CN112933104B - 核苷酸的新用途 - Google Patents

核苷酸的新用途 Download PDF

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CN112933104B
CN112933104B CN202110145510.8A CN202110145510A CN112933104B CN 112933104 B CN112933104 B CN 112933104B CN 202110145510 A CN202110145510 A CN 202110145510A CN 112933104 B CN112933104 B CN 112933104B
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李勇
刘欣然
徐美虹
陈玉松
曾峥
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Abstract

本发明公开了核苷酸的一种新用途及在制备预防、治疗过敏性鼻炎等疾病的药物或缓解过敏性鼻炎症状的功能性食品中的用途。核苷酸是由CMP、AMP、UMP、GMP、IMP五种核苷酸的混合物。核苷酸分子量小，摄入人体吸收较快且生物利用率高。本发明发现了摄入核苷酸可减轻小鼠过敏性鼻炎症状，缓解由过敏引起的脾肿大，显著降低血清和鼻腔灌洗液中组胺水平，有效调节炎症因子，从而起到治疗过敏性疾病的作用。可用于制备预防、治疗过敏性鼻炎等疾病的药物或缓解过敏性鼻炎症状的功能性食品，并为膳食干预方式调节免疫功能提供了一种新途径。

Description

核苷酸的新用途
技术领域
本发明涉及药物开发技术领域，功能性食品技术领域，具体是核苷酸的新用途。
背景技术
过敏性疾病是指机体接触某种或多种致敏物质(过敏原)后产生大量抗体，从而引起组织或器官功能障碍或损伤的一类疾病，其主要包括过敏性鼻炎、哮喘、特应性皮炎、过敏性胃肠道疾病和食物过敏。过敏性疾病已成为一种普遍的公共健康问题，发病率正逐年增加，对患者造成了巨大的医疗负担。目前，过敏性疾病最主要的治疗方式是化学药物治疗，虽然在一定程度上可缓解病情，但药物治疗并不能改变过敏性疾病的进程，在停药之后也无长期持续药效，病情很容易复发，且长期使用化学药物治疗可能对机体产生负面影响，因而也就不能从根本上达到治愈的效果。因此，探索一种能够有效缓解或治疗过敏性疾病的有效方法显然十分必要。
通过研究发现，摄入核苷酸可减轻小鼠过敏性鼻炎症状，缓解由过敏引起的脾肿大，显著降低血清和鼻腔灌洗液中组胺水平，有效调节炎症因子，从而起到预防、治疗过敏性鼻炎的作用。若将此项技术应用于健康产业中可以充分满足过敏疾病患者的保健、医疗需求。
发明内容
本发明的目的在于提供一种分子量较低、吸收快的核苷酸制剂在制备预防、治疗过敏性鼻炎等疾病的药物或缓解过敏性鼻炎症状的功能性食品中的用途，为通过膳食补充剂来预防、治疗过敏性鼻炎等疾病提供一种新途径。与此同时，建立一种稳定有效、可重复的实验动物模型方法。
为实现上述发明目的，本发明采用以下技术方案：
本发明一方面提供了一种核苷酸在制备预防、治疗过敏性鼻炎药物中的应用。
本发明另一方面提供了一种核苷酸在缓解过敏性鼻炎症状的功能性食品中的应用。
上述技术方案中，进一步地，所述核苷酸是由五种5’单核苷酸或者其钠盐的形式的核苷酸混合物，各种核苷酸折合成CMP、AMP、UMP、GMP、IMP分子计总量为100％，其中各核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP23-78％、AMP6-44％、UMP7-40％、GMP7-51％、IMP为0、或大于0且不高于2.5％。
