CN108358998B - 一种星虫肽及其在制备妊娠期高血压治疗药物中的应用 - Google Patents
一种星虫肽及其在制备妊娠期高血压治疗药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种星虫肽在制备妊娠期高血压治疗或预防产品中的应用，星虫肽的氨基酸序列为His‑Thr‑Arg‑Asp‑Gly。该星虫肽可以有效降低L‑亚硝酸左旋精氨酸甲酯所引起的妊娠期高血压大鼠的血压和尿蛋白，抑制妊娠期高血压大鼠的氧化应激指标的增加，还可以降低炎症标志分子的上调。星虫肽是一种可以有效干预妇女妊娠期产生的妊娠期高血压疾病的化合物。星虫肽对于具有妊娠期高血压疾病的人群‑孕妇的使用安全性高，具有无毒、低副作用的特点。可广泛应用于制药、保健品和食品中，用于预防和治疗。
Description
技术领域
本发明属于功能多肽筛选技术领域，具体涉及一种星虫肽及其在制备妊娠期高血压治疗药物中的应用。
背景技术
妊娠期高血压是一种妊娠期特有的产科严重疾病，主要表现为高血压、蛋白尿，是导致孕产妇和围产儿病死率升高的主要原因之一。近年来对其发病机制的研究认为，妊娠期孕妇体内异常的氧化应激是诱发妊娠期高血压的危险因素。氧化应激的毒性效应对孕妇的血管内皮细胞、细胞膜和血管内壁等造成严重损伤，使血压异常升高，此外妊娠期高血压的血管内过度炎症也导致内皮细胞损伤。但目前妊娠期高血压的临床治疗方法以硫酸镁解痉治疗，施用降压药如硝酸甘油、地平类药物等为主，达到直接降压目的，或利用丹参川芎嗪注射液等活血、低分子肝素抗凝血等，但这些手段并不能从根本上改变并修正引发妊娠高血压的因素。因此，基于氧化应激的病因分析，抗氧化结合降压方法不失为一种针对病因的缓解和治疗策略。
星虫是一种高蛋白低脂肪的海洋生物，氨基酸含量丰富、种类齐全，是一种优质的蛋白源，被称之为“动物人参”、“海洋冬虫夏草”。星虫肽被报道具有较好的抗氧化作用，将星虫肽在动物运动模型中做研究发现，星虫肽能显著提高大鼠血清、肝组织的、酶活性，降低肝组织水平及稳定血液中酶活性等，在体外能够有效清除羟基自由基和抑制亚油酸自氧化作用。但目前并没有使用星虫肽作为妊娠期高血压疾病的防治化合物。
发明内容
本发明所要解决的问题是针对妊娠期高血压治疗的方法匮乏、不治本，且治疗需谨慎等问题，而提供一种星虫肽在制备治疗妊娠期高血压产品的用途及应用方法。
本发明首先提供一种从星虫中筛选的多肽，其氨基酸序列为His-Thr-Arg-Asp-Gly(SEQ ID NO:1)；
本发明所提供的星虫肽在制备治疗妊娠期高血压疾病产品中的应用。
与现有技术相比，本发明的优点在于：将星虫肽制备成用于孕妇妊娠期高血压基本的相关产品，具有良好的防治效果。本发明填补了目前妊娠期高血压疾病治疗中没有针对病因的药物的问题。同时星虫肽来源于天然蛋白的酶解，具有无毒、低副作用，对孕妇这种人群的使用安全性高。而且其作用机制明确，可添加于食品、保健品或药品中，起到预防和治疗妊娠期高血压的作用，为治疗这类疾病提供基础。
附图说明
图1星虫肽对妊娠期高血压大鼠胎盘中的HO-1、NF-κB和ROCK II的表达变化的影响。A为HO-1，B为NF-κB，C为ROCK II。1为空白组，2为建模组，3为星虫肽组。
具体实施方式
氧化应激是妊娠期高血压重要的致病因素，孕妇体内代谢的显著变化，会促使超氧阴离子自由基及单线态氧等ROS过量产生，出现血浆中的MDA增高，SOD、HO-1降低等变化，而孕妇体内的氧化应激又会显著抑制NOS活性和NO的合成，导致了孕妇血压的异常升高。而且妊娠期高血压时，孕妇产生大量的炎症反应，导致炎症相关的细胞因子的表达增加，如NF-κB等。
本发明将酶解并纯化获得的序列为His-Thr-Arg-Asp-Gly的星虫肽溶解于生理盐水中，以25-50mg/d.kg体重的应用于以L-亚硝酸左旋精氨酸甲酯诱导所产生的妊娠期高血压怀孕大鼠，发现星虫肽具有明显的治疗妊娠期高血压疾病的作用。在大鼠怀孕同时灌喂星虫肽，饲养至怀孕第5天开始注射L-亚硝酸左旋精氨酸甲酯诱导形成妊娠期高血压的发生。在产仔前，大鼠血压明显降低，尿蛋白减少。血液中的MDA下降，NO和SOD升高，同时星虫肽明显下调了胎盘组织中的Rock II,NF-κB。
以下结合附图实施例对本发明作进一步详细描述。
实施例1
