CN110917201A - 聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用 - Google Patents
聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用 Download PDFInfo
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Abstract
本发明涉及聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用，该聚普瑞锌的用量为每次75‑150mg；本发明通过研究发现，通过提高聚普瑞锌颗粒的使用剂量，能够显著提高对萎缩性胃炎伴随胃粘膜上皮的异型增生的治疗效果。
Description
技术领域
本发明涉及医疗领域，特别涉及聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用。
背景技术
萎缩性胃炎为胃粘膜上皮和腺体萎缩，胃粘膜变薄，伴幽门腺化生和肠化生的慢性消化系统疾病，萎缩性胃炎会影响消化道功能，中、重度者还可发展为胃癌，严重危害患者的身心健康和生活质量；HIF-1α是缺氧诱导因子-1的一个亚单位，受缺氧调控并调节HIF-1的活性，可以与上下游多种蛋白组成不同的信号通路，介导低氧信号，调控细胞产生一些列缺氧的代偿反应，在机体的生长发育及生理和病理过程中发挥重要作用，是生物医学研究的一个焦点；STAT3在细胞内起着重要的信号传递作用，负责将细胞外的信号传递到细胞核，通过诱导靶基因转录表达生物刺激的效应作用。
胃粘膜上皮的异型增生是指胃粘膜上皮和腺体的一类偏离正常分化，形态和机能上呈异型性病变，一般认为，恶性肿瘤发生前，恶性肿瘤发生前，几乎均先有异型增生，很少不经过这个阶段而直接从正常转化为恶性的，研究表明，HIF-1α和STAT3在胃癌前病变组织中的表达会升高，因此，如何制备一种治疗萎缩性胃炎伴随胃粘膜上皮的异型增生是当前需要迫切解决的问题。
发明内容
本发明提供了聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用。
本发明具体技术方案如下：
本发明提供了聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用，该聚普瑞锌的用量为每次75-150mg。
进一步地，聚普瑞锌的用量为每次150mg。
进一步地，聚普瑞锌的给药次数为每日1次。
进一步地，聚普瑞锌的给药次数为每日2次。
进一步地，聚普瑞锌使用前制备成聚普瑞锌颗粒。
进一步地，聚普瑞锌的给药方法为口服。
本发明通过研究发现，通过提高聚普瑞锌颗粒的使用剂量，能够显著提高对萎缩性胃炎伴随胃粘膜上皮的异型增生的治疗效果。
附图说明
图1为实验1对各组小鼠的胃组织中HIF-α1，STAT3表达的影响；
图2为实验2对各组小鼠的胃组织中HIF-α1，STAT3表达的影响；
其中，图1A和图1B中的C1和C2为Ⅰ组，M1和M2为Ⅱ组，Y1和Y2为Ⅲ组，H1和H2为Ⅳ组，L1和L2为Ⅴ组；
图2A和图2B中的，M1和M2为Ⅶ组，Y1和Y2为Ⅷ组，H为Ⅸ组，L为Ⅹ组。
具体实施方式
一.试验材料
1.实验用聚普瑞锌颗粒：聚普瑞锌颗粒(Polaprezinc granules)，白色颗粒，商品名：瑞莱生，规格：0.5g:75mgx4袋/盒，颗粒剂(含原料药75mg)/袋，产品批号25-180907，生产日期20180905，有效期至2020年9月4日，吉林省博大伟业制药有限公司生产，批准文号，国药准字H20120091，执行标准，国家食品药品监督管理局标准YBH03082012。实验前用蒸馏水配制摇匀，小鼠灌胃给药。
2.阳性对照药：叶酸片(Folic acid tablets)，黄色片，规格0.4mg原料/片，产品批号20180713，生产日期20180725，有效期至2021年6月，批准文号，国药准字H20044917，江苏联环药业股份有限公司产品，执行标准，中国药典2015年版二部，实验前用乳钵研细后加蒸馏水配制，小鼠灌胃给药。
