CN108794603A - 一种生物活性多肽tvtmlmttil及其制备方法和应用 - Google Patents
一种生物活性多肽tvtmlmttil及其制备方法和应用 Download PDFInfo
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- CN108794603A CN108794603A CN201810717713.8A CN201810717713A CN108794603A CN 108794603 A CN108794603 A CN 108794603A CN 201810717713 A CN201810717713 A CN 201810717713A CN 108794603 A CN108794603 A CN 108794603A
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- tvtmlmttil
- biologically active
- active polypeptide
- thr
- leu
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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TVTMLMTTIL及其制备方法和应用,生物活性多肽TVTMLMTTIL其氨基酸序列为Thr‑Val‑Thr‑Met‑Leu‑Met‑Thr‑Thr‑Ile‑Leu。经过体外抗炎活性实验、体内抗衰老实验,验证了多肽TVTMLMTTIL具有较好的抗炎活性和抗衰老活性,一方面,本发明的生物活性多肽TVTMLMTTIL能够促进巨噬细胞分泌细胞因子,促进巨噬细胞一氧化氮诱生量的增加,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,对开发具有抗炎功能、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TVTMLMTTIL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,具有抗炎功能。李素萍等人用合成的乳源肽(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抗炎功能有显著的增强。
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、促进巨噬细胞一氧化氮诱生量的增加、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TVTMLMTTIL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TVTMLMTTIL,其氨基酸序列为Thr-Val-Thr-Met-Leu-Met-Thr-Thr-Ile-Leu,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_0494|m.460LBH_0494|g.460 ORF LBH_0494|g.460LBH_0494|m.460 type:complete len:668(+)LBH_0494:1-2004(+)蛋白,并且为此蛋白第380~389位的氨基酸残基。LBH_0494|m.460LBH_0494|g.460ORF LBH_0494|g.460 LBH_0494|m.460type:complete len:668(+)LBH_0494:1-2004(+)蛋白氨基酸序列如SEQ ID NO:3所示。
LBH_0494|m.460LBH_0494|g.460ORF LBH_0494|g.460LBH_0494|m.460 type:complete len:668(+)LBH_0494:1-2004(+)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380~389位氨基酸残基的核苷酸片段能编码成熟的生物活性多肽TVTMLMTTIL。
较优的,所述生物活性多肽具有抗炎功能和抗衰老功能。
本发明第二方面,提供了编码所述生物活性多肽TVTMLMTTIL的核苷酸片段,其序列为:5’-ctg tca cta tgt tga tga cta caa tat tat-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TVTMLMTTIL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TVTMLMTTIL在制备具有抗炎功能的食品、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TVTMLMTTIL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TVTMLMTTIL在制备同时具有抗炎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TVTMLMTTIL可以用于制备减少自由基对皮肤伤害的化妆品、制备具有抗炎和/或抗衰老的药物;并且由于本发明的生物活性多肽TVTMLMTTIL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抗炎和/或抗衰老的药物。
