CN114129713A - 乳铁蛋白活性肽或编码该活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用 - Google Patents
乳铁蛋白活性肽或编码该活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用 Download PDFInfo
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- CN114129713A CN114129713A CN202111397461.3A CN202111397461A CN114129713A CN 114129713 A CN114129713 A CN 114129713A CN 202111397461 A CN202111397461 A CN 202111397461A CN 114129713 A CN114129713 A CN 114129713A
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- lactoferrin
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Abstract
本发明公开了乳铁蛋白活性肽或编码该活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用,所述乳铁蛋白活性肽的氨基酸序列如Seq ID No.1~3中任一种所示或为Seq ID No.1~3中任一种所示的氨基酸序列经修饰、取代、缺失或添加至少一个氨基酸获得氨基酸序列,所述核苷酸序列如Seq ID No.4~6中任一种所示。本发明方案的乳铁蛋白活性肽具有良好的抗炎、抗氧化特性,其抗炎效果可达全长乳铁蛋白的10倍以上;本发明方案的活性肽源自天然蛋白,具有较低的毒性,可实现安全高效抗炎、抗氧化,具有良好的工业应用前景。
Description
技术领域
本发明属于生物医学技术领域,具体涉及乳铁蛋白活性肽或编码该活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用。
背景技术
慢性炎症参与人体多种疾病的发生发展,是多种疾病的致病基础。心、血管和淋巴管内表面的单层扁平上皮细胞,即血管内皮细胞,在血管生物学中起着至关重要的作用,如调节血管紧张度、止血、嗜中性粒细胞募集、激素运输和液体过滤等。血管炎症是导致内皮功能失调的关键性因素之一,与多种疾病密切相关,包括动脉粥样硬化、糖尿病、冠状动脉疾病、高血压和高胆固醇血症。目前,临床上针对炎症的治疗药物主要包括甾体类和非甾体类两种。然而这些药物易对人体健康产生一定影响,开发生物性药物通常可降低其对人体健康的不利影响,因此,开发生物活性产品作为传统化学药物作为抗炎药物的替代品成为了当前的研究热点,其具有广阔的应用前景。
正常生命过程中生物体会不断地产生自由基,适量的自由基能够维持生物体的正常生理代谢,但是过量的自由基会导致机体组织受到氧化胁迫,致使机体的氧化系统和抗氧化系统失衡,而导致机体组织中的细胞、蛋白和核酸等生物大分子发生氧化损伤,进而引发心血管以及衰老等问题,对机体的健康造成极大损害。因此,抗氧化作用对于维护机体健康具有极其重要的作用。目前,在医学上有多种抗氧化药物,但这些药物大多具有不同程度的副作用,不宜长期服用。
生物活性肽(Bioactive Peptides,BAP)是蛋白质中20种天然氨基酸以不同组成和排列方式构成的从二肽到复杂的线性、环形结构的不同肽类的总称,是源于蛋白质的多功能化合物。生物活性肽具有多种人体代谢和生理调节功能,易消化吸收,有促进免疫、激素调节、抗菌、抗病毒、降血压、降血脂等作用,其通常具有低毒、高效等优点,是当前国际食品界最热门的研究课题和极具发展前景的功能因子。
基于此,开发具有抗炎和/或抗氧化的生物活性肽具有重要意义。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种乳铁蛋白活性肽或编码该活性肽的核苷酸序列的新用途,能够应用于制备抗炎和/或抗氧化产品中。
根据本发明的一个方面,提出了乳铁蛋白活性肽或者编码所述乳铁蛋白活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用,所述乳铁蛋白活性肽的氨基酸序列如Seq ID No.1~3中任一种所示或为Seq ID No.1~3中任一种所示的氨基酸序列经修饰、取代、缺失或添加至少一个氨基酸获得氨基酸序列,所述核苷酸序列如Seq ID No.4~6中任一种所示。
根据本发明的一种优选的实施方式,至少具有以下有益效果:本发明方案的乳铁蛋白活性肽具有良好的抗炎、抗氧化特性,其抗炎效果可达全长乳铁蛋白的10倍以上;本发明方案的活性肽源自天然蛋白,具有较低的毒性,可实现安全高效抗炎、抗氧化,具有良好的工业应用前景。
在本发明的一些实施方式中,所述产品为药品或化妆品。可将本申请方案的活性肽制备成具有抗炎、抗氧化作用的药品或化妆品。
在本发明的一些实施方式中,所述药品的剂型为固体、半固体或液体的形式;优选为水溶液、非水溶液、混悬液或膏体;更优选地为片剂、胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
在本发明的一些实施方式中,所述药品的制备原料还可以包括药用辅料。
