CN108794598A - 一种生物活性多肽nariqdnlylav及其制备方法和应用 - Google Patents
一种生物活性多肽nariqdnlylav及其制备方法和应用 Download PDFInfo
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- CN108794598A CN108794598A CN201810713446.7A CN201810713446A CN108794598A CN 108794598 A CN108794598 A CN 108794598A CN 201810713446 A CN201810713446 A CN 201810713446A CN 108794598 A CN108794598 A CN 108794598A
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- nariqdnlylav
- biologically active
- active polypeptide
- polypeptide
- ala
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Abstract
本发明涉及蛋白领域,具体涉及一种生物活性多肽NARIQDNLYLAV及其制备方法和应用,生物活性多肽NARIQDNLYLAV其氨基酸序列为Asn‑Ala‑Arg‑Ile‑Gln‑Asp‑Asn‑Leu‑Tyr‑Leu‑Ala‑Val。经过体外免疫功能调节实验、体内抗衰老实验,验证了多肽NARIQDNLYLAV具有较好的免疫调节功能和抗衰老活性,一方面,本发明的生物活性多肽NARIQDNLYLAV能够增强淋巴细胞和巨噬细胞的体外增殖能力,提高机体抵御外界病原体感染的能力,降低机体发病率;另一方面,能够提高体内抗过氧化酶系的活力,增强机体抵抗外源性刺激的功能,从而降低机体老化、衰老和生病的机率,对开发具有免疫调节功能、抗衰老功能的食品、保健品和药物具有十分重要的意义。
Description
技术领域
本发明涉及蛋白领域,尤其是涉及一种生物活性多肽NARIQDNLYLAV及其制备方法和应用。
背景技术
在牛乳经乳酸菌发酵的过程中,牛乳中的一部分蛋白质被乳酸菌代谢利用,并发生了一系列生理生化反应,使蛋白质变为多肽或者游离的氨基酸,被人体消化吸收或通过小肠上皮细胞的吸收转运直接进入人体的血液循环。乳酸菌菌体也存在一些自身合成的蛋白质多肽片段,供细菌生长利用。在这些多肽中,有一部分具有特殊的生理功能,被称为“生物活性肽”。
在天然食物来源中寻找安全的生物活性肽尤为重要。近些年来,人们发现一些食物来源的多肽类物质具有良好的生物活性,如玉米短肽、大豆肽、牛乳多肽等。这些多肽可以通过微生物发酵、消化酶解等多种途径得到,并且大多具有生物活性的多肽是由2~20个氨基酸残基组成,分子量小于6000Da,含有一定量的疏水氨基酸、芳香族氨基酸。
免疫活性肽是继阿片肽发现后首次从乳中获得并证明其生理活性的一类生物活性多肽。1981年Jolles等人首次发现,利用胰蛋白酶水解人乳蛋白,可以得到一个氨基酸序列为Val-Glu-Pro-Ile-Pro-Tyr的六肽,体外实验证明该肽能够增强小鼠腹腔巨噬细胞对绵羊红细胞的吞噬作用。Migliore-Samour等人发现来自酪蛋白的六肽Thr-Thr-Met-Pro-Leu-Trp能够刺激绵羊血红细胞对小鼠腹膜巨噬细胞的吞噬作用以及增强对于肺炎克雷伯菌的抵抗。李素萍等人用合成的乳源免疫调节肽(PGPIPN)饲喂大鼠发现大鼠腹腔巨噬细胞的吞噬作用和红细胞相关的免疫调节功能有显著的增强。
研究表明,免疫活性肽不仅能够增强机体免疫力,刺激机体淋巴细胞的增殖,增强巨噬细胞的吞噬功能,促进细胞因子的释放、提高机体抵御外界病原体感染的能力,降低机体发病率,而且不会引起机体的免疫排斥反应。