上述技术方案中，进一步地，各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP42-43％、AMP16-17％、UMP21-22％、GMP18％、IMP为0、或大于0且不高于2.5％。
上述技术方案中，进一步地，各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP43％、AMP17％、UMP21％、GMP18％、IMP1％。
上述技术方案中，进一步地，所述药物为粉剂、片剂、软硬胶囊或口服液。
上述技术方案中，进一步地，所述功能性食品为粉剂、液体饮料，优选奶粉、奶制品或烘焙制品。
上述技术方案中，进一步地，核苷酸显著降低有过敏性鼻炎症状小鼠血清、鼻腔灌洗液中组胺(Histamine，HIS)含量，使血清IgG、IgE、IL-4、IL-12显著降低，IL-10显著升高；所用实验动物模型为以特定量卵白蛋白(OVA)联合特定量氢氧化铝凝胶免疫佐剂致BALB/c小鼠过敏性鼻炎的模型。
本发明发现了现有物质——核苷酸，具有预防、治疗过敏性鼻炎等疾病的功能，发现了其在制备预防、治疗过敏性鼻炎等疾病的药物或缓解过敏性鼻炎症状的功能性食品中的用途。动物实验证实摄入核苷酸能够通过缓解由过敏引起的脾肿大，显著降低血清和鼻腔灌洗液中组胺水平，有效调节炎症因子，从而起到预防、治疗过敏性疾病的作用，表明其具有显著的预防、治疗过敏性鼻炎等疾病的功效。
附图说明
图1核苷酸对小鼠血清及鼻腔灌洗液中HIS含量的影响；
图2核苷酸对小鼠血清IgE含量的影响；
图3核苷酸对小鼠血清IgG含量的影响。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但不以任何方式限制本发明。
实施例1
1.本实施例核苷酸是由五种5’单核苷酸或者其钠盐的形式按照：CMP43％、AMP17％、UMP21％、GMP18％、IMP1％比例混合。
2.具体制备方式如下：
(1)将五种5’单核苷酸或者其钠盐分别进行检测，合格后备用。
(2)将质检合格的五种5’单核苷酸或者其钠盐过60目筛备用。
(3)按比例计算称取所需的各单核苷酸样品量，全部加入后进行总混，混合时间不低于40分钟。所得样品常温保存。
实施例2
本实施例核苷酸是由五种5’单核苷酸或者其钠盐的形式按照：CMP78％、AMP6％、UMP8％、GMP7％、IMP1％比例混合。制备方法同实施例1。
实施例3
本实施例核苷酸是由五种5’单核苷酸或者其钠盐的形式按照：CMP23％、AMP44％、UMP25％、GMP7％、IMP1％比例混合。制备方法同实施例1。
实施例4
本发明所述核苷酸是由五种5’单核苷酸或者其钠盐的形式按照CMP23％、AMP17％、UMP40％、GMP19％、IMP1％比例混合。制备方法同实施例1。
实施例5
本发明所述核苷酸是由五种5’单核苷酸或者其钠盐的形式按照CMP24％、AMP17％、UMP7％、GMP51％、IMP1％比例混合。制备方法同实施例1。
实验验证
一、材料与方法
1.样品：上述实施例1-5中所得的核苷酸样品。
2.实验动物：由北京大学医学部实验动物中心提供的6-8周龄BALB/c健康雌性小鼠(SPF级，实验动物使用许可证号：SYXK(京)2011-0039；实验动物生产许可证号：SCXK(京)2011-0012)，重18～22g，共50只，分笼饲养于北京大学医学部实验动物部，每笼5只，自由进食和饮水。动物室温度范围25℃±1℃，相对湿度50％～60％，室内照明控制在12h/12h光暗周期节律。