在本发明的一些优选实施方式中,所述药用辅料为本领域常规药用载体,可以为任意合适的生理学或药学上可接受的药物辅料;优选地,所述药用辅料选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种;更优选地,所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种;更优选地,所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种;更优选地,所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种;更优选地,所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种;更优选地,所述湿润剂选自十二烷基硫酸钠;更优选地,所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种;更优选地,所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种;更优选地,所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种;更优选地,所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
在本发明的一些实施方式中,所述抗炎包括抗由基因TNF-α、NF-κΒ、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、COX-2或白细胞介素-8(IL-8)表达引起的炎症。
在本发明的一些实施方式中,所述化妆品包括洗面奶、化妆水、护肤乳、面膜、面霜、粉底、隔离乳或防晒乳中的至少一种。
在本发明的一些实施方式中,所述产品为功能性食品。可将本申请方案的活性肽制备成具有抗炎、抗氧化作用的功能性食品。
在本发明的一些更优选的实施方式中,所述功能性食品的形式包括汤剂、饮料、糖果、口服液、胶囊剂、片剂和粉剂中的至少一种。
根据本发明的再一个方面,提出了一种抗炎和/或抗氧化产品,所述产品中含有乳铁蛋白活性肽或者编码所述乳铁蛋白活性肽的核苷酸序列,所述乳铁蛋白活性肽的氨基酸序列如Seq ID No.1~3中任一种所示或为Seq ID No.1~3中任一种所示的氨基酸序列经修饰、取代、缺失或添加至少一个氨基酸获得氨基酸序列,所述核苷酸序列如Seq ID No.4~6中任一种所示。
具体地,所述核苷酸序列如下:tacaagttaa gaccagttgc tgctgaagtt tacggtactgaaagacaacc tagaactcat tattacgctg ttgccgttgt taagaagggt ggttcttttc aattgaacgaattgcaaggt ttgaagtctt gtcataccgg tttgagaaga actgctggtt ggaatgttcc aatcggtactttaagaccat tcttgaattg gactggtcca ccagaaccta ttgaagctgc tgttgctaga tttttctctgcttcttgtgt tccaggtgct gataagggtc aatttccaaa tttgtgtaga ttgtgtgctg gtactggtgaaaacaagtgt gctttttcat ctcaagaacc atacttctct tactccggtg cttttaagtg tttgagagatggtgctggtg atgttgcttt cattagagaa tctaccgttt tcgaagattt gtccgatgaa gctgaaagagatgaatacga attattgtgc ccagacaaca ctagaaagcc agttgataag ttcaaggatt gccatttggctagagttcca tctcatgctg ttgttgcaag atctgttaac ggtaaagaag atgccatttg gaacttgttgagacaagctc aagaaaagtt cggtaaggat aagtctccaa agttccaatt attcggttct ccatctggtcaaaaggactt gttgtttaag gattccgcta tcggtttttc tagagttcca ccaagaattg actctggtctatatttgggt tctggttact tcaccgctat ccaaaatttg agaaagtccg aagaagaagt tgctgctagaagagctagag ttgtttggtg tgcagttggt gaacaagaat tgagaaagtg caatcaatgg tccggtttgtctgaaggttc tgttacttgt tcttctgctt ctactaccga agattgcatt gctttggttt tgaaaggtgaagctgatgcc atgtctttgg atgaaggtta tgtttacact gctggtaagt gtggtttggt tccagttttggctgaaaact acaagtccca acaatcttct gatccagatc caaactgtgt tgatagacca gttgaaggttatttggctgt tgctgttgtc agaagatctg atacttcttt gacttggaac tccgttaagg gtaaaaagtcatgtcatact gctgttgata gaacagccgg ttggaatatt cctatgggtt tgttgtttaa tcaaaccggttcttgcaagt tcgacgaata cttttctcaa tcttgtgctc caggttcaga tccaagatct aatttgtgtgctttgtgcat cggtgatgaa caaggtgaaa acaaatgcgt tccaaactcc aacgaaagat attacggttacactggtgct ttcagatgc(如Seq ID No.4所示)