衰老是一个自然现象,且过程常伴有抗氧化水平、器官组织、免疫因子的变化,其中细胞因子发生着复杂的变化,如促炎细胞因子IL-6、IL-4、TNF-α等呈现增长的趋势,IL-6与TNF-a均被认为在老年性疾病的发生过程中扮演重要角色。随着遗传学和分子生物学的发展,生物衰老机理的研究取得了可喜的进展。研究人员通过利用一些模式生物,如小鼠、果蝇和秀丽线虫等的单一基因突变实验,发现有些基因能够显著增加这些生物体的寿命达6倍之多。
抗衰老肽作为一种新兴的抗衰老剂,在生理功能方面具有氨基酸所不能比拟的优势,其能对生物体内的酶产生促进或抑制作用,改善对矿物质及其他营养元素的吸收和利用,清除体内自由基,增强机体自身的抗氧化力,以延缓衰老。因此,生物活性肽的营养保健作用已成为国内外学者课题研究的重点。邱隽等人经实验研究发现,乳源性生物活性小肽能有效延长果蝇寿命,延缓其衰老,并且还具有较好的抗氧化作用,推测可能是其中富含琉基肽类。周之辉等发现牛初乳提取物能显著性提高老年人体内血清中SOD活力,减少其脂质过氧化物和增强机体抗氧化力,具有一定的抗衰老功能。
目前关于生物活性多肽的研究有很多,比如中国专利CN105254738A公布了一种来源于β-酪蛋白的乳源性生物活性多肽DELQDKIH,中国专利CN105254739A公布了一种来源于αs1-酪蛋白的乳源性生物活性多肽GTQYTD,中国专利CN105254740A公布了一种来源于αs2-酪蛋白的乳源性生物活性多肽NQFYQKF。
发明内容
本发明的目的在于提供一种生物活性多肽NARIQDNLYLAV及其制备方法和应用。
本发明的目的可以通过以下技术方案来实现:
本发明第一方面,提供一种生物活性多肽NARIQDNLYLAV,其氨基酸序列为Asn-Ala-Arg-Ile-Gln-Asp-Asn-Leu-Tyr-Leu-Ala-Val,如SEQ ID NO:1所示。
较优的,所述生物活性多肽来源于瑞士乳杆菌菌体蛋白。具体来源于LBH_0948|m.881LBH_0948|g.881ORF LBH_0948|g.881LBH_0948|m.881type:complete len:649(+)LBH_0948:1-1947(+)蛋白,并且为此蛋白第19~30位的氨基酸残基。LBH_0948|m.881LBH_0948|g.881ORF LBH_0948|g.881LBH_0948|m.881type:complete len:649(+)LBH_0948:1-1947(+)蛋白氨基酸序列如SEQ ID NO:3所示。
LBH_0948|m.881LBH_0948|g.881ORF LBH_0948|g.881LBH_0948|m.881type:complete len:649(+)LBH_0948:1-1947(+)蛋白的氨基酸序列以及对应的核苷酸序列为既有技术,编码此蛋白第19~30位氨基酸残基的核苷酸片段能编码成熟的生物活性多肽NARIQDNLYLAV。
较优的,所述生物活性多肽具有免疫调节功能和抗衰老功能。
本发明第二方面,提供了编码所述生物活性多肽NARIQDNLYLAV的核苷酸片段,其序列为:5’-caa tgc ccg cat tca aga taa ctt ata ctt agc cgt-3’,如SEQ ID NO:2所示。
本发明第三方面,提供了所述生物活性多肽NARIQDNLYLAV的制备方法,可以通过基因工程的方法人工合成,可以从瑞士乳杆菌菌体通过细胞破碎分离纯化的方法直接获得,可以直接通过化学合成制备。
本发明第四方面,提供了所述生物活性多肽NARIQDNLYLAV在制备具有免疫调节功能的食品、保健品、药物或化妆品中的应用。
本发明第五方面,提供了所述生物活性多肽NARIQDNLYLAV在制备具有抗衰老功能的食品、保健品或药物中的应用。
本发明第六方面,提供了所述生物活性多肽NARIQDNLYLAV在制备同时具有免疫调节功能和抗衰老功能的食品、保健品或药物中的应用。
具体而言,本发明的生物活性多肽NARIQDNLYLAV可以用于制备减少自由基对皮肤伤害的化妆品、制备具有免疫调节和/或抗衰老的药物;并且由于本发明的生物活性多肽NARIQDNLYLAV通过胃肠道降解后的产物仍旧具有生物活性,因此还可以用于制备酸奶等食品、调节免疫力的保健品,以及口服的用于制备具有免疫调节和/或抗衰老的药物。