本发明第七方面,提供了一种抗炎产品,包括所述生物活性多肽TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL的衍生物;所述的抗炎产品包括抗炎食品、抗炎保健品、抗炎药物或抗炎化妆品;所述生物活性多肽TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL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TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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抗炎功能和抗衰老功能的产品,包括所述生物活性多肽TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL的衍生物;具有抗炎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TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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TVTMLMTTIL的有益效果为:本发明的生物活性多肽TVTMLMTTIL具有较好的抗炎活性和抗衰老活性;一方面,本发明的生物活性多肽TVTMLMTTIL能够促进巨噬细胞分泌细胞因子,促进巨噬细胞一氧化氮诱生量的增加,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,对开发具有抗炎功能、抗衰老功能的食品、保健品和药物具有十分重要的意义。
附图说明
图1:质量色谱提取图(m/z=570.8167);
图2:质荷比为570.8167的片段的二级质谱图;
图3:质荷比为570.8167的多肽az、by断裂情况;
图4:IL-4标准曲线;
图5:生物活性多肽TVTMLMTTIL对细胞因子IL-4分泌量的影响;
图6:不同浓度TVTMLMTTIL对秀丽线虫生殖能力的影响;
图7:不同培养条件下线虫在L4期时生长状态;
图8:生物活性多肽TVTMLMTTIL对秀丽线虫体长的影响;
图9:生物活性多肽TVTMLMTTIL对秀丽线虫在氧化应激下的影响。
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TVTMLMTTIL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Thr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Val、Thr、Met、Leu、Met、Thr、Thr、Ile和Leu。
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TVTMLMTTIL。
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TVTMLMTTIL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570.8167Da,保留时间是33.3min。
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570.8167Da的片段序列为Thr-Val-Thr-Met-Leu-Met-Thr-Thr-Ile-Leu(TVTMLMTTIL),记为SEQ ID NO:1。该片段与LBH_0494|m.460 LBH_0494|g.460ORF LBH_0494|g.460LBH_0494|m.460type:complete len:668(+)LBH_0494:1-2004(+)蛋白第380~389位的残基序列相对应,序列见SEQ ID NO:3。
实施例2生物活性肽的抗炎活性实验
一、生物活性多肽TVTMLMTTIL的促巨噬细胞分泌细胞因子的实验(ELISA法)
1.实验试剂及仪器:
试剂:实验动物balb/c小鼠(雄性6-8周龄),上海斯莱克实验动物有限公司;小鼠淋巴细胞提取液,上海索莱宝生物科技有限公司;RPMI1640培养基,GIBCO公司;牛血清白蛋白(bovine serum albumin,BSA),Genebase公司;实施例1获得的生物活性多肽TVTMLMTTIL;ELISA细胞因子快速试剂盒(IL-4),武汉博士德生物工程有限公司。
