CN114377024B - 一种用于治疗和/或预防高血脂疾病的药物 - Google Patents
一种用于治疗和/或预防高血脂疾病的药物 Download PDFInfo
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Abstract
本发明公开了一种用于治疗和/或预防高血脂疾病的药物,所述药物包括光辉霉素、光辉霉素药前体和药学上可接受的光辉霉素的盐中的一种或两种以上的组合。本发明的药物能够抑制泡沫细胞的形成、调节胆固醇和脂质的代谢,进而有效的治疗和预防高血脂疾病。
Description
技术领域
本发明涉及药学领域,具体涉及一种用于治疗和/或预防高血脂疾病的药物。
背景技术
高血脂疾病,又可称高脂血症,是指因为血脂水平过高,而引起一系列严重危害人体健康的疾病,如动脉粥样硬化、冠心病、脂肪肝等疾病。如动脉粥样硬化,经研究发现(《PSRC1过表达调节胆固醇转运和炎症抑制小鼠动脉粥样硬化》,南方医科大学2015级博士学位论文,作者:郭凯,论文提交日期:2018年5月26日),动脉壁上形成巨噬细胞、脂质代谢紊乱和胆固醇代谢与动脉粥样硬化疾病密切相关。具体来说,胆固醇摄取的增加或胆固醇转出的减少都可导致巨噬细胞内脂质含量的增加,形成泡沫细胞;而经研究发现,巨噬细胞的PSRC1基因可以下调巨噬细胞SR-A1和LDLR,以减少巨噬细胞对于胆固醇的摄取,还能够上调ABCA1、ABCG1和SR-B1的表达,促进胆固醇转出,从而减少巨噬细胞内胆固醇酯的含量,抑制泡沫细胞的形成。此外,PSRC1基因可以增加胆固醇转出率和PON-1活性,减少MPO活性、MPO/PON-1比值和HII,可以调节胆固醇的代谢,包括LDL-C和HDL-C水平,甚至是HDL功能;此外,肝细胞PSRC1过表达可以增加PPAR-γ和LXR-α的表达,发挥脂质代谢的作用。
由上所述可知,对于动脉粥样硬化等高血脂疾病的预防和治疗,可以通过调节PSRC1的表达进行实现。因此,寻求一种能够提升PSRC1基因表达的药物成为治疗和预防高血脂疾病的关键。
发明内容
本发明的目的在于克服上述现有技术中不足,提供一种能够用于预防和/或治疗高血脂疾病的药物(即光辉霉素在用于制备治疗高血脂疾病药物中的应用/用途)。
为实现上述目的,本发明采用如下技术方案实现:
一种用于治疗和/或预防高血脂疾病的药物,所述药物包括光辉霉素、光辉霉素药前体和药学上可接受的光辉霉素的盐中的一种或两种以上的组合。
本发明中,进一步优选的方案为,所述高血脂疾病为动脉粥样硬化、冠心病或脂肪肝。
本发明中,进一步优选的方案为,所述药物为口服固体制剂、口服液体制剂或注射剂。
本发明中,进一步优选的方案为,所述口服固体制剂为片剂、胶囊剂、颗粒剂、丸剂或粉剂。
本发明中,进一步优选的方案为,所述药物为缓释制剂。
相比现有技术,本发明的有益效果在于,通过研究发现,SP1可与PSRC1基因的开放区结合并抑制PSRC1基因的表达,而光辉霉素作为SP1的抑制剂,可以降低SP1水平,进而能够上调PSRC1基因的表达,从而上调ABCA1、ABCG1、SR-B1、PPAR-γ和LXR-α的表达,下调巨噬细胞SR-A1和LDLR,可以增加胆固醇转出率和PON-1活性,减少MPO活性、MPO/PON-1比值和HII,从而抑制泡沫细胞的形成,调节胆固醇和脂质的代谢,进而治疗和/或预防高血脂疾病(如动脉粥样硬化)。
附图说明
图1为实验例1中3.2部分western blot检测目的蛋白表达的电泳图;
图2为实验例1中的光辉霉素处理组与对照组与的ChIP-qPCR富集分析的数据图;
图3为实验例1中的SP1特异性抗体与IgG非特异性抗体ChIP-qPCR富集分析的数据图;