本发明第七方面,提供了一种免疫调节产品,包括所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;所述的免疫调节产品包括免疫调节食品、免疫调节保健品、免疫调节药物或免疫调节化妆品;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化等修饰,得到的多肽衍生物。
本发明第八方面,提供了一种抗衰老产品,包括所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;所述的抗衰老产品包括抗衰老食品、抗衰老保健品或抗衰老药物;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化等修饰,得到的多肽衍生物。
本发明第九方面,提供了一种同时具有免疫调节功能和抗衰老功能的产品,包括所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;具有免疫调节功能和抗衰老功能的产品包括食品、保健品或药物;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化等修饰,得到的多肽衍生物。
本发明生物活性多肽NARIQDNLYLAV的有益效果为:本发明的生物活性多肽NARIQDNLYLAV具有较好的调节机体免疫力活性和抗衰老活性;一方面,本发明的生物活性多肽NARIQDNLYLAV能够增强淋巴细胞和巨噬细胞的体外增殖能力,提高机体抵御外界病原体感染的能力,降低机体发病率;另一方面,能够提高体内抗过氧化酶系的活力,增强机体抵抗外源性刺激的功能,从而降低机体老化、衰老和生病的机率,对开发具有免疫调节功能及抗衰老功能的乳制品和保健品具有十分重要的意义。
附图说明
图1:质量色谱提取图(m/z=695.8757);
图2:质荷比为695.8757的片段的二级质谱图;
图3:质荷比为695.8757的多肽az、by断裂情况;
图4:生物活性多肽NARIQDNLYLAV对雌性果蝇存活率的影响情况;
图5:过氧化氢(H2O2)急性实验。
具体实施方式
在进一步描述本发明具体实施方案之前,应理解,本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围。
当实施例给出数值范围时,应理解,除非本发明另有说明,每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
除非另外说明,本发明中所公开的实验方法、检测方法、制备方法均采用本技术领域常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组DNA技术及相关领域的常规技术。这些技术在现有文献中已有完善说明,具体可参见Sambrook等MOLECULAR CLONING:A LABORATORY MANUAL,Second edition,Cold Spring HarborLaboratory Press,1989and Third edition,2001;Ausubel等,CURRENT PROTOCOLS INMOLECULAR BIOLOGY,John Wiley&Sons,New York,1987and periodic updates;theseries METHODS IN ENZYMOLOGY,Academic Press,San Diego;Wolffe,CHROMATINSTRUCTURE AND FUNCTION,Third edition,Academic Press,San Diego,1998;METHODS INENZYMOLOGY,Vol.304,Chromatin(P.M.Wassarman and A.P.Wolffe,eds.),AcademicPress,San Diego,1999;和METHODS IN MOLECULAR BIOLOGY,Vol.119,ChromatinProtocols(P.B.Becker,ed.)Humana Press,Totowa,1999等。
下面结合附图和具体实施例对本发明进行详细说明。