仪器设备:CM-230型摩尔超净水,上海摩勒科学仪器有限公司;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;Heracell 150CO2培养箱,Heraeus公司;Dragon Wellscan MK3酶标仪,Labsystems公司。
2.实验方法:
(1)标准曲线的制备
制作IL-4标准曲线:将浓度为500pg/mL,250pg/mL,125pg/mL,62.5pg/mL,31.3pg/mL,15.6pg/mL,7.8pg/mL的IL-4标准品分别依次加入酶标板孔内,再加入生物素标记抗小鼠IL-4抗体(ELISA细胞因子快速试剂盒),酶标板加上盖,37℃反应90min。甩去酶标板内液体,每孔依次加入亲和素-过氧化物酶复合物(ELISA细胞因子快速试剂盒)0.1mL。37℃反应60min。0.01M PBS洗涤3次,每孔加入0.1mL ABC工作液,37℃反应30min。0.01M PBS洗涤5次,每孔加入90ul TMB显色液,37℃避光反应25min。每孔加入0.1mL TMB终止液,用酶标仪在450nm测定吸光值。制作的IL-4检测用标准曲线如图4所示。IL-4标准曲线是以浓度为横坐标(单位pg/mL),450nm下的吸光值为纵坐标,进行一次回归拟合,获得标准曲线Y=0.0038X+0.1224,R2=0.9979。其中X代表IL-4浓度,单位为pg/mL,Y代表OD450下的吸光值。
(2)多肽TVTMLMTTIL的促巨噬细胞分泌细胞因子检测
在无菌条件下取小鼠脾脏淋巴细胞,调整细胞浓度至5×105/mL接种于96孔板,实验组加入生物活性多肽TVTMLMTTIL进行培养,调整生物活性多肽TVTMLMTTIL的终浓度分别为100,50,10μg/mL,与淋巴细胞共同培养36小时后进行细胞因子IL-4的测定。空白组不加生物活性多肽TVTMLMTTIL,培养36h作为对照。
3.实验结果及分析:
实验结果见图5,与空白对照组相比,随着多肽浓度的增加,IL-4的分泌量逐渐增加;当多肽添加浓度达到50和100μg/mL时,IL-4分泌量显著大于空白组;可见生物活性多肽TVTMLMTTIL具有促进淋巴细胞增殖的功能,并且通过对IL-4细胞因子分泌的调节,起到对机体体液免疫的调节作用。
二、生物活性多肽TVTMLMTTIL的促巨噬细胞一氧化氮诱生量的测定(Griess法)
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TVTMLMTTIL;LPS,购自Sigma公司;中性红染色液,碧云天生物技术研究所生产。
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:
加入细胞个数为2×106/ml的细胞悬液100μl/孔,贴壁纯化后加入含肽的RPMI1640完全培养液(10%FBS)200μl/孔,炎症组在24h时加入LPS至终浓度10μg/ml,连续培养48h后,收集培养液上清50μl/孔,在培养液上清中依次添加Griess试剂1和Griess试剂2各50μl/孔,室温反应10分钟后,在540nm波长下测定吸光度值(OD540)。
3.实验结果及分析:
表1生物活性多肽TVTMLMTTIL促巨噬细胞一氧化氮诱生量的测定
实验分组 | 正常组 | 炎症组 |
细胞空白 | 0.0592±0.00525 | 0.3241±0.0381 |
TVTMLMTTIL 1mg/ml | 0.1375±0.0352** | 0.4885±0.0732** |
TVTMLMTTIL 0.5mg/ml | 0.1296±0.0436** | 0.3823±0.0552** |
TVTMLMTTIL 0.1mg/ml | 0.2816±0.0351** |
注:*,与阴性对照比较,有显著性差异(P<0.05);
**,与阴性对照组比较,有显著性差异(P<0.01)
实验结果见表1,由表1可知,在实验组中添加生物活性多肽TVTMLMTTIL,浓度分别为1mg/mL和0.5mg/mL,对于正常情况下生长和LPS造炎症情况下生长的促进巨噬细胞的一氧化氮诱生量均有促进作用。与细胞空白组相比,具有显著性差异(P<0.05)。当生物活性多肽TVTMLMTTIL的添加浓度为0.1mg/mL,在LPS造炎症情况下相比,也能促进巨噬细胞一氧化氮诱生量的增加,并具有显著性差异(P<0.05)。但是与正常情况下生长的细胞空白组相比,没有显著性差异。说明生物活性多肽TVTMLMTTIL在一定浓度条件下具有促进巨噬细胞一氧化氮诱生量增加的能力。
实施例3生物活性肽的抗衰老活性实验
一、生物活性多肽TVTMLMTTIL对秀丽线虫生殖能力影响的实验
1.实验试剂及仪器:
试剂:秀丽线虫(Caenorhabditis elegans),复旦大学附属中西结合研究院;大肠菌株E.coli OP50,复旦大学附属中西结合研究院;琼脂粉,国药集团化学试剂有限公司;酵母粉,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TVTMLMTTIL。