图4为实验例2中预测SP1与PSRC1启动子结合位点示意图;
图5为实验例2中的SP1蛋白表达载体质粒(pcDNA3.1+质粒)图谱;
图6为实验例2中的荧光素酶表达载体质粒(PGL-3质粒质粒)图谱;
图7为实验例2中的三种不同质粒转染细胞后荧光素酶相对表达量数据图;
图8为实验例2中的通过western blot检测不同浓度光辉霉素刺激THP-1细胞后PSRC1表达水平变化的电泳数据图;
图9为实验例2中western blot灰度值统计数据的柱状图;
其中,图3中,图形中的奇数列柱形为IgG的相关测试数据,偶数列柱形为SP1的相关测试数据。
具体实施方式
下面,结合具体实施方式对本发明做进一步描述,需要说明的是,在不相冲突的前提下,以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。除特殊说明的之外,本实施例中所采用到的材料及设备均可从市场购得。具体的实施例是示例性的,仅用于解释本申请,而不能理解对本申请保护范围的限制。
一种用于治疗和/或预防高血脂疾病的药物,所述药物包括光辉霉素、光辉霉素药前体和药学上可接受的光辉霉素的盐中的一种或两种以上的组合。
光辉霉素,又称光神霉素,CAS号为18378-89-7,具有一定的毒性,在现有的临床中,主要用于***,如睾丸癌、脑胶质细胞瘤、脑转移癌、恶性淋巴瘤、绒毛膜上皮癌、乳腺癌等症状。
本发明通过研究发现,SP1可与PSRC1基因的开放区结合并抑制PSRC1基因的表达,而光辉霉素作为SP1的抑制剂,可以降低SP1水平,进而能够上调PSRC1基因的表达,从而上调ABCA1、ABCG1、SR-B1、PPAR-γ和LXR-α的表达,下调巨噬细胞SR-A1和LDLR,可以增加胆固醇转出率和PON-1活性,减少MPO活性、MPO/PON-1比值和HII,从而抑制泡沫细胞的形成,调节胆固醇和脂质的代谢,进而治疗和/或预防高血脂疾病(如动脉粥样硬化)。
本发明的高血脂疾病,又可称高脂血症,如动脉粥样硬化、冠心病或脂肪肝等疾病。
为了便于本发明药物的施用,可以根据需要制成口服固体制剂、口服液体制剂或注射剂等剂型;对应的,所述口服固体制剂为片剂、胶囊剂、颗粒剂、丸剂或粉剂;本发明还可以根据需要,将药物加入相应的辅料进行组方,制成缓释制剂。
实验例1-ChIP-qPCR实验
1、实验仪器与试剂
1.1主要试剂
1.2主要仪器和器材
2、蛋白及预测基因结合位点
2.1蛋白信息
目的蛋白:SP1;
种属:人;
抗体:SP1(品牌CST、货号9389S);
阳性对照蛋白:H3K27ac;
种属:(人,小鼠,大鼠);
抗体:Anti-Histone H3(acetyl K27)抗体(品牌:abcam、货号:ab4729)。
2.2 qPCR引物设计
具体的PCR扩增的引物序列参见下表1:
表1预测位点的引物序列
3、实验方法
3.1细胞交联
1)细胞计数后过夜培养至细胞贴壁,细胞数不少于1x107个。
2)于细胞培养基中加入浓度为16%的甲醛(不含甲醇),至其终浓度为1%,轻轻晃动,使液体均匀,于通风厨中室温孵育10min,显微镜下看交联情况。
3)加入浓度为甘氨酸(10x),至其终浓度为1x,于通风厨中室温孵育5min,终止交联反应。
4)通风厨中吸除培养基,用等体积预冷的PBS洗细胞两次。
5)加入含10μl/ml Halt Cocktail的预冷PBS,刮下细胞,吸入1.5ml预冷的离心管中,离心去掉上清。
3.2 western blot检测目的蛋白表达情况
1)取少量细胞提取总蛋白,加入5x SDS上样缓冲液,100℃煮10min。
2)配置12%的分离胶,加异丙醇静置20min,待分离胶凝固,吸除异丙醇,再用水冲洗残余的异丙醇,吸水纸吸去残液。加入配置好的5%的浓缩胶,***梳子,静置20min,待浓缩胶凝固后拔出梳子。