3.无菌氯化钠注射液：无菌0.9％氯化钠注射液，华润双鹤药业股份有限公司产品，批号F201704074，
生产日期2017年4月，有效期至2020年4月，国药准字H11021191，规格250ml含氯化钠2.25g。
4.枯矾(KAl(SO4)2·12H2O burnt alum)：白色块状物用于诱导小鼠萎缩性胃炎模型，该模型简单易行，与人类AG存在众多相似性，北京同仁堂制药集团提供，北京三和药业有限公司产品，执行标准，北京市中药饮片炮制规范2008版，质量合格，生产许可证号，京20150235，批号74940601，白色或灰白色粉末。实验前用乳钵研细后加蒸馏水配制，小鼠灌胃给药。
二.动物
1.ICR小鼠，雄，17-18g，SPF级动物，斯贝福(北京)生物技术有限公司提供，实验动物质量合格证号：SCXK(京)2016-0002。
2.动物饲养：居住在中国医学科学院肿瘤研究所肿瘤医院实验动物室。实验动物使用许可证号：SYXK(京)2014-0003。
三.试剂
1.小鼠胃泌素(Gastrin，Gas)ELISA检测试剂盒：北京绿源伯德生物科技有限公司产品。
2.小鼠胃蛋白酶(Pepsin，PG)ELISA检测试剂盒：北京绿源伯德生物科技有限公司产品。
3.小鼠超氧化物歧化酶(Superoxide Dismutase，SOD)ELISA检测试剂盒：北京绿源伯德生物科技有限公司产品。
4.小鼠谷胱甘肽过氧化物酶(Glutathione peroxidase，GSH-Px)ELISA检测试剂盒：北京绿源伯德生物科技有限公司产品。
5.小鼠丙二醛(Malondialdehyde，MDA)ELISA检测试剂盒：北京绿源伯德生物科技有限公司产品。
6.Western blot一抗：HIF-1α多克隆抗体，Abbkine产品。STAT3多克隆抗体，Abbkine产品。
四.仪器设备
1.超净工作台：北京新城县梁家营净化设备厂生产。奥豪斯电子精密天平：量程范围0.01～510g，U.S.A OHAUS corp产品。日本NIKON倒置显微镜、Olympus/PM-6显微镜，解剖显微镜。
2.全自动血液分析仪，型号ABX Pentra Dx 120，HOR IBA ABX SAS产品。
3.酶标分析仪：Rayto RT-6100型。
4.制冰机：AF10 SCOTSMAN,美国产品。去离子水仪：PALL，Purelab Plus，美国产品。
5.冷冻离心机heal force neofuge 13R，纯水仪重庆艾科浦AJC-0501-P，掌上离心机Servicebio D1008E，涡旋混合器Servicebio MX-F，磁力搅拌器Servicebio MS-PB，脱色摇床Servicebio TSY-B，双垂直电泳仪北京六一仪器厂DYCZ-24DN，转印电泳仪北京六一仪器厂DYCZ-40D，扫描仪EPSON V300，灰度分析软件Alpha Innotech alphaEaseFC，图像分析软件Adobe Adobe PhotoShop，匀浆仪KZ-IIServicebio。
6.医用净化工作台，CJ-2F型，净化等级100级(美国联邦标准209E)，平均菌落数≤0.5个/皿·时，平均风速0.4±20％，噪声≦62dB(A)，振动≦3μm(X，Y，Z方向)，苏州市冯氏实验动物设备有限公司产品。
五.试验方法
1.通过表1的方法对各组小鼠造模和给药；
表1.各组小鼠的造模及给药方法
注：PO-给药方式为口服；qod-给药频率为隔天一次；qd-给药频率为每天一次；每0.5g聚普瑞锌颗粒中国含有75m聚普瑞锌，因此，聚普瑞锌颗粒的灌胃量为0.4g/kg，使用前将聚普瑞锌颗粒溶解于水中，小鼠60mg/kg对应于人的150mg/天，每天1次，小鼠120mg/kg对应于人的150mg/天，每天2次。