仪器设备:力康RO15纯水系统,力康生物医疗科技有限公司;G136T型Zealway智能高温灭菌锅,厦门致微仪器科技有限公司;THZ-32型台式恒温振荡器,上海精密实验设备有限公司;TDL-40B离心机,上海安亭科学仪器厂;卢湘仪GL-22M高速冷冻离心机,上海卢湘仪仪器有限公司;博迅BJ-CD SERIES生物安全柜,上海博讯实业有限公司;Nikko倒置电子显微镜,尼康株式会社。
2.实验方法:
(1)NGM平板制备
取大肠杆菌菌种于LB平板划线,挑取单菌落于10ml LB液体培养基中,37℃,200rpm,振荡培养24h,至OD600=0.4用于接种NGM平板喂养线虫。取100μL菌液涂于60mmNGM平板,注意菌液边缘应距离平板边缘0.5cm左右。已涂布的NGM平板在室温(21-25℃)过夜后即可使用。
(2)线虫培养
本实验中所用的线虫均为雌雄同体,在标准培养条件(温度20℃,湿度40%~60%)下培养生长。
(3)线虫的同期化处理
1)高氯酸钠漂白法
准备孕虫生长板(即板中80%以上虫子处于生殖期)2-3板,取5ml M9缓冲液冲洗2次,将缓冲液吸入15ml离心管中,1000r/min离心3min,弃去上清。加入5ml新配同期化漂白液,室温下剧烈振荡2.5min,以将成虫虫体腐蚀。离心,弃去上清。保证总处理时间不能超过5min,防止损伤虫卵。再加入M9缓冲液将沉淀重悬,混匀后离心,弃去上清,重复此过程3次。
2)限时产卵法
挑取若干条处于产卵期的线虫于同一平板内,挑取的具体数量以所需同期化线虫数目为依据。一般条件下,一条产卵期线虫能在1h以内产卵6个左右。在平板中培养0.5h后,挑出平板中线虫,则平板中的卵处于同一生长时期。
(4)指标测定
本实验以秀丽线虫作为动物模型,挑取同期化处理后的L4期线虫到相应浓度的NGM板中。每个浓度至少8条线虫,每个NGM板转入一条,记为0天,以后每天移至新板中直至线虫生殖基本不再产卵,在其进入产卵期之前对线虫总产卵数进行计数。
3.实验结果及分析:
实验结果如图6所示,与不喂食多肽TVTMLMTTIL的空白组相比较,喂食不同质量浓度的实验组中,其平均产卵数均有不同程度的增加。喂食的多肽TVTMLMTTIL浓度为300mg/L时,线虫平均产卵数与空白组相比具有极其显著的差异(P<0.01),而在其浓度为400mg/L、500mg/L时,与空白组相比却只呈现显著性差异(P<0.05),这也进一步证明了300mg/L为混合肽多肽TVTMLMTTIL作用最佳浓度,随着肽浓度的提高并不会抑制线虫生殖,而是其作用效果减弱。综上所述,多肽TVTMLMTTIL在一定浓度下能明显提升线虫的生殖能力。同时,此实验结果表明,多肽TVTMLMTTIL 300mg/L为最适浓度。但随着浓度的增加,线虫的生殖能力却不再出现明显提高。
二、生物活性多肽TVTMLMTTIL对秀丽线虫体长影响的实验
1.实验试剂及仪器:
试剂:秀丽线虫(Caenorhabditis elegans),复旦大学附属中西结合研究院;大肠菌株E.coli OP50,复旦大学附属中西结合研究院;琼脂粉,国药集团化学试剂有限公司;酵母粉,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TVTMLMTTIL。
仪器设备:力康RO15纯水系统,力康生物医疗科技有限公司;G136T型Zealway智能高温灭菌锅,厦门致微仪器科技有限公司;THZ-32型台式恒温振荡器,上海精密实验设备有限公司;TDL-40B离心机,上海安亭科学仪器厂;卢湘仪GL-22M高速冷冻离心机,上海卢湘仪仪器有限公司;博迅BJ-CD SERIES生物安全柜,上海博讯实业有限公司;Nikko倒置电子显微镜,尼康株式会社。
2.实验方法:
(1)NGM平板制备
取大肠杆菌菌种于LB平板划线,挑取单菌落于10ml LB液体培养基中,37℃,200rpm,振荡培养24h,至OD600=0.4用于接种NGM平板喂养线虫。取100μL菌液涂于60mmNGM平板,注意菌液边缘应距离平板边缘0.5cm左右。已涂布的NGM平板在室温(21-25℃)过夜后即可使用。
(2)线虫培养
本实验中所用的线虫均为雌雄同体,在标准培养条件(温度20℃,湿度40%~60%)下培养生长。
(3)线虫的同期化处理
1)高氯酸钠漂白法
准备孕虫生长板(即板中80%以上虫子处于生殖期)2-3板,取5ml M9缓冲液冲洗2次,将缓冲液吸入15ml离心管中,1000r/min离心3min,弃去上清。加入5ml新配同期化漂白液,室温下剧烈振荡2.5min,以将成虫虫体腐蚀。离心,弃去上清。保证总处理时间不能超过5min,防止损伤虫卵。再加入M9缓冲液将沉淀重悬,混匀后离心,弃去上清,重复此过程3次。
2)限时产卵法
挑取若干条处于产卵期的线虫于同一平板内,挑取的具体数量以所需同期化线虫数目为依据。一般条件下,一条产卵期线虫能在1h以内产卵6个左右。在平板中培养0.5h后,挑出平板中线虫,则平板中的卵处于同一生长时期。
(4)指标测定
实验分组:空白组和多肽组。不同组线虫,在同一时期下体长之间的差异,可以在一定程度上反映出该活性物质对于线虫生长发育的影响。各组同期化培养的线虫在生长至L2期(培养2天左右)时,分别挑取40条线虫至各自NGM平板,连续2天、3天、4天、5天、6天、8天、10天用倒置显微镜观察其生长状态,测定和记录其体长,每组取其平均值。