3)安装好电泳装置,上样,先70V,15min,后120V,90min。
4)转膜,湿转120V稳压转100min。
5)封闭,将PVDF膜放入5%的脱脂牛奶中,封闭30min。
6)TBST洗膜3次,每次5min。
7)孵育一抗(TBST稀释),4℃孵育过夜。
8)TBST洗膜3次,每次10min。
9)孵育二抗(1:5000,TBST稀释),室温孵育2h。
10)TBST洗膜3次,每次10min。
11)按1:1的比例加入试剂盒中的两种发光剂,孵育1min。
12)显影、定影,扫描结果参见图1。
3.3细胞裂解与核酸酶消化
1)在细胞中加入100μl含有蛋白酶抑制剂的Lysis Buffer 1,涡旋15s,冰浴10min,9000g离心,去上清。
2)用MNase Digestions Buffer工作液100μl重悬沉淀。
3)加入0.25μl Micrococcal Nuclease,混匀,37℃水浴15min,每5min上下翻转混匀。
5)加入10μl MNase Stop Solution终止反应,冰浴5min。9000g离心5min,去上清。
6)用50μl含蛋白酶/磷酸酶抑制剂的Lysis Buffer 2重悬沉淀,冰浴15min,每5min涡旋15s。
7)9000g离心5min,转移上清至新的1.5ml预冷的离心管。
3.4染色质免疫沉淀
1)取上述步骤所得上清液5μl至1.5ml离心管,储存于-20℃,此为Input。
2)取上述步骤所得上清液45μl至含有450μl 1×IP Dilution Buffer的1.5ml离心管中。
3)每个IP,加入500μl Diluted lysate至plug spin柱,加入一抗,4℃翻转混匀过夜。
Positive control IP:5ug H3K27ac Antibody。
Negative control IP:5ug Normal Rabbit Ig G。
Target-specific IP:5ug antibody。
4)加20μl ChIP Grade Protein A/G plus Agarose至每个IP,4℃摇床孵育1h。将plug柱放到一个2ml的收集管。
5)3000g离心30s,弃掉收集液。
6)加入500μl IP Wash Buffer 1,3000g离心30s,弃掉收集液。
7)加入500μl IP Wash Buffer 2,3000g离心30s,弃掉收集液。
8)重复步骤7。
9)加入500μl IP Wash Buffer 3,3000g离心30s,弃掉收集液。
10)3000g离心1min。
3.5染色质免疫沉淀的洗脱
1)把plug柱重新放到1.5ml离心管上,加入150μl 1×的IP Elution Buffer洗树脂,65℃孵育40min,每10min轻弹以重悬Agarose磁珠。
2)6000g离心1min,弃掉柱子。
3)向离心管中,加入6μl 5M NaCl,以及2μl的20mg/mL的蛋白酶K混匀。
4)解冻Input,加入150μl的IP Elution Buffer,加入6μl 5M NaCl,以及2μl的20mg/mL的蛋白酶K。
5)65℃金属浴1.5h。
3.6 DNA纯化复原
1)加入750μl的DNA Binding Buffer。
2)吸500μl加入到DNA Clean-Up柱,柱放到一个2ml的收集管上。10,000g离心1min,弃掉收集液。
3)将剩余的样品加入同一个DNA Clean-Up柱,重复2。
4)将柱子放在收集管,然后加入750μl DNA Column Wash Buffer,10,000g离心1min,弃收集管中的液体。