或tacaagttaa gaccagttgc tgctgaagtt tacggtactg aaagacaacc tagaactcattattacgctg ttgccgttgt taagaagggt ggttcttttc aattgaacga attgcaaggt ttgaagtcttgtcataccgg tttgagaaga actgctggtt ggaatgttcc aatcggtact ttaagaccat tcttgaattggactggtcca ccagaaccta ttgaagctgc tgttgctaga tttttctctg cttcttgtgt tccaggtgctgataagggtc aatttccaaa tttgtgtaga ttgtgtgctg gtactggtga aaacaagtgt gctttttcatctcaagaacc atacttctct tactccggtg cttttaagtg tttgagagat ggtgctggtg atgttgctttcattagagaa tctaccgttt tcgaagattt gtccgatgaa gctgaaagag atgaatacga attattgtgcccagacaaca ctagaaagcc agttgataag ttcaaggatt gccatttggc tagagttcca tctcatgctgttgttgcaag atctgttaac ggtaaagaag atgccatttg gaacttgttg agacaagctc aagaaaagttcggtaaggat aagtctccaa agttccaatt attcggttct ccatctggtc aaaaggactt gttgtttaaggattccgcta tcggtttttc tagagttcca(如Seq ID No.5所示)
或caatggtgtg ctgtttctca acctgaagct actaagtgtt ttcaatggca aagaaacatgagaaaggtta gaggtccacc agtttcttgc attaagagag attctccaat ccaatgcatt caagctattgctgaaaacag agctgatgct gttactttgg atggtggttt tatctatgaa gctggtttgg ctccatacaagttaagacca gttgctgctg aagtttacgg tactgaaaga caacctagaa ctcattatta cgctgttgccgttgttaaga agggtggttc ttttcaattg aacgaattgc aaggtttgaa gtcttgtcat accggtttgagaagaactgc tggttggaat gttccaatcg gtactttaag accattcttg aattggactg gtccaccagaacctattgaa gctgctgttg ctagattttt ctctgcttct tgtgttccag gtgctgataa gggtcaatttccaaatttgt gtagattgtg tgctggtact ggtgaaaaca agtgtgcttt ttcatctcaa gaaccatacttctcttactc cggtgctttt aagtgtttga gagatggtgc tggtgatgtt gctttcatta ga(如Seq IDNo.6所示)。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1:本发明实施例中全长乳铁蛋白及活性肽的表达情况分析图:表达量的SDS-PAGE电泳图(A)、纯化活性肽样品实物图及其铁饱和度百分比(B)、全长乳铁蛋白flHLF的结构(C)、活性肽rtHLF4的蛋白结构(D)、活性肽rteHLF1的蛋白结构(E)、活性肽rpHLF2的蛋白结构(F)和乳铁蛋白及乳铁蛋白衍生片段的序列长度对比(铁结合位点:61、122、118、186、247和93(黑色短划线表示);N-糖基化位点:138、479和624(灰色虚线表示),图中,M、标准蛋白;1、flHLF;2、rtHLF4;3、rteHLF1;4、rpHLF2;图(B)为重复三次测定的结果平均值;
图2:本发明实施例中的重组乳铁蛋白及活性肽的溶血效率分析结果图:不同浓度的全长乳铁蛋白flHLF的溶血效率分析实物图及柱状图(A)、不同浓度的活性肽rtHLF4的溶血效率分析实物图及柱状图(B)、不同浓度的活性肽rtHLF1的溶血效率分析实物图及柱状图(C)和不同浓度的活性肽rpHLF2的溶血效率分析实物图及柱状图(D),图中,n=10,阴性对照为PBS,***p≤0.05,p≤0.01和***p≤0.001;
图3:本发明实施例中人结肠成纤维细胞和结直肠癌细胞中不同基因的定量PCR结果图:与管家基因ACTB(蛋白浓度:10μM/0.1μM/0.005μM)比较结果图(A)、TNF-α在CCD-841-CON和HT29细胞中的基因表达水平(B)、Il-1β在CCD-841-CON和HT29细胞中的基因表达水平(C)、Il-6在CCD-841-CON和HT29细胞中的基因表达水平(D)、COX2在CCD-841-CON和HT29细胞中的基因表达水平(E)、IL-8在CCD-841-CON和HT29细胞中的基因表达水平(F),图中,1、基因诱导的CCD-841-CON;2、flHLF-10μM;3、rtHLF4-10μM;4、rtHLF1-10μM;5、rpHLF2-10μM;6、基因诱导的HT29细胞;7、flHLF-10μM;8、rtHLF4-10μM;9、rtHLF1-10μM;10、rpHLF2-10μM;