实施例1活性肽NARIQDNLYLAV的人工合成
一、生物活性肽的合成
1.称取RINK树脂3g(取代度0.3mmol/g)于150ml的反应器中,用50ml的二氯甲烷(DCM)浸泡。
2.2小时后,用3倍树脂体积的氮-二甲基甲酰胺(DMF)洗涤树脂,然后抽干,如此重复四次,将树脂抽干后待用。
3.向反应器中加入一定量的20%哌啶(哌啶/DMF=1:4,v:v),放在脱色摇床上摇晃20min,以此来脱去树脂上的Fmoc保护基团。脱完保护后用3倍树脂体积的DMF洗涤四次,然后抽干。
4.取少量树脂用茚三酮(九井水合茚三酮)法检测(检A、检B各两滴,100℃反应1min),树脂有颜色,说明脱保护成功。
5.称取氨基酸Asn适量和1-羟基-苯骈三唑(HOBT)适量于50ml的离心管中,加入20ml的DMF将其溶解,然后加入3ml的N,N二异丙基碳二亚胺(DIC)振荡摇匀1min,待溶液澄清后加入到反应器中,然后将反应器置于30℃的摇床中反应。
6.2小时后,用一定量的醋酸酐封头(醋酸酐:DIEA:DCM=1:1:2,v:v:v)半小时,然后用3倍树脂体积的DMF洗涤四次,抽干待用。
7.向反应器中加入一定量的20%哌啶(哌啶/DMF=1:4,v:v),放在脱色摇床上摇晃20min,以此来脱去树脂上的Fmoc保护基团。脱完保护后用DMF洗涤四次,然后抽干。
8.取少量树脂用茚三酮(九井水合茚三酮)法检测(检A、检B各两滴,100℃反应1min),树脂有颜色,说明脱保护成功。
9.称取后面第二个氨基酸适量和HOBT适量于50ml的离心管中,加入25ml的DMF将其溶解,然后加入2.5ml的DIC振荡摇匀1min,待溶液澄清后加入到反应器中,然后将反应器置于30℃的摇床中反应。
10. 1小时后,取少量树脂检测,用茚三酮法检测(检A、检B各两滴,100℃反应1min),若树脂为无色,说明反应完全;若树脂有颜色,说明缩合不完全,继续反应。
11.待反应完全后,用DMF洗涤树脂四次,然后抽干,向反应器中加入一定量的20%哌啶(哌啶/DMF=1:4,v:v),放在脱色摇床上摇晃20min,以此来脱去树脂上的Fmoc保护基团。脱完保护后用DMF洗涤四次,然后抽干检测保护是否脱去。
12.按照步骤9-11依次接上氨基酸Ala、Arg、Ile、Gln、Asp、Asn、Leu、Tyr、Leu、Ala和Val。
13.待接上最后一个氨基酸后,脱去保护,用DMF洗涤四次,然后用甲醇将树脂抽干。然后用95切割液(三氟乙酸:1,2乙二硫醇:3,异丙基硅烷:水=95:2:2:1,v:v:v)将多肽从树脂上切割下来(每克树脂加10ml切割液),并用冰乙醚(切割液:乙醚=1:9,v:v)离心沉降四次。
至此,人工合成了生物活性肽NARIQDNLYLAV。
二、生物活性肽的确认
1)UPLC分析
UPLC条件如下:
仪器:Waters ACQUITY UPLC超高效液相-电喷雾-四级杆-飞行时间质谱仪
色谱柱规格:BEH C18色谱柱
流速:0.4mL/min
温度:50℃
紫外检测波长:210nm
进样量:2μL
梯度条件:A液:含有0.1%甲酸(v/v)的水,B液:含有0.1%甲酸(v/v)的乙腈
2)质谱分析
质谱条件如下:
离子方式:ES+
质量范围(m/z):100-1000
毛细管电压(Capillary)(kV):3.0
采样锥(V):35.0
离子源温度(℃):115
去溶剂温度(℃):350
去溶剂气流(L/hr):700.0
碰撞能量(eV):4.0
扫描时间(sec):0.25
内扫描时间(sec):0.02
根据以上分析方法,利用超高效液相-电喷雾-四级杆-飞行时间质谱,对生物活性肽NARIQDNLYLAV进行色谱分析和质谱分析,其质量色谱提取图如图1所示,提取此峰的二级质谱图和az、by断裂情况如图2和3所示,可得此峰的多肽质荷比为695.8757Da,保留时间是48.1min。
3)结果