将星虫解剖，去除内脏，将星虫虫体清洗干净，按照虫体:去离子水＝1:20(m/V)的比例加入适量的去离子水，倒入组织捣碎机中，髙速搅拌捣碎，然后冰浴超声破碎。超声完成后，放入50℃水浴揽拌提取水溶性蛋白，随后用纱布粗过滤，去掉残渣，将溶液离心(6000rpm，15min)，收集上清液，将上清液于放入冷冻干燥机中干燥至成蛋白粉末。
采用Novozymes公司生产protemax蛋白质水解酶，酶与底物比浓度为(0.4AU:1g)的比例进行水解，先将1000ml星虫蛋白质提取溶液在恒温水浴锅加热至恒温，温度为50℃，pH调整为7.0左右，然后加入蛋白质水解酶，搅拌酶解4h。水解结束后，水浴锅温度迅速升至90℃，保持15min使酶灭活。酶灭活后冷却后过滤，过滤去除变性的蛋白酶沉淀物，再以截留分子量为3KDa的超滤器过滤，获得的分子量低于3KDa的肽溶液。
用1mol/l HCL溶液，将肽溶液pH值调整到2左右，上阳离子交换柱，先用蒸馏洗脱，充分地洗脱不吸附物质，然后采用2mol/l的氨水充分洗脱，直至茚三酮检测不到有肽与氨基酸为止。将洗脱得到的肽溶液冻干成肽粉，再配成50mg/ml的溶液，利用RP-HPLC进一步纯化，半制备柱Ultimate XB-C18，10*150mm，10μm。将收集得到的肽溶液浓缩冻干后，以itrap-MS鉴定为序列为His-Thr-Arg-Asp-Gly(SEQ ID NO:1)。
实施例2
怀孕SD大鼠，随机分为三组：正常对照组，L-亚硝酸左旋精氨酸甲酯(L-NAME)模型组，星虫肽灌胃组。合笼第六天，实验组动物灌胃50mg/d.kg.bw星虫肽，正常对照组、L-NAME组每天灌胃等量的生理盐水，直至结束；自合笼第10天，L-NAME组和实验组每天皮下注射L-亚硝酸左旋精氨酸甲酯125mg/d·kg·bw，正常对照组注射等量的生理盐水。在第21天时，测血压、尿蛋白。随后股动脉放血处死，收集各组大鼠腹主动脉血液，分离血清，检测血清中的过氧化物(MDA)、一氧化氮(NO)；超氧化物歧化酶(SOD)、一氧化氮合酶(NOS)酶活性。同时取胎盘组织，进行免疫组化检测胎盘组织中NF-κB、HO-1和Rock II蛋白表达。
孕鼠经L-NAME处理后尿蛋白升高22.48％，而收缩压升高34.66％，舒张压升高25.59％，说明建模成果。应用星虫肽灌胃处理后，尿蛋白和血压都下降，特别是血压下降非常显著(P<0.01),其中尿蛋白比建模组下降19.40％，收缩压下降27.31％，舒张压下降32.98％。说明星虫肽能改善妊娠期高血压孕鼠的两个典型症状。
血清中的各指标结果中，孕鼠经L-NAME处理后，MDA增高，NO出现显著降低，而SOD和NOS酶活都出现相应的下降，这些都是妊娠期高血压的典型变化。经星虫肽处理后，各指标都有所改善，MDA较建模组出现显著降低，NO、NOS和SOD酶活也出现回升，特别是SOD出现显著升高，增加2.09倍。说明星虫肽通过调节NO的合成体系，使血压得到恢复，同时发挥超强的抗氧化能力，使氧化应激得到缓解，抗氧化酶活增加(表1和表2)。
免疫组化结果显示(图1)，空白组HO-1在胎盘组织细胞胞浆中的表达明显，但模型组明显减少，而星虫肽组的表达量高于模型组。核因子-κB(nuclear factor kappa B,NF-κB)主要存在于胎盘组织的细胞滋养细胞，NF-κB在建模组细胞滋养细胞中可见大量棕黄色颗粒的阳性表达，而星虫肽组内仅可见少量阳性表达。而蛋白在建模组的胎盘组织中的胞浆中有明显表达，经星虫肽处理后，Rock II的表达明显下降。
表1：星虫肽对大鼠血压和尿蛋白含量的影响
注：星虫肽组与建模组比，*P<0.05；**P<0.01；建模组与空白组比，#P<0.05。
表2：星虫肽对大鼠血清氧化指标的影响
注：星虫肽组与建模组比，*P<0.05；**P<0.01；建模组与空白组比，#P<0.05。
Claims (4)
1.一种星虫肽，其特征在于，所述的星虫肽的序列为His-Thr-Arg-Asp-Gly。
2.权利要求1所述的星虫肽在制备降低妊娠期高血压疾病个体的胎盘氧化状态制品中的应用。
3.一种制品，其特征在于，所述的制品包含了药理有效浓度的权利要求1所述的星虫肽。
4.如权利要求3所述的制品，其特征在于，所述的制品为药物。
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