、C9、S1-9分别配制成0.1%(w/v,g/ml)浓度的溶液,将样品S4配制成0.05%(w/v,g/ml)、0.1%(w/v,g/ml)、0.2%(w/v,g/ml)、0.3%(w/v,g/ml)浓度的溶液,经0.22μm滤膜过滤除菌。
(1)活性氧自由基清除试验
二氯荧光素二乙酸酯(DCFH-DA)探针溶液的配制:将DCFH-DA用PBS溶液(0.1M,pH7.4)稀释,按0.375μL加入1mLPBS稀释。
取处于对数生长期的HaCaT细胞,以5×104个/mL密度接种于12孔培养板,每孔2mL细胞悬液,置二氧化碳培养箱37℃、5%CO2常规培养24h。按照以下方式分组操作:
(1)照射组弃去1mL培养液,盖保鲜膜,UVA用2000μW/cm2的强度照射2-3h,UVB用700μW/cm2的强度照射7min;照射完毕后弃去旧培养液,分别加入各样品溶液,每孔均为2mL;
(2)损伤模型组与照射组相同操作,照射完毕后弃去旧培养液,加入无血清培养液,每孔均为2mL;
(3)正常对照组常规培养,与照射组同时换液,加入无血清培养液,每孔均为2mL;
然后继续培养16h后,弃去全部培养液,用PBS洗两遍。每孔加入1.5mL DCFH-DA溶液,放入细胞培养箱中继续孵育30min,每隔5min混匀一次使探针充分结合。弃去探针液,用无血清培养基洗两遍,每孔加入1mL无血清培养基37℃孵育10min。PBS洗一遍后,胰酶消化细胞,PBS洗两遍,300μL PBS重悬,用流式细胞仪双通道检测,上机前细胞过滤,FL1-H通道,每个样品收集10000个细胞。根据1通道(FL1-H)获取的信号数据,即DCF产生的荧光强度或荧光总量计算ROS清除率。用平均荧光强度计算ROS清除率:
(2)活性氧自由基抑制试验
取处于对数生长期的HaCaT细胞,以4×104个/mL密度接种于12孔培养板,每孔2mL细胞悬液,置二氧化碳培养箱37℃、5%CO2常规培养24h。
弃去旧培养液,实验组加入样品溶液,正常对照组加入无血清培养液,每孔均为2mL,继续培养24h后照射,正常对照组用铝箔纸覆盖不照射。
照射组弃去1mL培养基,盖保鲜膜,UVA用2000μW/cm2的强度照射1h,UVB用700μW/cm2的强度照射3min,正常对照组不照射。弃去培养基,用PBS洗两遍。每孔加入1.5mL DCFH-DA,放入细胞培养箱中继续孵育30min,每隔5min混匀一次使探针充分结合。弃去探针,用预热的无血清培养基洗两遍,每孔加入1mL无血清培养基37℃孵育10min。PBS洗一遍后,胰酶消化细胞,PBS洗两遍,300μL PBS重悬,用流式细胞仪双通道检测(上机前细胞需要过滤),FL1-H通道,每个样品收集10000个细胞。根据1通道(FL1-H)获取的信号数据,即DCF产生的荧光强度或荧光总量计算ROS抑制率。用平均荧光强度计算ROS抑制率:
得到的各样品的ROS清除率和抑制率结果如表4和表5所示。
表4 0.1%浓度样品对活性氧自由基(ROS)生成的影响
表5不同样品浓度对活性氧自由基(ROS)生成的影响
样品浓度(%) | 0.05 | 0.1 | 0.2 | 0.3 |
ROS清除率(%) | 20.19 | 32.43 | 26.71 | 23.15 |
ROS抑制率(%) | 10.01 | 19.28 | 16.71 | 17.45 |
从表4的结果看,采用本发明得到的麦角硫因组合物具有较好的抗氧化作用,同时使用透明质酸盐和海藻糖复合作辅料得到的组合物对细胞内活性氧自由基的抑制和清除作用明显高于单一的透明质酸盐或海藻糖作辅料得到的组合物,且透明质酸盐和海藻糖添加比例为1:19-1:10时,抑制和清除活性氧自由基的作用最为明显。从表5结果中可以看出,样品S4在0.01%、0.05%、0.1%、0.2%的浓度范围内,0.1%浓度下麦角硫因对紫外损伤导致的细胞内活性氧自由基具有最强的抑制与清除功效,抑制率和清除率分别为19.28%和32.43%,较低浓度和较高浓度下,抑制与清除功效都有所下降。
2.DPPH自由基清除试验
将上述制备的样品S4溶解于水,配制终浓度为0.05%(w/v)、0.1%(w/v)、0.2%(w/v)、0.3%(w/v)的溶液备用。分别精密量取1,1-二苯基-2-三硝基苯肼(DPPH)溶液5.0mL和不同浓度的S5的样品溶液5.0mL置具塞试管中,混匀。以等体积的95%乙醇-水混合溶液调零。室温放置30分钟,于523nm处分别测定溶液吸光度值,每浓度3个重复;另设一组分别精密量取DPPH溶液5.0mL和纯化水5.0mL混合,作为空白对照,操作同上。计算方法如下:
得到的结果如表6所示。
表6不同浓度样品的清除DPPH自由基活性结果
从表6中结果可以看出,随着组合物浓度的提高,对DPPH自由基的清除率也随之提高,组合物浓度为0.3%时,清除率可达74.80%,浓度为0.5%时,清除率达到88.14%。
实施例5组合物的抗凋亡功效评价