3.实验结果及分析:
在20℃的培养条件下,从线虫生长的L2期(第2天)开始观察,L3期(第3天)、L4期(第4天)、成虫期(第6天),连续观察8天,直至线虫生长的第10天,测定每个时间点下线虫的体长。结合图7和图8可以看出,各组线虫在L4期时其体长均为1000μm左右,无明显区别。同时,从线虫体长变化曲线中也可看出,实验组体长变化曲线也几乎和空白组体长变化曲线相重合,在线虫L3期(第3天)时,虽然线虫平均体长稍有区别,但是在统计学上并不呈现显著性差异。实验表明,多肽TVTMLMTTIL的浓度并不会影响线虫的生长。同时,也可发现线虫在L3期(第3天)至L4期(第4天),是其生长最为快速的阶段。
三、生物活性多肽TVTMLMTTIL的急性氧化应激存活率实验
1.实验试剂及仪器:
试剂:秀丽线虫(Caenorhabditis elegans),复旦大学附属中西结合研究院;大肠菌株E.coli OP50,复旦大学附属中西结合研究院;琼脂粉,国药集团化学试剂有限公司;酵母粉,国药集团化学试剂有限公司;30%过氧化氢溶液,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TVTMLMTTIL。
仪器设备:力康RO15纯水系统,力康生物医疗科技有限公司;G136T型Zealway智能高温灭菌锅,厦门致微仪器科技有限公司;THZ-32型台式恒温振荡器,上海精密实验设备有限公司;TDL-40B离心机,上海安亭科学仪器厂;卢湘仪GL-22M高速冷冻离心机,上海卢湘仪仪器有限公司;博迅BJ-CD SERIES生物安全柜,上海博讯实业有限公司;Nikko倒置电子显微镜,尼康株式会社。
2.实验方法:
(1)NGM平板制备
取大肠杆菌菌种于LB平板划线,挑取单菌落于10ml LB液体培养基中,37℃,200rpm,振荡培养24h,至OD600=0.4用于接种NGM平板喂养线虫。取100μL菌液涂于60mmNGM平板,注意菌液边缘应距离平板边缘0.5cm左右。已涂布的NGM平板在室温(21-25℃)过夜后即可使用。
(2)线虫培养
本实验中所用的线虫均为雌雄同体,在标准培养条件(温度20℃,湿度40%~60%)下培养生长。
(3)线虫的同期化处理
1)高氯酸钠漂白法
准备孕虫生长板(即板中80%以上虫子处于生殖期)2-3板,取5ml M9缓冲液冲洗2次,将缓冲液吸入15ml离心管中,1000r/min离心3min,弃去上清。加入5ml新配同期化漂白液,室温下剧烈振荡2.5min,以将成虫虫体腐蚀。离心,弃去上清。保证总处理时间不能超过5min,防止损伤虫卵。再加入M9缓冲液将沉淀重悬,混匀后离心,弃去上清,重复此过程3次。
2)限时产卵法
挑取若干条处于产卵期的线虫于同一平板内,挑取的具体数量以所需同期化线虫数目为依据。一般条件下,一条产卵期线虫能在1h以内产卵6个左右。在平板中培养0.5h后,挑出平板中线虫,则平板中的卵处于同一生长时期。
(4)指标测定
实验分组:空白组和多肽组。将同期化处理后的L4期线虫置于相应NGM板中,实验在含20mM H2O2的NGM平板中进行,每板数量不少于10条,每半小时计数线虫死亡、存活数目,线虫死亡判断标准:无移动及吞咽动作,轻触后仍无任何反应。剔除标准:①逃离至平板壁或盖上而干死;②虫卵在体内孵化而成袋样虫:③钻入琼脂中。
3.实验结果及分析:
表2生物活性多肽TVTMLMTTIL对线虫在氧化应激下的影响
由表2可以看出,实验组线虫在氧化应激下平均寿命具有显著性提高(P<0.05),多肽TVTMLMTTIL组呈现极其显著性差异(P<0.05)。各组半数死亡时间也相应在一定程度上有所延长,与其他实验组相比混合肽组呈现显著性提高(P<0.05)。如图9所示,在氧化应激条件下,实验组存活率均明显高于空白组存活率。这说明在氧化应激条件下,线虫的存活率得到了显著提高,可能是由于多肽TVTMLMTTIL能有效帮助线虫抵抗氧化损伤,清除体内产生的自由基以及降低过氧化物的积累,而非通过增强其耐热力实现的。机体寿命的延长在一定程度上是由于改善了细胞对胁迫条件的抵抗力,因而延缓衰老与压力应激条件下的存活率存在很大关系。本实验结果证明多肽TVTMLMTTIL能显著地增加线虫的氧化应激能力,提高线虫的存活率,说明一定浓度的多肽TVTMLMTTIL对于线虫具有抗衰老的功效。
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TVTMLMTTIL及其制备方法和应用
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Thr Val Thr Met Leu Met Thr Thr Ile Leu
1 5 10
<210> 2
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
ctgtcactat gttgatgact acaatattat 30
<210> 3
<211> 667