3.过敏性鼻炎动物模型建立：模型为卵白蛋白联合4％氢氧化铝凝胶免疫佐剂致小鼠过敏性鼻炎模型。具体流程分为两部分：(1)初始致敏：在第0天、第7天、第14天和第21天，向小鼠腹腔内注射含25μg卵白蛋白及2mg氢氧化铝凝胶的200μL生理盐水中致敏。(2)再次激发；在初始致敏后的第23、25和27天，向小鼠双侧鼻腔滴注含500μg卵白蛋白的生理盐水20μL，两侧鼻腔轮流滴注，每侧10μL。对照组用生理盐水代替。每次鼻腔激发时的20分钟内，观察记录小鼠打喷嚏及鼻瘙痒动作次数，模型组打喷嚏和鼻瘙痒次数显著高于对照组即视为模型建立成功。
4.分组与剂量：按体重将小鼠随机分为5个组，每组10只，分别为空白对照组、模型对照组、核苷酸低剂量组、核苷酸中剂量组、核苷酸高剂量组。空白对照组小鼠不经历造模过程，而其他组小鼠在模型建成后每日以固定时间灌胃给予各组相应受试物。核苷酸低剂量组给予0.3g/kg.bw核苷酸，核苷酸中剂量组给予0.6g/kg.bw核苷酸，核苷酸高剂量组给予1.2g/kg.bw核苷酸。模型对照组和空白对照组均给予等量无菌蒸馏水。干预周期为14天，期间自由进食和饮水。
5.主要仪器与试剂：Bio-Rad酶标仪(美国)；卵白蛋白(美国)，氢氧化铝凝胶佐剂(中国)，Elisa试剂盒(中国)。
6.实验方法：
6.1体重及脏器系数测定：灌胃14天后，称小鼠体重，麻醉取血后立即颈椎脱臼处死，取肝脏、肾脏、脾脏和胸腺，去尽筋膜，用滤纸吸干脏器表面血污并称重，计算各脏器系数。公式为脏器系数＝(脏器重量/体重)*100。
6.2血清及鼻腔灌洗液中组胺含量测定：灌胃14天后，小鼠麻醉后取血至1.5mL离心管中，静置离心并分离血清。用Elisa试剂盒检测血清中HIS含量。小鼠处死后断其头部，用1mL注射器吸取预冷的生理盐水从小鼠气管处小心***至鼻咽部，将生理盐水缓慢推出，用离心管在小鼠鼻孔处承接鼻腔灌洗液，离心并分离灌洗液上清。用Elisa试剂盒检测鼻腔灌洗液中HIS含量。
6.3血清中免疫蛋白测定：灌胃14天后，小鼠麻醉后取血至离心管中，静置离心并分离血清。用Elisa试剂盒检测血清中IgG和IgE的含量。
6.4血清中炎症因子测定：灌胃14天后，小鼠麻醉后取血至离心管中，静置离心并分离血清。用Elisa试剂盒检测血清中IL-4、IL-10和IL-12的含量。
7.统计方法：所有结果均以均数±标准差表示，统计检验采用SPSS 23.0软件进行单因素方差分析，以p<0.05作为差异具有统计学意义。
二、实施例1实验结果
1.核苷酸对小鼠体重及脏器系数的影响
由表1结果可见，各组小鼠的体重、肾脏系数、胸腺系数差异均无统计学意义(p>0.05)。过敏模型对照组肝脏系数较空白对照组有显著升高，而核苷酸干预后的三个组小鼠肝脏系数均较模型对照组显著降低，接近空白对照组水平。说明核苷酸干预可改善过敏小鼠可能发生的一些肝损伤症状。
过敏模型小鼠脾脏系数均显著高于空白对照组，但核苷酸低剂量组干预后小鼠脾脏系数较模型对照组有显著降低，说明核苷酸干预可减轻由过敏引起的脾肿大情况，对于过敏的治疗有一定的意义。
表1实施例1核苷酸对小鼠体重及重要脏器系数的影响(
Figure BDA0002930054340000041
n＝10)
Figure BDA0002930054340000042
Figure BDA0002930054340000051
注：a与空白对照组有相比有统计学差异，b与模型对照组相比有统计学差异。
由图1可见，模型对照组血清及鼻腔灌洗液中的HIS含量均显著高于空白对照组，说明模型建立非常成功，小鼠局部和全身的过敏反应明显。而核苷酸干预的高剂量组小鼠表现为血清HIS含量的显著降低；另一方面，在鼻腔灌洗液HIS含量中，核苷酸中剂量组和核苷酸高剂量组的HIS含量也显著降低。表明核苷酸的摄入具有一定治疗过敏的作用。