由图3可知,根据az、by断裂的情况,经过Mascot软件分析计算,得到质荷比695.8757Da的片段序列为Asn-Ala-Arg-Ile-Gln-Asp-Asn-Leu-Tyr-Leu-Ala-Val(NARIQDNLYLAV),记为SEQ ID NO:1。该片段与LBH_0948|m.881LBH_0948|g.881ORF LBH_0948|g.881LBH_0948|m.881type:complete len:649(+)LBH_0948:1-1947(+)蛋白第19~30位的残基序列相对应,序列见SEQ ID NO:3。
实施例2生物活性肽的调节机体免疫力活性实验
一、MTT法测定生物活性多肽NARIQDNLYLAV的体外淋巴细胞增殖能力实验
1.实验材料与仪器:
试剂与材料:实验动物balb/c小鼠(雄性6-8周龄,上海交通大学农业与生物学院动物实验中心);实施例1获得的生物活性多肽NARIQDNLYLAV;小鼠淋巴细胞提取液(购自索来宝公司);RPMI1640培养基(购自GIBCO公司);3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT,购自Amresco公司);伴刀豆蛋白(ConA,购自Sigma公司);牛血清白蛋白(BSA,购自Genebase公司);胃蛋白酶(购自Sigma公司);胰酶(Corolase PP,购自AB公司)。
仪器设备:LRH-250F生化培养箱,上海恒科技有限公司;GL-22M高速冷冻离心机,上海卢湘仪离心机仪器有限公司;Hera cell 150CO2培养箱,Heraeus公司;DragonWellscan MK3酶标仪,Labsystems公司;ALPHA 1-2-LD真空冷冻干燥机,Christ公司;超高效液相色谱-四极杆飞行时间质谱仪,waters公司。
2.实验方法:
无菌条件下取小鼠脾脏,用淋巴细胞提取液提取小鼠淋巴细胞,进行元代培养。用完全RPMI1640培养液将细胞密度调整为2.5×106个/mL。在96孔细胞培养板中依次加入:100μL小鼠淋巴细胞悬液,100μL RPMI1640完全培养液,20μL伴刀豆蛋白,100μL样品。另外,设置空白对照组(pH7.2~7.4,3mol/L的PBS)和阴性对照组(500μg/mL BSA),研究表明其对于体外淋巴细胞增殖没有影响。每组3个平行实验样。在5%CO237℃培养箱中培养68h后,无菌条件下每孔加入20μL MTT,继续培养4h,小心弃去上清液,每孔加入100μL二甲基亚砜,37℃生化培养箱孵化10min,摇匀,用酶标仪在570nm处测定吸光值。
体外淋巴细胞增殖能力用刺激指数来表示,计算方法如下:
式中:A1为空白对照在570nm处下的吸光值;A2为阴性对照组在570nm处下的吸光值,A3为实验组在570nm处下的吸光值。
3.实验结果及分析:
表1生物活性多肽NARIQDNLYLAV对体外淋巴细胞增殖的影响
实验分组 | 刺激指数SI |
阴性对照组 | 1 |
NARIQDNLYLAV | 1.175±0.041* |
注:*号标记为与阴性对照比较,有显著性差异(P<0.05)。
实验结果见表1。由表1可知,在生物活性肽NARIQDNLYLAV的质量浓度为100μg/mL的条件下,生物活性肽NARIQDNLYLAV的刺激指数大于BSA,说明NARIQDNLYLAV一定程度上能刺激体外小鼠淋巴细胞的增殖。并且NARIQDNLYLAV的刺激指数达到了1.175,和阴性对照组具有显著差异(P<0.05)。因此,可以认定该活性多肽NARIQDNLYLAV具有显著促进小鼠淋巴细胞增殖的能力,可以作为一种保健品或者添加剂食用,能够提高动物和人体的免疫力。
二、MTT法测定生物活性多肽NARIQDNLYLAV的体外巨噬细胞增殖能力实验
1)实验试剂及仪器
试剂:实验动物balb/c小鼠(雄性6-8周龄)上海交通大学农业与生物学院动物实验中心;实施例1获得的生物活性多肽NARIQDNLYLAV;3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)Amresco公司;LPS(脂多糖)Sigma公司;牛血清白蛋白(Bovine SerumAlbumin,BSA)Genebase公司;三联溶解液,含10%SDS、5%异丁醇以及0.012mol/L HCl的水溶液。