图4:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中TNF-α基因的表达情况及对应蛋白的Western blot结果图;
图5:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中NF-κΒ基因的表达情况及对应蛋白的Western blot结果图;
图6:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中IL-1β基因的表达情况及对应蛋白的Western blot结果图;
图7:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中IL-6基因的表达情况及对应蛋白的Western blot结果图;
图8:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中COX-2基因的表达情况及对应蛋白的Western blot结果图;
图9:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-18co中IL-8基因的表达情况及对应蛋白的Western blot结果图;
图10:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中TNF-α基因的表达情况及对应蛋白的Western blot结果图;
图11:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中NF-κΒ基因的表达情况及对应蛋白的Western blot结果图;
图12:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中IL-1β基因的表达情况及对应蛋白的Western blot结果图;
图13:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中IL-6基因的表达情况及对应蛋白的Western blot结果图;
图14:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中COX-2基因的表达情况及对应蛋白的Western blot结果图;
图15:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞CCD-841-CON中IL-8基因的表达情况及对应蛋白的Western blot结果图;
图16:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中TNF-α基因的表达情况及对应蛋白的Western blot结果图;
图17:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中NF-κΒ基因的表达情况及对应蛋白的Western blot结果图;
图18:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中IL-1β基因的表达情况及对应蛋白的Western blot结果图;
图19:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中IL-6基因的表达情况及对应蛋白的Western blot结果图;
图20:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中COX-2基因的表达情况及对应蛋白的Western blot结果图;
图21:本发明实施例中不同浓度flHLF、rtHLF4、rteHLF1和rpHLF2诱导人结肠上皮细胞HT29中IL-8基因的表达情况及对应蛋白的Western blot结果图;
图22:本发明实施例中推测的活性肽rtHLF4、rthlf1和rpHLF2的抗炎机制图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,均可从商业途径得到的试剂和材料。
本发明的描述中,参考术语“一个实施例”、“一些实施例”、“示意性实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
实施例
本实施例提供了三种乳铁蛋白(flHLF)活性肽在制备抗炎和/或抗氧化产品中的应用,其中,上述乳铁蛋白活性肽分别为rtHLF4、rteHLF1和rpHLF2,其氨基酸序列如下:
YKLRPVAAEVYGTERQPRTHYYAVAVVKKGGSFQLNELQGLKSCHTGLRRTAGWNVPIGTLRPFLNWTGPPEPIEAAVARFFSASCVPGADKGQFPNLCRLCAGTGENKCAFSSQEPYFSYSGAFKCLRDGAGDVAFIRESTVFEDLSDEAERDEYELLCPDNTRKPVDKFKDCHLARVPSHAVVARSVNGKEDAIWNLLRQAQEKFGKDKSPKFQLFGSPSGQKDLLFKDSAIGFSRVPPRIDSGLYLGSGYFTAIQNLRKSEEEVAARRARVVWCAVGEQELRKCNQWSGLSEGSVTCSSASTTEDCIALVLKGEADAMSLDEGYVYTAGKCGLVPVLAENYKSQQSSDPDPNCVDRPVEGYLAVAVVRRSDTSLTWNSVKGKKSCHTAVDRTAGWNIPMGLLFNQTGSCKFDEYFSQSCAPGSDPRSNLCALCIGDEQGENKCVPNSNERYYGYTGAFRC(rtHLF4,SEQ ID No.1);