由图2可见，与模型对照组比较，核苷酸高剂量组可显著降低血清IgE含量，对于治疗过敏有显著的效果。
由图3可见，与模型对照组比较，核苷酸高剂量组可显著降低血清IgG含量，对于治疗过敏有显著的效果。
由表2可见，核苷酸高剂量组可显著降低过敏模型小鼠血清IL-4和IL-12的水平。
与空白对照组相比，模型对照组小鼠血清IL-10显著降低，而核苷酸高剂量组干预后小鼠血清IL-10水平显著高于模型对照组，其含量接近空白对照组健康小鼠。表明核苷酸干预对于纠正过敏小鼠血清炎症因子紊乱有很显著的作用。
表2实施例1核苷酸对小鼠血清炎症因子的影响(x±s，n＝10)
Figure BDA0002930054340000052
注：a与空白对照组有相比有统计学差异，b与模型对照组相比有统计学差异。
三、实施例2～5实验结果
由表3可见，实施例2～5的核苷酸高剂量组可显著降低过敏模型小鼠血清IL-4和IL-12的水平。
与空白对照组相比，模型对照组小鼠血清IL-10显著降低，而实施例2—5的核苷酸高剂量组干预后小鼠血清IL-10水平显著高于模型对照组，其含量接近空白对照组健康小鼠。表明核苷酸干预对于纠正过敏小鼠血清炎症因子紊乱有很显著的作用。
表3实施例2～5核苷酸对小鼠血清炎症因子的影响(x±s，n＝10)
Figure BDA0002930054340000061
由表4可见，实施例2～5的核苷酸高剂量组可显著降低过敏模型小鼠血清HIS和鼻腔HIS的含量。
表4实施例2～5核苷酸对小鼠血清HIS和鼻腔HIS的含量的影响(x±s，n＝10)
Figure BDA0002930054340000062
四、实验结论
本研究通过设立空白对照组、模型对照组作为对照组，探讨核苷酸的预防、治疗过敏性鼻炎等疾病的作用。动物实验结果表明，核苷酸可以通过缓解由过敏引起的脾肿大、显著降低血清和鼻腔灌洗液中组胺水平、有效调节炎症因子，从而起到治疗过敏性疾病的作用。表明其具有显著的治疗过敏性鼻炎等疾病的功效，具备作为一种新型治疗过敏性疾病药物的潜力，其适宜浓度范围为每天摄入0.6～1.2g/kg.bw。
对于任何熟悉本领域的技术人员而言，在不脱离本发明技术方案范围情况下，都可利用上述揭示的技术内容对本发明技术方案作出许多可能的变动和修饰，或修改为等同变化的等效实施例。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化及修饰，均应仍属于本发明技术方案保护的范围内。

Claims (4)

1.核苷酸作为唯一活性成分在制备治疗过敏性鼻炎药物中的应用；所述核苷酸是五种5’单核苷酸的混合物，各种核苷酸折合成CMP、AMP、UMP、GMP、IMP分子计总量为100％，其中各核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP23-78％、AMP6-44％、UMP7-40％、GMP7-51％、IMP为大于0且不高于2.5％。
2.根据权利要求1所述的应用，其特征在于，各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP42-43％、AMP16-17％、UMP21-22％、GMP18％、IMP为大于0且不高于2.5％。
3.根据权利要求2所述的应用，其特征在于，各种核苷酸有效百分含量以CMP、AMP、UMP、GMP、IMP分子计分别为：CMP43％、AMP17％、UMP21％、GMP18％、IMP1％。
4.根据权利要求1所述的应用，其特征在于，所述药物为粉剂、片剂、软硬胶囊或口服液。
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