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Asn Lys Ile Thr Lys Lys Gln Lys Met Ser Phe Ala Gly Leu Leu
1 5 10 15
Ile Ala Ile Gly Ile Val Tyr Gly Asp Ile Gly Thr Ser Pro Leu Tyr
20 25 30
Val Met Lys Ser Ile Val Thr Glu Asn Gly Gly Ile Ala Asn Val Asn
35 40 45
Arg Glu Leu Ile Val Gly Ser Ile Ser Leu Ile Leu Trp Thr Val Thr
50 55 60
Leu Leu Thr Thr Val Lys Tyr Val Met Ile Ala Leu Lys Ala Thr Asn
65 70 75 80
His Gly Glu Gly Gly Ile Phe Ser Leu Tyr Ala Leu Val Arg Lys Arg
85 90 95
Ala Gln Trp Leu Val Ile Pro Ala Leu Met Gly Gly Ala Ala Leu Leu
100 105 110
Ala Asp Gly Thr Leu Thr Pro Ala Val Thr Val Thr Thr Ser Ile Glu
115 120 125
Gly Leu Lys Asn Met Arg Phe Gly Asp Val Ile Pro Val Pro Ser Gln
130 135 140
Glu Val Val Ile Met Ile Thr Ile Ile Ile Leu Val Ile Leu Phe Ser
145 150 155 160
Ile Gln Arg Met Gly Thr Ser Val Ile Gly Lys Ala Phe Gly Pro Ile
165 170 175
Met Leu Val Trp Phe Thr Phe Leu Gly Val Val Gly Ile Ala Asn Leu
180 185 190
Ser His Asp Trp Ser Leu Leu Glu Ala Ile Asn Pro Ile His Ala Ile
195 200 205
Arg Ile Leu Phe Ser Pro Ala Asn Lys Val Gly Ile Leu Ile Leu Gly
210 215 220
Ser Val Phe Leu Ala Thr Thr Gly Ala Glu Ala Leu Tyr Ser Asp Val
225 230 235 240
Gly His Val Gly Lys Ala Asn Ile Met Gly Ser Trp Pro Tyr Val Phe
245 250 255
Val Cys Leu Ser Leu Asn Tyr Leu Gly Gln Gly Val Trp Ile Leu His
260 265 270
Asn Ala Ser Tyr His Ala Gly Asn Gly Asp Phe Asn Pro Phe Phe Glu
275 280 285
Val Val Pro Ser Asn Leu Arg Leu Phe Ala Ile Ala Leu Ala Thr Ile
290 295 300
Ala Ala Ile Ile Ala Ser Gln Ala Leu Ile Thr Gly Ser Phe Thr Leu
305 310 315 320
Val Ala Glu Ala Ser Ser Leu Lys Phe Leu Pro Arg Met Asn Ile Ile
325 330 335
Tyr Pro Ser Thr Glu Lys Gly Gln Ile Tyr Ile Pro Ser Ile Asn Lys
340 345 350
Met Ile Cys Val Val Thr Val Ala Ile Val Phe Leu Phe Arg Thr Ser
355 360 365
His His Met Glu Ala Ala Tyr Gly Leu Ala Ile Thr Val Thr Met Leu
370 375 380
Met Thr Thr Ile Leu Leu Phe Glu Tyr Leu Gly Lys Lys Gly Lys Pro
385 390 395 400
Leu Tyr Leu Arg Leu Ile Phe Leu Ile Ala Phe Ala Phe Ile Glu Gly
405 410 415
Met Phe Leu Ile Ser Ser Leu Thr Lys Phe Leu His Gly Gly Tyr Val
420 425 430
Thr Val Leu Ile Ala Gly Phe Ile Leu Ala Ile Met Tyr Val Trp Phe
435 440 445
Tyr Gly Asn Lys Ile Arg Asp Lys Arg Glu Ala Lys Asn Ala Tyr Val