YKLRPVAAEVYGTERQPRTHYYAVAVVKKGGSFQLNELQGLKSCHTGLRRTAGWNVPIGTLRPFLNWTGPPEPIEAAVARFFSASCVPGADKGQFPNLCRLCAGTGENKCAFSSQEPYFSYSGAFKCLRDGAGDVAFIRESTVFEDLSDEAERDEYELLCPDNTRKPVDKFKDCHLARVPSHAVVARSVNGKEDAIWNLLRQAQEKFGKDKSPKFQLFGSPSGQKDLLFKDSAIGFSRVP(rteHLF1,SEQ ID No.2);
QWCAVSQPEATKCFQWQRNMRKVRGPPVSCIKRDSPIQCIQAIAENRADAVTLDGGFIYEAGLAPYKLRPVAAEVYGTERQPRTHYYAVAVVKKGGSFQLNELQGLKSCHTGLRRTAGWNVPIGTLRPFLNWTGPPEPIEAAVARFFSASCVPGADKGQFPNLCRLCAGTGENKCAFSSQEPYFSYSGAFKCLRDGAGDVAFIR(rpHLF2,SEQIDNo.3)。
为验证其抗炎、抗氧化效果进行如下实验:
1、制备上述活性肽
1)基因克隆
利用引物从全长乳铁蛋白基因中扩增出rtHLF4、rthlf1和rpHLF2基因片段。引物序列如下:rtHLF4-上游:5'-aaaaaagctagcgaagttaagaccagttgctgc-3',下游:5'-aaaaaactcgagcatctgaaagcaccagtgta-3';rteHLF1-上游:5'-cgggatcctacaagttaagaccagttg-'3,下游:5'-ccctcgagtggaactctagaaaaaccg-'3;rpHLF2-上游:5'-cgggatcccaatggtgtgctgtt-'3,下游:5'-ccctcgagtctaatgaaagcaacatc-'3。这些片段被酶切并连接到pET28b表达载体中。所有这些结构都通过通用引物的自动DNA测序得到了证实。
2)蛋白质纯化
质粒pET28b-flHLF、pET28b-rtHLF4、pET28b-rteHLF1、pET28b-rpHLF2转化大肠杆菌BL21(DE3),37℃220rpm,OD600nm=0.6,16℃160rpm,0.5mM IPTG诱导20小时。收集细胞,用裂解缓冲液(50mM Na2HPO4,300mM NaCl,10%甘油,1mM二硫苏糖醇,pH 7.5)重悬,并用乳化剂c3(Avestin)裂解。用固定化金属离子亲和层析镍氮三乙酸(IMAC Ni-NTA)纯化表达的乳铁蛋白全长和活性肽(rtHLF4、rthlf1和rpHLF2)。乳铁蛋白全长和活性肽rtHLF4纯化,然后用Hiload Superdex 200大小排斥柱色谱(GE Healthcare)。活性肽rteHLF1和rpHLF2纯化,然后用Hiload Superdex 75大小排斥柱层析(GE Healthcare)。纯化后的蛋白经浓缩后-80℃保存。
3)重组工程活性肽的表达与鉴定
通过凝胶电泳(SDS-PAGE)验证上述重组表达的活性肽,结果如图1(A)所示,从图中可以看出,重组表达的蛋白大小正确。不同活性肽的铁饱和度曲线如图1(B)所示,从图中可以看出,flHLF的截断扰乱了活性肽的铁结合位点,且由柱状图上方的实物图可以看出,纯化蛋白的颜色进一步支持了这一观察。rtHLF4的结合能力是flHLF的一半,证明了乳铁蛋白C端广泛的截断导致结合功能的丧失。rpHLF2和rteHLF1都不携带C端叶,只包含部分N端叶。这些rpHLF2和rteHLF1的截断状态完全消除了这两个蛋白的结合能力。
通过I-TASSER服务器(https://zhanggroup.org//I-TASSER/)预测人乳铁蛋白的三维结构,结果如图1(C~F)所示,从图中可以看出,这三种蛋白质的模型结构与观察结果一致,即由于结构扰动,特别是在铁离子结合袋中,无法结合铁离子。传统上,乳铁蛋白的两个叶依赖于保守的残基,包括两个酪氨酸,一个组氨酸和一个天冬氨酸,以及另外两个在隔离金属离子中起作用的碳酸盐相互作用残基。rtHLF4和rteHLF1都保留了3个缺失D63的保守残基,而rpHLF2保留了3个缺失H249的保守残基(图1G)。
2、重组乳铁蛋白的溶血效率测定
采集健康志愿者(年龄在20~40岁之间,两周未服用任何非甾体抗炎药物)的新鲜血液,与等量无菌Alsever溶液(2%葡萄糖,0.8%柠檬酸钠,0.5%柠檬酸,0.42%氯化钠)混合。血液3000rpm离心5分钟。用生理盐水(0.9%w/v NaCl)重悬细胞微球制备浓缩细胞株。细胞浆用等生理盐水稀释10倍以达到工作浓度。在蛋白缓冲液中制备不同浓度的flHLF/rtHLF4/rteHLF1/rpHLF2蛋白(100μM、80μM、50μM、30μM、10μM、8μM、5μM、3μM、1μm),分别加入1mL磷酸盐缓冲液、2mL低钾素和0.5mL HRBC(人红细胞)悬液。细胞悬液37℃孵育30min,3000rpm离心20min,在560nm分光光度法测定上清液中的血红蛋白含量。以吲哚美辛(100μg/mL)为标准品。假设对照组产生的溶血率为100%,计算溶血率。HRBC膜稳定或保护的百分率计算公式如下:百分率保护=100-(蛋白处理样品的OD值/对照样品OD值)*100)。