5)10,000g离心2min。
6)将柱子放入一个新的1.5ml的收集管,加入20μl DNA Elution Solution,10,000g离心1min,收集管即为纯化后的DNA,进行qPCR。
3.7 qPCR
1)qPCR的总反应体系为20μl,反应体系如表2所示:
表2
2)qPCR采用两步法扩增体系,反应条件如表3所示,循环数为49个循环。
表3
95℃(预变性) | 10min |
95℃(变性) | 15sec |
60℃(延伸) | 1min |
3)q-pcr数据处理
ΔCt[normalized IP]=(Ct[IP]-(Ct[Input]-Log2(Input Dilution Factor)))
%Input=2^(-ΔCt[normalized IP])*100%
我们的input通常为总量的1/10,即稀释了10倍,Log2(Input Dilution Factor)≈3.2
计算示例:
input SNP70
U1 14.05 17.55
ΔCt=17.55-(14.05-3.2)=6.7 %input=2^(-6.7)*100%=0.961831573%
采用上述实验方法对光辉霉素处理组和对照组中的THP-1细胞中的基因富集情况进行测试,其中光辉霉素处理组具体为:THP-1细胞使用无血清培养基饥饿6-8h后,以100nM的浓度加入光辉霉素处理24h,对照组的细胞不进行光辉霉素处理,通过测试具体数据参见表4和图2-3;
表4:启动子基因富集数据表
结合图2-3,通过上表4数据来看,位点1对照组和处理组细胞SP1都能特异性富集,并且富集率差不多,位点2、4处理组富集降低,位点3处理组富集降低最明显;SP1能够与PSRC1启动子区域结合。
实验例2-双荧光素酶实验
1、实验材料
1.1主要试剂
1.2主要仪器及器材
1.3基因信息
蛋白信息:SP1;
种属:人;
***质粒片段长度:2214bp;
靶标基因启动子:PSRC1;
种属:人;
片段长度:724bp;
预测SP1与PSRC1启动子结合位点参照图4(具体为:A位点:1899-1904;B位点:2111-2120;C位点:2186-2196;D位点:2413-2418);
1.4引物序列
SP1蛋白表达质粒(pcDNA3.1+)制备过程中的PCR基因扩增引物序列:
正向引物序列(5′-3′):atgagcgaccaagatcactcc;
反向引物序列(5′-3′):tcagaagccattgccactg;
荧光素酶表达质粒(PGL-3质粒)制备过程中的PCR基因扩增引物序列:
正向引物序列(5′-3′):cccacaactgaggaacctc;
反向引物序列(5′-3′):acctccgggaacgatacg;
上述各引物序列均由苏州金唯智合成。
1.5载体信息(质粒图谱)
SP1蛋白表达质粒:pcDNA3.1+,其质粒图谱参见图5;
荧光素酶表达质粒:PGL-3质粒,其质粒图谱参见图6。
2、实验方法
2.1 PCR扩增基因的片段
在0.2mlEP管中,以基因组DNA为模板,PCR扩增野生型和MUT基因3’UTR区片段,扩增反应体系如表5所示。PCR反应条件为94℃预变性5min,循环参数分别为94℃30s,60℃30s,72℃2min,共35个循环,72℃充分延伸10min,1.5%琼脂糖凝胶电泳检测扩增情况。
表5 PCR反应体系
2.2回收基因片段
1)柱平衡:向吸附柱CB2中(吸附柱放入收集管中)加入500μl平衡液BL,12,000rpm离心1min,倒掉废液,将吸附柱重新放回收集管中。
2)将单一的目的DNA条带从琼脂糖凝胶中切下,放入干净EP管中,称取重量。