450 455 460
Arg Leu Asp Glu Tyr Thr Glu Met Leu Thr Asp Leu Ser His Cys Glu
465 470 475 480
Asp Tyr Pro Val Tyr Ala Thr Asn Val Val Tyr Met Ala Lys Val Lys
485 490 495
Tyr Asn Lys Phe Ile Lys Arg Glu Val Leu Tyr Ser Ile Leu Asp Lys
500 505 510
Arg Pro Lys Arg Ala Lys Ala Tyr Trp Phe Val Thr Val Asn Val Thr
515 520 525
Asn Glu Pro Tyr Thr Ala Glu Tyr Ala Val Asn Thr Tyr Gly Thr Lys
530 535 540
Asn Val Ile Asn Val Gln Leu Tyr Leu Gly Phe Arg Lys Gln Thr Ser
545 550 555 560
Val Asn Val Tyr Leu Arg Gln Ile Val His Glu Leu Ile Ala Asp Gly
565 570 575
Thr Ile Glu Ala Gln Pro Gln Arg Phe Thr Thr Thr Pro Gly Arg Asp
580 585 590
Val Gly Asp Phe Ser Phe Val Ile Val Asn Asp Val Ile Ser Pro Leu
595 600 605
Thr Lys Leu Thr Gly Tyr Glu Lys Phe Met Val Glu Ala Arg Val Trp
610 615 620
Leu Gln Asn Leu Ser Ser Asn Pro Ala Ser Trp Phe Gly Leu Glu Tyr
625 630 635 640
Ala Asp Thr Val Val Glu Arg Val Pro Leu Ile Leu Gly Lys His Gln
645 650 655
Glu Ser Tyr Ile Lys Arg Ile Lys Pro Lys Lys
660 665
Claims (10)
1.一种生物活性多肽TVTMLMTTIL,其特征在于,其氨基酸序列为Thr-Val-Thr-Met-Leu-Met-Thr-Thr-Ile-Leu。
2.根据权利要求1所述的一种生物活性多肽TVTMLMTTIL,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TVTMLMTTIL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TVTMLMTTIL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TVTMLMTTIL的应用,其特征在于,所述生物活性多肽TVTMLMTTIL在制备具有抗炎功能的食品、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TVTMLMTTIL的应用,其特征在于,所述生物活性多肽TVTMLMTTIL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TVTMLMTTIL的应用,其特征在于,所述生物活性多肽TVTMLMTTIL在制备具有抗炎功能和抗衰老功能的食品、保健品或药物中的应用。
8.一种抗炎产品,其特征在于,包括如权利要求1所述生物活性多肽TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL的衍生物;所述的抗炎产品包括抗炎食品、抗炎保健品、抗炎药物或抗炎化妆品;所述生物活性多肽TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL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TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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。
10.一种具有抗炎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TVTMLMTTIL或所述生物活性多肽TVTMLMTTIL的衍生物;具有抗炎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TVTMLMTTIL的衍生物,是指在生物活性多肽TVTMLMTTIL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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