仪器设备:LRH-250F生化培养箱上海恒科技有限公司;GL-22M高速冷冻离心机上海卢湘仪离心机仪器有限公司;Hera cell 150CO2培养箱Heraeus公司;Dragon WellscanMK3酶标仪Labsystems公司。
2)试验方法:
balb/c小鼠腹腔注射2ml的2%(w/w)灭菌淀粉溶液,连续注射三天,最后一次注射24小时后断颈处死。剥去腹部皮肤,用注射器吸取4℃磷酸盐缓冲液(PBS)反复冲洗腹腔,离心管收集冲洗液后,离心(1000rpm,4℃)10分钟后弃上清,用4℃RPMI1640完全培养液(含10%FBS)洗涤两次,0.2%台盼蓝溶液染色做细胞活力检测,确认采集到的有活力巨噬细胞占95%以上。细胞计数板读数后,调整细胞浓度至合适浓度。
将已吹打至完全悬浮的细胞悬液以合适体积加入96孔细胞培养板,37℃、5%CO2环境下培养4小时后,吸弃孔中液体,用37℃RPMI1640完全培养液小心清洗细胞培养板孔底,洗去未贴壁的细胞和细胞碎片,得到纯化后的贴壁腹腔巨噬细胞。每孔加入0.2mlRPMI1640完全培养基,实验用小肽样品及LPS事先溶解于培养基后加入,开始细胞培养。
得到纯化后的贴壁腹腔巨噬细胞后,实验组每孔加溶解有生物活性多肽NARIQDNLYLAV(1mg/ml)的RPMI1640完全培养液(10%FBS)200μl/孔,连续培养48h;阴性对照组每孔加溶解有BSA(500μg/mL)的RPMI1640完全培养液(10%FBS)200μl/孔;空白组添加RPMI1640完全培养液(10%FBS)200μl/孔,连续培养48h。并且,实验组、阴性对照组和空白组又分别设正常组和炎症组;炎症组在培养到24h时加入LPS至终浓度为100ng/ml;正常组不加LPS;并且正常组和炎症组在44h时加入5%MTT 20μl/孔;细胞培养达到48h后加入100μl/孔的三联溶解液以终止培养,隔夜溶解后,在波长570nm下用酶标仪测各孔的吸光度值(OD570),生长指数(Growth Indices)的计算公式如下:
其中,空白培养液为含10%FBS的RPMI1640完全培养液。
3)实验结果及分析
表2生物活性多肽NARIQDNLYLAV对体外巨噬细胞增殖的影响
注:*表示与阴性对照比较,有显著性差异(P<0.05);**表示与阴性对照组比较,有显著性差异(P<0.01)
实验结果见表2,由表2可知,在添加1mg/ml生物活性多肽NARIQDNLYLAV的条件下,正常组和炎症组的巨噬细胞均有增殖。而且与阴性对照组比较,均有显著性差异(P<0.01)。说明生物活性多肽NARIQDNLYLAV对体外巨噬细胞具有显著的增殖作用。
实施例3生物活性肽的抗衰老活性实验
一、生物活性多肽NARIQDNLYLAV提高果蝇生存能力的实验
1.实验试剂及仪器:
试剂:Oregon K野生型黑腹果蝇,上海交通大学农学院遗传学实验室;琼脂粉,国药集团化学试剂有限公司;实施例1获得的生物活性多肽NARIQDNLYLAV。
仪器设备:CM-230型摩尔超净水,上海摩勒科学仪器有限公司;G136T型Zealway智能高温灭菌锅,厦门致微仪器科技有限公司;BJ-CD SERIES生物培养箱,上海博讯实业公司;GRX-9073型热空气消毒箱,上海一恒科技有限公司。
2.实验方法:
以果蝇为实验模型:收集8小时内新羽化的果蝇成虫,麻醉后分雌雄随机转移到各实验组中,每组每个性别100只,每组设置3个平行,对照组给予普通玉米粉培养基,实验组分别为含有0.05mg/ml、0.5mg/ml、1mg/ml的NARIQDNLYLAV生物活性肽-玉米培养基。每2天更换新鲜培养基一次,每天观察并记录不同性别果蝇的死亡数,直到果蝇全部死亡为止。绘制果蝇生存曲线,并计算出不同性别果蝇的平均寿命和最高寿命(取最后死亡的5只果蝇进行统计)。
3.实验结果及分析:
本实验对喂食不同浓度生物活性肽的果蝇寿命的研究结果如下:从图4可以发现,相对于空白对照组雄性果蝇而言,喂食浓度为0.05mg/ml的NARIQDNLYLAV并没有显著改变雄性果蝇的存活率,而当肽浓度达到0.5mg/ml和1mg/ml时,相同时间点,雌性果蝇的存活率有所提高,但结果差异不明显。