溶血试验主要研究人红细胞的膜稳定性,类似于炎症过程中溶酶体膜稳定性被扰乱。使用溶血分析来阐明分离的活性肽的抗炎活性,结果发现上述操作制得的重组乳铁蛋白和活性肽的存在能够阻止吲哚美辛诱导的红细胞溶解。同时还发现重组flHLF在80μM以上的最低抑制浓度为50%(MIC50),表明全长乳铁蛋白具有抗炎活性(见图2(A))。截断片段rtHLF4在MIC50高于5μM时表现出最突出的细胞裂解预防作用,这比flHLF低一个数量级(见图2(B))。由图2(C)可以看出,活性肽rtHLF1的MIC50大于100μM;另一方面,rpHLF2显示了比flHLF有所改善,其中MIC50高于50μM(见图2D)。
3、细胞活性和活性氧(ROS)生成测定
为研究flHLF和各种活性肽对细胞活力和ROS生成的影响,使用非恶性人结肠成纤维细胞进行细胞活性,结直肠癌细胞进行细胞活性和ROS生成测定。人非癌结肠成纤维细胞CCD-841-CON和CCD-18co,HT29人结直肠腺癌细胞取自美国型培养收集物(ATCC,Manassas,VA,USA)。CCD-841-CON和CCD-18co在Eagle’s Minimum Essential培养基(WISENT,320-006-CL)中培养,HT29细胞在McCoy’s 5A培养基(CELL COOK,CM2002)中培养。所有细胞培养基均添加1%抗生素(青霉素/链霉素)和10%胎牛血清(v/v)。所有细胞培养保持在37℃、5%CO2的环境中。
1)细胞活力分析
将CCD-841-CON、CCD-18co和HT29细胞接种于96孔板中,培养24小时使细胞附着。用全长乳铁蛋白(flHLF)、rtHLF4、rthlf1和rpHLF2孵育培养至3h、24h时间点。使用CellTiter Aqueous One Solution Kit(美国Promega)进行细胞活力测定。抽吸细胞培养液,磷酸缓冲液(PBS)冲洗细胞,MTS在37℃5%CO2中孵育1-4h。加入10%十二烷基硫酸钠(SDS)结束反应。在490nm的吸光度波长下读取所有孔。以荧光强度为100%计算对照组的相对细胞活力,进行了三个独立的实验。
2)活性氧(ROS)生成测定
将CCD-841-CON、CCD-18co和HT29细胞接种于96孔板,培养24小时。用TNF-α(10ngmL-1)对CCD-841-CON和CCD-18co细胞进行ROS诱导,所有培养物分别用flHLF、rtHLF4、rthlf1和rpHLF2处理24小时。活性氧测定试剂盒(Beyotime,中国)用于活性氧测定。用PBS洗涤细胞两次,然后用DCFH-DA在37℃孵育20分钟,用酶标仪在488nm激发和525nm发射下测量每孔的荧光强度。以荧光强度为100%计算对照组的相对ROS生成,进行了三个独立的实验。
上述细胞活力分析和活性氧生成测定结果如下表1所示:
表1
从上表可以看出,flHLF、rteHLF1、rpHLF2和rtHLF4都不能抑制成纤维细胞CCD-841-CON和CCD-18co细胞株的细胞生长,这表明flHLF和各种活性肽对正常健康细胞不构成任何毒性。flHLF和不同活性肽对肿瘤坏死因子-α(TNF-α)诱导的ROS生成的抑制性能研究表明,rpHLF2和rtHLF4对ROS生成的抑制效果更好。这种抑制表明这些蛋白质具有所需的抗炎活性。在TNF-α诱导的成纤维细胞中,rtHLF4对ROS生成的抑制程度最高,与未处理组相比,用10mM的多肽处理后,ROS生成的减少超过40%。在HT29细胞中,当处理0.1mM的rtHLF4时,rtHLF4对ROS生成的抑制程度最高。另外两种多肽rteHLF1和rpHLF2能够在两个成纤维细胞中降低10~20%的ROS生成,其中rteHLF1表现得和flHLF一样好。同样,在HT29细胞培养中,除了rteHLF1外,这一趋势也很明显,rteHLF1蛋白对ROS的生成没有抑制作用。这些ROS水平的变化产生了一种缓冲液,可以对抗对健康结肠细胞造成的直接氧化损伤。因此,本发明方案多肽在抗氧化产品中具有良好的应用前景。
4、重组工程活性肽的抗炎机制研究
为了全面了解调控上述活性肽的抗炎机制,通过实时逆转录聚合酶链反应对ROS产生相关的各种生物标志物和关键炎症相关基因的转录组水平进行研究。此外,还通过细胞内蛋白的western blot进一步研究了这些基因的表达水平。
1)实时逆转录聚合酶链反应(RT-PCR)操作步骤
将CCD-841-CON、CCD-18co和HT29细胞接种于6孔板中培养24小时。用乳铁蛋白flHLF、活性肽rtHLF4、rthlf1和rpHLF2处理细胞24小时。在CCD-841-CON和CCD-18co细胞中,使用10ng mL-1TNF-α诱导炎症。阴性(仅细胞)和阳性(TNF-α)对照组。按照制造商的要求,使用Super Total RNAExtraction Kit(Promega,USA)提取三个井中的RNA。对于cDNA的合成,使用GoScriptTM反转录系统(Promega,USA),根据制造商的说明书,将每个样品的1μg RNA反转录为cDNA。随后,将20ng cDNA与特异性引物混合,使用FasStartUniversal SYBR Green Master(ROX)(Promega),使用ABI StepOne Plus Real-time PCRSystem(Applied Biosystems,Foster City,CA,USA)进行定量PCR(qPCR)。以β肌动蛋白(ACTB)作为内参基因,分析核因子κB(NF-κB)、肿瘤坏死因子-α(TNF-α)、白介素1β(IL-1β)、白介素6(IL-6)、白介素8(IL-8)和环氧合酶-2(COX-2)的mRNA表达。实验过程中使用的引物序列见表2。使用经典的2-ΔΔCt方法计算相对于对照组的数据。