样品溶液的配制:分别用无血清培养基将样品S4配制成浓度为0.1%(w/v)、0.3%(w/v)、0.5%(w/v)的溶液,0.22μm滤膜过滤除菌。
(1)供试品对UVB照射凋亡的修复作用
铺板:取处于对数生长期的HaCaT细胞,胰酶消化后,调细胞密度1×106个/mL,接种于6孔细胞培养板,每孔2mL细胞悬液,置二氧化碳培养箱37℃、5%CO2常规培养过夜。
照射:打开6孔板盖子,用保鲜膜封板,采用70mJ/cm2UVB(400μW 3min)照射HaCaT细胞,试验分组如表7:
表7供试品对UVB照射凋亡的修复作用分组情况
加药:照射结束后,弃去培养液,试验组每孔加入2mL不同浓度样品溶液,正常组和模型组加入等量的培养基,放入培养箱中继续培养。
检测:继续培养24h后,收集6孔板中各组细胞,将旧培养液吸取至EP管中,使用PBS清洗细胞1次,加入胰蛋白酶进行消化,再加入旧培养液终止消化,收集至上述EP管中,1000rpm/min,离心5分钟,弃上清,预冷的PBS洗两遍后,用1×BindingBuffer重悬细胞,调整细胞密度为1×106个/mL,取100μL细胞悬液转移至新的1.5mL EP管中,按照试剂盒说明书,分别加入5μL Annexin V-FITC和PI染色液,轻轻混匀,室温避光孵育10分钟,用流式细胞仪检测。
(2)供试品对UVB照射凋亡的防护作用
铺板:取处于对数生长期的HaCaT细胞,胰酶消化后,调细胞密度1×106个/mL,接种于6孔细胞培养板,每孔2mL细胞悬液,置二氧化碳培养箱37℃、5%CO2常规培养过夜。
加药:弃去旧培养液,试验组每孔加入2mL不同浓度样品溶液,正常组和模型组加入等量的培养基,放入培养箱中继续培养。
照射:打开6孔板盖子,用保鲜膜封板,采用70mJ/cm2 UVB(400μW 3min)照射HaCaT细胞,试验分组如表8:
表8供试品对UVB照射凋亡的防护作用分组情况
分组 | 处理方法 |
正常组 | 加无血清培养基,不照射 |
模型组 | 加无血清培养基后,UVB照射 |
试验组 | 加不同浓度的麦角硫因样品溶液后,UVB照射 |
检测:照射后继续培养24h后,收集6孔板中各组细胞,将旧培养液吸取至EP管中,使用PBS清洗细胞1次,加入胰蛋白酶进行消化,再加入旧培养液终止消化,收集至上述EP管中,1000rpm/min,离心5分钟,弃上清,预冷的PBS洗两遍后,用1×BindingBuffer重悬细胞,调整细胞密度为1×106个/ml,取100μL细胞悬液转移至新的1.5mL EP管中,按照试剂盒说明书,分别加入5μL Annexin V-FITC和PI染色液,轻轻混匀,室温避光孵育10分钟,用流式细胞仪检测。
在正常细胞中,磷脂酰丝氨酸(PS)只分布在细胞膜脂质双层的内侧,而在细胞凋亡早期,细胞膜中的磷脂酰丝氨酸(PS)由脂膜内侧翻向外侧。Annexin V是一种分子量为35~36kD的Ca2+依赖性磷脂结合蛋白,与磷脂酰丝氨酸有高度亲和力,故可通过细胞外侧暴露的磷脂酰丝氨酸与凋亡早期细胞的胞膜结合。碘化丙啶(Propidium Iodide,PI)是一种核酸染料,它不能透过完整的细胞膜,但对凋亡中晚期的细胞和死细胞,PI能够透过细胞膜而使细胞核染红。因此将Annexin V与PI匹配使用,就可以将处于不同凋亡时期的细胞区分开来。
结果如表9所示,不论是在紫外损伤之前先与样品接触还是在紫外照射损伤之后再与样品接触,0.1%浓度下样品S4的抑制凋亡的作用都是最强的,而随着样品浓度的进一步增加,抗凋亡作用反而减弱。
表9S4对紫外损伤造成的HaCaT细胞凋亡的影响
样品浓度(%) | 0.05 | 0.1 | 0.2 | 0.3 |
防护作用的凋亡抑制率(%) | 6.05 | 8.28 | 4.41 | 5.29 |
修复作用的凋亡抑制率(%) | 21.31 | 34.22 | 27.63 | 19.81 |
Claims (6)
1.一种用于稳定麦角硫因的添加剂,其特征在于,所述添加剂包括透明质酸或其盐和海藻糖,所述透明质酸或其盐和海藻糖的质量比为1:19-1:10。
2.根据权利要求1所述的添加剂,其特征在于,所述透明质酸或其盐的分子量为3KDa-30KDa,优选为3KDa-10KDa。
3.根据权利要求1所述的添加剂,其特征在于,所述添加剂用作喷雾干燥处理麦角硫因发酵液的辅料。
4.一种组合物,其特征在于,所述组合物包括麦角硫因、透明质酸或其盐和海藻糖。
5.根据权利要求4所述的组合物,其特征在于,按重量份计,麦角硫因为1重量份,透明质酸或其盐为20-1000重量份,优选为100-180重量份,海藻糖为1000-1980重量份,优选为1800-1900重量份。
6.根据权利要求4所述的组合物,其特征在于,所述透明质酸或其盐的分子量为3KDa-30KDa,优选为3KDa-10KDa。
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