表3-1NARIQDNLYLAV对雄性果蝇寿命的影响情况
注:*标示与空白对照组比较,有显著性差异(P<0.05);下同。
表3-2NARIQDNLYLAV对雌性果蝇寿命的影响情况
从表3-1中可知,相对于空白对照组,低剂量组雄性果蝇平均寿命没有明显变化,但中剂量组和高级量组雄性果蝇平均寿命均有提高,分别为17.14%和10.83%,但仅中剂量组产生了显著性差异(p<0.05),说明中剂量组雄性果蝇的平均寿命显著性提高。同时,中剂量组和高剂量组果蝇的半数死亡时间得到了提高,但最长寿命方面均未有明显差异。由表3-2可知,雌性果蝇低剂量组、中剂量组和高剂量组在平均寿命方面均有所提高,但均未产生显著性差异。但中剂量组和高剂量组的最长寿命均有所提高,较空白对照组分别延长7天和6天,并产生了显著性差异(P<0.05)。
本实验结果说明,生物活性多肽NARIQDNLYLAV在一定浓度下可以提高果蝇的平均寿命和最长寿命,但与浓度和性别有关。这种与受试物浓度、品系相关的现象可能是因为NARIQDNLYLAV参与果蝇的部分生物代谢,或者是通过改善果蝇组织的抗氧化体系来达到延长果蝇寿命的效果。由于不同品系果蝇的代谢会有区别,从而造成结果的差异。而性别的差异,可能是由于雌性果蝇本身就具有一定的保守性和对外界环境的抵抗力,所以NARIQDNLYLAV对雌性果蝇寿命延长并不明显。
二、生物活性多肽NARIQDNLYLAV提高果蝇繁殖能力的实验
1.实验试剂及仪器:
试剂:Oregon K野生型黑腹果蝇,上海交通大学农学院遗传学实验室;琼脂粉,国药集团化学试剂有限公司;实施例1获得的生物活性多肽NARIQDNLYLAV。
仪器设备:CM-230型摩尔超净水,上海摩勒科学仪器有限公司;G136T型Zealway智能高温灭菌锅,厦门致微仪器科技有限公司;BJ-CD SERIES生物培养箱,上海博讯实业公司;GRX-9073型热空气消毒箱,上海一恒科技有限公司。
2.实验方法:
收集8小时内新羽化的果蝇成虫,将其雌雄分开喂养,培养基中分别加入浓度为0mg/ml、0.05mg/ml、0.5mg/ml、1mg/ml的NARIQDNLYLAV溶液,连续培养12天。第13天收集相同浓度下培养的成年果蝇并转移到新的普通培养瓶中,每个培养瓶保证1只雌性和2只雄性(每组5瓶),每瓶给予准确的24小时进行产卵。产卵后将亲本果蝇转移到新的普通培养瓶中,旧培养瓶继续繁殖培养,待幼虫羽化后统计后代数量,连续测定7天,并重复3次。
3.实验结果及分析:
表4繁殖力测定结果
从表4可以看出,低浓度实验组繁殖力与对照组相比未产生显著性变化,但中剂量实验组和高剂量实验组果蝇的繁殖力与空白对照组相比有显著提高(P<0.05)。说明一定浓度的NARIQDNLYLAV能够促进果蝇的繁殖力。本实验结果表明,果蝇寿命的延长是NARIQDNLYLAV直接作用的结果,而非NARIQDNLYLAV通过降低繁殖力所产生的二级生理效应。同时也说明NARIQDNLYLAV对果蝇是安全的,没有毒性危害。
三、生物活性多肽NARIQDNLYLAV过氧化氢急性氧化性实验
1.实验试剂及仪器:
试剂:Oregon K野生型黑腹果蝇,上海交通大学农学院遗传学实验室;琼脂粉,国药集团化学试剂有限公司;过氧化氢,上海凌峰化学试剂有限公司;实施例1获得的生物活性多肽NARIQDNLYLAV。
仪器设备:CM-230型摩尔超净水,上海摩勒科学仪器有限公司;密理博MilliporeMILLEX GP0.22μm滤膜,美国密理博公司;GL-22M高速冷冻离心机,上海卢湘仪离心机仪器有限公司。
2.实验方法:
收集8小时内新羽化的果蝇成虫,麻醉后分雌雄随机转移到各实验组中,取寿命实验中结果较好的肽浓度培养基,设置空白对照组和实验组,对照组给予普通玉米粉培养基。每组雌雄性别果蝇均为50只,对果蝇培养三周。然后每次取5只雄性和5只雌性果蝇转移到一个新的容器中,新的容器内含有一个纸质圆盘,圆盘含有300μL浓度为5%的蔗糖溶液以及浓度为30%过氧化氢1ml,空白组和实验组均暴露在这种过氧化氢产生的毒性过氧化物环境中,每组设置10个平行样,观察其抗氧化能力。每4小时记录果蝇死亡数量和性别,直到果蝇全部死亡。