表2
2)免疫印迹操作步骤
western blot检测蛋白表达水平。将细胞接种于6孔板,用乳铁蛋白flHLF、rtHLF4、rthlf1、rpHLF2孵育24小时。用PBS洗涤细胞,并用RIPA缓冲液(0.6057g Tris碱,0.877gNaCl,10mL Non-ident P40,5mL 10%脱氧胆酸钠,1mL 10%十二烷基硫酸钠,pH设置为7.5,用H2O调节至100mL)裂解处理30min后,离心,收集上清液。20μL的全细胞提取物经十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,转移到聚偏二氟乙烯(PVDF)膜上。用5%的非脂乳阻断膜,然后在一抗中孵育:ACTB(Abcam,UK,ab213262),NF-KB(Abcam,UK,ab76302),TNF-α(Abcam,UK,ab183218),IL-1β(Abcam,UK,ab216995),IL-6(Abcam,UK,ab233706),IL-8(Abcam,UK,ab235584)和COX-2(Abcam,UK,ab179800)在4℃过夜。然后用二抗(Abcam,UK,ab6721)孵育膜2h。采用增强化学发光(ECL)法观察印迹。
转录组水平进行研究结果如图3(A)所示,为了响应ROS的产生,监测TNF-α的水平。在抗炎活性研究中,广泛研究了转录因子NF-κΒ以及相应的导致血管生成的基因(白细胞介素-6(IL-6)、白细胞介素-8(IL-8))和细胞增殖(IL-6,COX2)的mRNAs相对表达量,此外,还研究了NF-κΒ的调控元件,如白细胞介素-1β(IL-1β),结果如图3(B~G)所示)。
由图3可以看出,经flHLF处理的结肠成纤维细胞和各种活性肽显示TNF-α和其他炎症相关基因的水平下调。在四种不同的蛋白或活性肽中,rtHLF4的保护效果最好,而其他两种活性肽与flHLF水平相当。western blot结果如图4~15所示。与flHLF处理相比,rtHLF4处理成纤维细胞时,TNF-α(见图3(B)、图4和图10)和IL-6(见图3(E)、图7和图13)的蛋白水平降低了约50%,NF-κΒ降低了30%(见图3(C)、图5和图11),IL-8降低了10%(见图3(G)、图9和图15)。因此,本发明方案序列的活性肽片段均能抑制ROS的产生和抑制炎症。尤其是rtHLF4,可以使用较低浓度的蛋白质诱发治疗反应,同时从治疗中产生较高的反应。
在结直肠癌细胞系HT29中,flHLF和各种活性肽的使用通过抑制血管生成和细胞增殖来触发ROS生成的下调,同时通过抑制血管生成和细胞增殖来防止炎症。与flHLF相比,经rtHLF4处理后,与血管新生相关的IL-6和与细胞增殖相关的IL-8的表达均降低了20%(见图16~21)。同样,与flHLF相比,rtHLF4表现出NF-κΒ表达水平低20%(见图3(C)和图17),IL-Iβ表达水平低30%(见图3(D)和图18),COX-2表达水平低60%(见图3(F)和图20)。
通过上述数据,推测出本发明方案的活性肽的抗炎作用机理如图22所示,TNF-α通过caspase-8的激活诱导ROS的产生,导致线粒体外膜渗透(MOMP)。MOMP释放激活caspase-9的ROS和细胞色素C。caspase-8和-9都负责激活caspase-3,导致细胞凋亡。生成的ROS物种还可以激活p50/p65复合物,诱导COX2表达。炎症反应中COX-2的过度表达通常会导致前列腺素的产生。由此表明,本发明方案的活性肽能够抑制TNF-α的表达。
综上所述,本发明方案的活性肽rtHLF4、rthlf1和rpHLF2对非恶性结肠成纤维细胞和结直肠癌细胞均具有良好的抗炎和抗氧化性能。通过研究处理后的细胞活性氧(ROS)的产生和细胞增殖,证明了本发明方案的活性肽都具有抗炎和抗氧化性能,其中rtHLF4的抗炎效果是flHLF的10倍。且通过对抗炎机制的进一步研究发现经活性肽处理的结肠成纤维细胞系和结直肠癌细胞均显示ROS和关键炎症相关基因的产生水平下调。
需要说明的是,上述实施例仅给出了制备本发明方案活性肽的一种常规制备方式,也可用其他常规制备方法制备得到或直接采购得到。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
序列表
<110> 南方科技大学
<120> 乳铁蛋白活性肽或编码该活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用
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<210> 4
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gctgaaaact acaagtccca acaatcttct gatccagatc caaactgtgt tgatagacca 1080
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<211> 720
<212> DNA
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tacaagttaa gaccagttgc tgctgaagtt tacggtactg aaagacaacc tagaactcat 60
