CN106913858B - 麒麟菜多肽防治肺纤维化的应用 - Google Patents
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Abstract
本发明公开了麒麟菜多肽在制备防治肺纤维化的药物或保健品中的应用。所述应用包括作为防治肺纤维化药物和保健品组分,或利用麒麟菜多肽组份作为防治肺纤维化药物前体改造,或与治疗肺纤维化药物联合应用治疗肺纤维化。本发明从麒麟菜中纯化获得的麒麟菜多肽组份,能够显著地抑制肺纤维化形成,具有显著的防治肺纤维化功能,在肺纤维化防治方面具有重要的应用价值和前景。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及麒麟菜多肽防治肺纤维化的应用。
背景技术
肺纤维化(pulmonary fibrosis,PF)是常见的呼吸系统并发症,近年来发病率和病死率呈上升趋势,对人类的健康造成极大威胁。
基于美国胸科学会(ATS)、欧洲呼吸学会(ERS)、日本呼吸学会(JRS)和拉丁美洲胸科学会(ALAT)共同制定的《特发性肺纤维化诊治循证指南》指出,一些药物对IPF患者有潜在作用,对于用药欲望强烈的患者可从以下4种治疗方案中选择:(1)N-乙酰半胱氨酸+硫唑嘌呤+泼尼松;(2)N-乙酰半胱氨酸单药治疗;(3)抗凝治疗;(4)吡非尼酮。但是,以上药物的使用会产生严重的副作用,因此寻找防治肺纤维化有效天然药物,一直是国内外药物研究的热点。从天然活性物质中寻找新的防治肺纤维化药物或药物前体的一个重要策略。
麒麟菜(Eucheuma),也叫鸡脚菜、鸡胶菜,属藻类的藻体肥厚多肉,圆柱状,扁压或扁平,辐射或两侧分枝,该属约有20种,中国约有5种,为热带性海藻,具有很高的药用价值。麒麟菜多肽组份来源于麒麟菜,本发明人团队前期研究(专利201510163788.2)从麒麟菜原料中制得一种多肽提取物,通过实验证明该提取物具有很好的抗血小板聚集,延长出血时间和凝血时间,抑制血栓形成的新性能,可以将该提取物应用于制备抗血小板聚集或抗血栓的药物、药物组分或药物前体。
目前国内外均尚未有麒麟菜多肽组份防治肺纤维化的相关研究,未有用麒麟菜多肽组份作防治肺纤维化药物使用的报道。
发明内容
本发明要解决的技术问题是克服现有肺纤维化治疗药物的缺陷和不足,提供一种低分子量麒麟菜多肽组份及其在防治肺纤维化的应用。本发明从麒麟菜中纯化获得的麒麟菜多肽组份,能够显著地抑制博来霉素诱导的肺纤维化形成,具有显著的防治肺纤维化功能。
本发明的目的是提供一种麒麟菜多肽在制备防治肺纤维化的药物中的应用。
本发明上述目的通过以下技术方案实现:
本发明公开了麒麟菜多肽在制备防治肺纤维化的药物中的应用。
具体地,麒麟菜多肽防治肺纤维化的用法:可单一使用;也可作为防治纤维化药物其中一个组份使用。所述应用包括作为防治肺纤维化药物组分,或利用麒麟菜多肽组份作为防治肺纤维化药物前体改造,或与治疗肺纤维化药物联合应用治疗肺纤维化。
麒麟菜多肽在防治肺纤维化的应用可以有如下多种方法:
方法1:口服麒麟菜多肽1~10mg/kg,每天一次,连续服药至少35天。
方法2:注射麒麟菜多肽1~10mg/kg,每天一次,连续服药至少35天。
方法3:与目前使用的治疗肺纤维化药物联合应用,口服麒麟菜多肽1~10mg/kg,每天一次。
具体优选地,所述麒麟菜多肽由如下方法制备得到:麒麟菜粉碎后利用HCl溶液匀浆和氯化钾溶液制得粗提液,粗提液过滤、柱层析纯化分离得到单一电泳条带的分子量低于10KDa的多肽组份。
更具体地,所述麒麟菜多肽由如下方法制备得到:
S1.取新鲜麒麟菜粉碎,加入浓度为15~25mmol/L的HCl溶液匀浆制得粗制液,所述HCl溶液的加入量按每千克麒麟菜加入8~12L;
S2.粗制液中加入适量饱和氯化钾溶液至氯化钾的浓度为1.3~1.8%;
S3.将步骤S2的粗制液离心分离,取上清液,上清液粗过滤后采用凝胶柱层析分离,使用浓度为15~25mmol/L的HCl溶液洗脱,洗脱峰有两组;
S3.收集第二组洗脱产物,调节溶液酸碱度至pH值6.0~7.0后,离心分离,上清液冷冻干燥制得所需提取物。
其中,优选地,所述凝胶柱层析采用的凝胶柱为葡聚糖G-50凝胶柱。
优选地,所述葡聚糖G-50凝胶柱的柱高为28~32cm,内径宽度为1.8~2.2cm。
更优选地,所述葡聚糖G-50凝胶柱的柱高30cm,内径宽度2.0cm。
优选地,所述凝胶柱层析分离时,粗制液的上样高度为凝胶柱柱高的5~10%。
优选地,所述凝胶柱层析分离时,洗脱液的流速控制为0.8~1.2mL/min。
优选地,所述上清液粗过滤具体为采用2~4层纱布过滤,所述纱布为本领域过滤常用的纱布。
优选地,步骤S1或S3所述离心分离为低速离心分离,具体离心的转速为8000~12000转/min,离心时间为13~18min。
一种包含有麒麟菜多肽的防治肺纤维化的药物,也在本发明的保护范围之内。
具体地,药物的剂型可以有如下使用形式:
(1)可制成粉剂,用生理盐水溶解口服。
(2)可制成注射针剂,按注射针剂要求使用。
(3)可制添加糖饮料,制成口服液产品。
使用条件无特殊要求,可在室温条件下使用,剂量为:1~10mg/kg/每天,按蛋白多肽组份类食品或药物的条件使,同时参照目前市面的防治肺纤维化药物的适用范围。
本发明研究发现,麒麟菜多肽组份具有很好的防治肺纤维化的效果,肺组织中羟脯氨酸(HYP)及血浆中丙二醛(MDA)的含量明显降低;血浆中总超氧化物歧化酶(T-SOD)谷胱甘肽过氧化物酶(GSH-PX)的含量明显增加。可以利用该成分制备防治肺纤维化的药物或药物组分或药物前体。
本发明具有以下有益效果:
本发明从麒麟菜中纯化获得的麒麟菜多肽组份能够显著地抑制肺纤维化形成,具有显著的防治肺纤维化功能,在肺纤维化防治方面具有重要的应用价值和前景。
附图说明
图1为小鼠肺组织切片HE染色观察(×200);A.对照组;B.模型组;C.麒麟菜多肽低剂量组;D.麒麟菜多肽中剂量组;E.麒麟菜多肽高剂量组;F.吡非尼酮组。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,实施例所用试剂和材料均为市购。
实施例1麒麟菜多肽的制备
1、制备麒麟菜多肽
取1kg麒麟菜粉碎,用10L 20mmol/L HCl溶液匀浆制备成粗制液,若溶液粘稠,则加入氯化钾至浓度1.5%;将所得粗制液用8000转/分钟离心15分钟,收集上清液,将上清液用三层纱布过滤,用葡聚糖G-50(Sephadex G-50)分离(柱高30cm,内径宽度2.0cm,上样品高度为柱高5~10%)。平衡后,用20mmol/L HCl溶液洗脱,流速1.0mL/min,洗脱峰有两组,收集第二组洗脱产物,调节溶液酸碱度至pH6.0~7.0,10000转/分钟离心15分钟,上清液冷冻干燥制得所需提取物。
2、经十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)证实是单一电泳条带,分子量低于10KDa的多肽组份。
实施例2防治肺纤维化实验
1、试验方法
(1)动物:SPF级KM小鼠,22g±2g,60只,雌性。
(2)分组
小鼠随机数字表法分为以下各组:对照组、模型组、吡非尼酮组(50mg/kg)、麒麟菜多肽低剂量组(1mg/kg)、麒麟菜多肽中剂量组(5mg/kg)、麒麟菜多肽高剂量组(10mg/kg),每组10只。
(3)用1%戊巴比妥钠按照50mg/kg的剂量腹腔注射麻醉小鼠后,仰卧固定于操作台,用镊子拉出舌头暴露气管,在冷光源放大镜下缓慢注入5mg/kg博莱霉素。注射完毕后迅速竖起鼠板,旋转3分钟,使药液在肺内均匀分布。对照组同前方法气管内注入等体积等渗盐水。10天后开始以0.1ml/10g进行灌胃给药,对照组及模型组灌胃等体积的等渗盐水,其余各组灌胃相应剂量的药物,连续给药至35天,每天1次。
(4)取材与指标测定:
给药35天后将小鼠麻醉取血处死,分离得到完整的两肺组织,称重,取右肺上叶同一部位,用4%的多聚甲醛固定48小时,石蜡切片,进行苏木精-伊红染色法(HE)染色供组织病理学观察。
取左肺中叶同一部位进行肺组织HYP含量的检测。
收集血浆,检测T-SOD、MDA、GSH-PX含量。
2、结果
(1)小鼠肺组织HYP含量分析
注:与正常组比较:*P<0.01;与模型组比较:#p<0.01。
(2)小鼠血浆T-SOD、MDA、GSH-PX含量分析
各组小鼠血浆T-SOD、MDA、GSH-PX含量与对照组相比,模型、低中、高剂量组小鼠血浆MDA含量上升(P<0.01);与对照组相比,各组小鼠血浆T-SOD、GSH-PX含量下降(P<0.01)。与模型组相比,各组小鼠血浆MDA含量明显下降(P<0.01);与模型组相比,各组小鼠血浆T-SOD、GSH-PX含量上升(P<0.01)。见表2。
注:与正常组比较:*P<0.01;与模型组比较:#p<0.01。
(3)肺组织病理变化分析
如图1,对照组肺结构清晰,模型组肺泡间隔显著变宽,肺泡结构破坏严重,萎缩塌陷严重,胶原纤维显著增多,出现大量炎症细胞浸润。而麒麟菜多肽低、中、高剂量组及吡非尼酮组肺纤维化逐步减轻。
Claims (1)
1.麒麟菜多肽在制备防治肺纤维化的药物中的应用;
所述麒麟菜多肽由如下方法制备得到:
S1.取新鲜麒麟菜粉碎,加入浓度为15~25mmol/L的HCl溶液匀浆制得粗制液,所述HCl溶液的加入量按每千克麒麟菜加入8~12L;
S2.粗制液中加入适量饱和氯化钾溶液至氯化钾的浓度为1.3~1.8%;
S3.将步骤S2的粗制液离心分离,取上清液,上清液粗过滤后采用凝胶柱层析分离,使用浓度为15~25mmol/L的HCl溶液洗脱,洗脱峰有两组;
S3.收集第二组洗脱产物,调节溶液酸碱度至pH值6.0~7.0后,离心分离,上清液冷冻干燥制得所需提取物。
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