3.实验结果及分析:
从图5(A)中可以看出,对于雄性果蝇,经过NARIQDNLYLAV喂食后,在各个时间点,雄性果蝇的存活率均高于未经NARIQDNLYLAV喂食的果蝇,且存活时间较空白对照组有所提高,说明喂食NARIQDNLYLAV后,雄性果蝇抗氧化能力有所提高。图5(B)中,喂食NARIQDNLYLAV的雌性果蝇,在高浓度的过氧化氢环境中15h内存活率明显高与对照组,说明这段时间雌性果蝇抗氧化能力有所提高。但后期实验组和对照组存活曲线基本重合,说明喂食NARIQDNLYLAV的雌性果蝇的抗氧化能力逐渐减弱,经过一定时间后与对照组没有差异。此实验结果表明,NARIQDNLYLAV可以提高果蝇的抗氧化能力。根据H2O2急性毒性实验结果,可以推测NARIQDNLYLAV可能通过调节过氧化氢酶CAT活性来提高果蝇对H2O2损伤的抵抗能力。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
序列表
<110> 浙江辉肽生命健康科技有限公司;上海铂辉生物科技有限公司
<120> 一种生物活性多肽NARIQDNLYLAV及其制备方法和应用
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Claims (10)
1.一种生物活性多肽NARIQDNLYLAV,其特征在于,其氨基酸序列为Asn-Ala-Arg-Ile-Gln-Asp-Asn-Leu-Tyr-Leu-Ala-Val。
2.根据权利要求1所述的一种生物活性多肽NARIQDNLYLAV,其特征在于,所述生物活性多肽来源于瑞士乳杆菌菌体蛋白。
3.编码权利要求1所述生物活性多肽NARIQDNLYLAV的核苷酸片段,其特征在于,所述核苷酸片段的序列如SEQ ID NO:2所示。
4.如权利要求1所述生物活性多肽NARIQDNLYLAV的制备方法,其特征在于,通过基因工程的方法人工合成,或瑞士乳杆菌菌体通过细胞破碎分离纯化的方法直接获得,或直接通过化学合成制备。
5.如权利要求1所述生物活性多肽NARIQDNLYLAV的应用,其特征在于,所述生物活性多肽NARIQDNLYLAV在制备具有免疫调节功能的食品、保健品、药物或化妆品中的应用。
6.如权利要求1所述生物活性多肽NARIQDNLYLAV的应用,其特征在于,所述生物活性多肽NARIQDNLYLAV在制备具有抗衰老功能的食品、保健品或药物中的应用。
7.如权利要求1所述生物活性多肽NARIQDNLYLAV的应用,其特征在于,所述生物活性多肽NARIQDNLYLAV在制备具有免疫调节功能和抗衰老功能的食品、保健品或药物中的应用。
8.一种免疫调节产品,其特征在于,包括如权利要求1所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;所述的免疫调节产品包括免疫调节食品、免疫调节保健品、免疫调节药物或免疫调节化妆品;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化修饰,得到的多肽衍生物。
9.一种抗衰老产品,其特征在于,包括如权利要求1所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;所述的抗衰老产品包括抗衰老食品、抗衰老保健品或抗衰老药物;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化修饰,得到的多肽衍生物。
10.一种具有免疫调节功能和抗衰老功能的产品,其特征在于,包括如权利要求1所述生物活性多肽NARIQDNLYLAV或所述生物活性多肽NARIQDNLYLAV的衍生物;具有免疫调节功能和抗衰老功能的产品包括食品、保健品或药物;所述生物活性多肽NARIQDNLYLAV的衍生物,是指在生物活性多肽NARIQDNLYLAV的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化修饰,得到的多肽衍生物。
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