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ttgaagtctt gtcataccgg tttgagaaga actgctggtt ggaatgttcc aatcggtact 180
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tttttctctg cttcttgtgt tccaggtgct gataagggtc aatttccaaa tttgtgtaga 300
ttgtgtgctg gtactggtga aaacaagtgt gctttttcat ctcaagaacc atacttctct 360
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<211> 612
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<213> 人工序列(Artificial Sequence)
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caatggtgtg ctgtttctca acctgaagct actaagtgtt ttcaatggca aagaaacatg 60
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caacctagaa ctcattatta cgctgttgcc gttgttaaga agggtggttc ttttcaattg 300
aacgaattgc aaggtttgaa gtcttgtcat accggtttga gaagaactgc tggttggaat 360
gttccaatcg gtactttaag accattcttg aattggactg gtccaccaga acctattgaa 420
gctgctgttg ctagattttt ctctgcttct tgtgttccag gtgctgataa gggtcaattt 480
ccaaatttgt gtagattgtg tgctggtact ggtgaaaaca agtgtgcttt ttcatctcaa 540
gaaccatact tctcttactc cggtgctttt aagtgtttga gagatggtgc tggtgatgtt 600
gctttcatta ga 612
Claims (10)
1.乳铁蛋白活性肽或者编码所述乳铁蛋白活性肽的核苷酸序列在制备抗炎和/或抗氧化产品中的应用,其特征在于:所述乳铁蛋白活性肽的氨基酸序列如Seq ID No.1~3中任一种所示或为Seq ID No.1~3中任一种所示的氨基酸序列经修饰、取代、缺失或添加至少一个氨基酸获得氨基酸序列,所述核苷酸序列如Seq ID No.4~6中任一种所示。
2.根据权利要求1所述的应用,其特征在于:所述产品为药品或化妆品。
3.根据权利要求2所述的应用,其特征在于:所述药品的剂型为固体、半固体或液体的形式;优选为水溶液、非水溶液、混悬液或膏体;更优选为片剂、胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
4.根据权利要求2所述的应用,其特征在于:所述药品的制备原料还可以包括药用辅料。
5.根据权利要求4所述的应用,其特征在于:所述药用辅料选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种。
6.根据权利要求5所述的应用,其特征在于:所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种;更优选地,所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种;更优选地,所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种;更优选地,所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种;更优选地,所述湿润剂选自十二烷基硫酸钠;更优选地,所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种;更优选地,所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种;更优选地,所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种;更优选地,所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
7.根据权利要求2所述的应用,其特征在于:所述化妆品包括洗面奶、化妆水、护肤乳、面膜、面霜、粉底、隔离乳或防晒乳中的至少一种。
8.根据权利要求1所述的应用,其特征在于:所述产品为功能性食品。
9.根据权利要求8所述的应用,其特征在于:所述功能性食品的形式包括汤剂、饮料、糖果、口服液、胶囊剂、片剂和粉剂中的至少一种。
10.一种抗炎和/或抗氧化产品,其特征在于:所述产品中含有乳铁蛋白活性肽或者编码所述乳铁蛋白活性肽的核苷酸序列,所述乳铁蛋白活性肽的氨基酸序列如Seq ID No.1~3中任一种所示或为Seq ID No.1~3中任一种所示的氨基酸序列经修饰、取代、缺失或添加至少一个氨基酸获得氨基酸序列,所述核苷酸序列如Seq ID No.4~6中任一种所示。
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