由表1可知，各组小鼠适应性饲养后，I组和Ⅵ组为正常对照组，其余小鼠造模给予20％枯矾灌胃，每次给予的容积为0.1mL/20g体重，隔天1次，连续36天，停止给予20％枯矾灌胃造模，然后将动物随机分组，胃炎模型对照组给予蒸馏水，每天1次，实验1的Ⅳ组和实验2的Ⅸ组，聚普瑞锌的灌胃量为120mg/kg，给药频率为1天1次，连续25天，实验1的Ⅴ组和实验2的Ⅹ组，聚普瑞锌的灌胃量为60mg/kg，给药频率为1天1次，连续25天，阳性药治疗组，灌胃叶酸，给药频率为1天1次，连续25天；实验1组的各组小鼠在连续给药25天后，使用二氧化碳麻醉后，处死各组小鼠，取血并分离血清，取胃组织，分析测定观察指标；实验2的各组小鼠在连续给药39天后再分别用二氧化碳麻醉后，处死各组小鼠,取血并分离血清，取胃组织，检测小鼠胃组织HIF-α1，STAT3表达。2.Western Blot检测小鼠胃组织HIF-α1，STAT3表达：
①组织总蛋白提取：将各组小鼠的胃组织块用冷PBS洗涤2次，去除血污，剪成小块置于匀浆管中，加入2个2mm的小磁珠，加入10倍组织体积的蛋白提取试剂(使用前数分钟内加入蛋白酶抑制剂)置于均质匀浆机中，选择程序彻底匀浆，匀浆时间为60s，将匀浆完成的样本管取出，冰浴30min，每隔5min震荡一次确保组织完全裂解，在12000rpm条件下离心10min，收集上清，即为总蛋白溶液；
②浆蛋白核蛋白提取：取细胞核蛋白与细胞浆蛋白抽提试剂盒，
室温融解试剂盒中的三种试剂，溶解后立即放置在冰上，混匀，取适当量的细胞浆蛋白抽提试剂A备用，在使用前数分钟内加入PMSF(苯甲基磺酰氟)，使PMSF的最终浓度为1mM，取适当量的细胞核蛋白抽提试剂备用，在使用前数分钟内加入PMSF，使PMSF的最终浓度为1mM；
③蛋白浓度测定：如果需要测蛋白浓度，取未变性的蛋白溶液，用BCA蛋白浓度测定试剂盒测蛋白浓度，具体方法参照试剂盒的说明书；
④蛋白变性：将蛋白溶液按照4:1的比例加入5*蛋白上样缓冲液，沸水浴变性15min，收入-20℃冰箱保存备用；
⑤SDS-PAGE电泳：清洗玻璃板；
⑥灌胶与上样：待玻璃板晾干后，将一个毛玻璃板和一个平玻璃板组成一对，玻璃板之间是灌胶的缝隙，放入制胶器，插入楔子将玻璃板固定，检查底部是否对齐以免漏胶，按实验安排配制所需浓度分离胶，加入TEMED后立即摇匀即可灌胶，将分离胶灌到适当高度，灌胶之前用梳子试一下，梳子齿距离分离胶上液面大约8mm，然后将纯水缓慢均匀加入到缝隙中直到灌满，约30min左右等分离胶凝固即可倒去胶上层水并用吸水纸将剩余水吸干，将样品加入电泳孔中，电泳，浓缩胶电压75V，分离胶用120V，电泳至溴酚蓝刚跑出即可终止电泳，进行转膜；
⑦化学发光：在暗室中将ECLA和ECLB两种试剂在离心管中等体积混合，在曝光匣上贴双层手套或者其他透明薄膜，将PVDF膜的蛋白面朝上放在曝光匣两层薄膜间，加入混合好的ECL溶液充分反应，2min后，去尽残液，盖上上面的一层薄膜开始曝光，曝光后的胶片用显影、定影试剂进行显影和定影；根据不同的发光强度调整曝光条件；
⑧凝胶图像分析：将胶片进行扫描存档，PhotoShop整理去色，Alpha软件处理系统分析目标带的光密度值；
六.实验结果
由图1A、1B、2A和2B可知，Western Blot结果显示，胃炎模型组HIF-α1，STAT3表达表达量升高，PZ治疗后可以下调HIF-α1，STAT3表达，降低异型细胞的增生，达到组织修复。
Claims (6)
1.聚普瑞锌在制备治疗萎缩性胃炎伴随胃粘膜上皮异型增生的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述聚普瑞锌的用量为每次150mg。
3.如权利要求2所述的应用，其特征在于，所述聚普瑞锌的给药次数为每日1次。
4.如权利要求2所述的应用，其特征在于，所述聚普瑞锌的给药次数为每日2次。
5.如权利要求1所述的应用，其特征在于，所述聚普瑞锌使用前制备成聚普瑞锌颗粒。
6.如权利要求1所述的应用，其特征在于，所述聚普瑞锌的给药方法为口服。
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