3)向胶块中加入等体积的溶液PC,50℃水浴放置10min左右,使胶块充分溶解。
4)将上一步所得溶液加入一个吸附柱CB2中,12,000rpm离心1min,倒掉废液,将吸附柱CB2放入收集管中。
5)向吸附柱中加入600μl漂洗液PW,12,000rpm离心1min,倒掉废液,将吸附柱CB2放入收集管中。
6)重复操作步骤5。
7)将吸附柱CB2放入收集管中,12,000rpm离心2min,将吸附柱置于室温,放置3min。
8)将吸附柱CB2放入一个新的离心管中,向吸附膜中间位置滴加30μl洗脱缓冲液EB,室温放置2min,12,000rpm离心1min,收集DNA溶液。
2.3双酶切胶回收片段和载体
按表6所示的酶切体系,双酶切载体与胶回收片段。轻轻混匀后,37℃孵育过夜,1.5%琼脂糖凝胶电泳检测。
表6双酶切体系
2.4胶回收酶切过的载体与目的片段
具体步骤同2.2回收基因片段的内容;
2.5目的片段与载体链接
配制如表7所示的连接体系,轻轻混匀,4℃连接过夜。
表7连接体系
2.6连接产物的转化
1)取装有200μl TOP10感受态细菌,加入连接后的产物;
2)冰上放置30min;
3)42℃热激90s;
4)迅速移至冰上静置2min;
5)在超净台内,加入1ml LB培养基(Amp-),37℃,160rpm摇1-2h;
6)菌液3000rpm离心10min,弃大部分上清,将沉淀重悬,菌液全部加入LB平板(Amp+)上,涂布均匀,37℃倒置培养(过夜12-15h);
7)将平板取出,于无菌操作台中挑取单克隆放入内含1ml LB培养基(Amp+)的15ml离心管中,于37℃200rpm摇床摇菌3-4h。
2.7菌液PCR鉴定阳性克隆
1)取2μl菌液作为模板,按照表5的PCR体系和步骤2.1中的PCR反应条件,进行PCR反应。1.5%琼脂糖凝胶电泳检测扩增情况。
2)选取阳性克隆提取质粒,测序检验。
2.8质粒小提
1)柱平衡:向吸附柱CP3中(吸附柱放入收集管中)加入500μl的平衡液BL,12,000rpm离心1min,尽量吸除上清。
2)取1.5ml过夜培养的菌液,加入离心管中,使用常规台式离心机,12,000rpm离心1min,吸除上清。
3)向留有菌体沉淀的离心管中加入250μl溶液P1使用移液器彻底细菌沉淀。
4)向离心管中加入250μl溶液P2,温和的上下翻转6-8次使菌体充***解。
5)向离心管中加入350μl溶液P3,立即温和的上下翻转6-8次,充分混匀,此时将出现白色絮状沉淀,12,000rpm,离心10min,此时在离心管底部形成沉淀。
6)将上一步收集的上清液用移液器转移到吸附柱CP3中,12,000rpm,离心30-60s,倒掉废液,将吸附柱CP3放入收集管中。
7)向吸附柱CP3中加入500μl去蛋白液PD,12,000rpm离心,离心30-60s倒掉废液,将吸附柱CP3重新放回收集管中。
8)向吸附柱CP3中加入600μl去蛋白液PW,12,000rpm离心,离心30-60s,倒掉废液,将吸附柱CP3重新放回收集管中。重复一次。
9)将吸附柱CP3重新放回收集管中,12000rpm离心2min。
10)将吸附柱CP3置于一个干净的离心管中,向吸附膜的中间部位滴加50μl洗脱缓冲液EB,室温放置2min,12,000rpm离心2min,将质粒溶液收集到离心管中,放冰盒,测浓度。-20℃保存备用。
3、Luciferase实验
3.1实验目的:在小鼠肝细胞中,通过荧光素酶实验验证SP1蛋白与PSRC1启动子的结合。
3.2实验材料
3.2.1主要试剂
3.2.2主要仪器及器材
仪器名称 仪器来源 cat.No
细胞超净台 佳宝净化 JB-CJ-2FC
细胞培养箱 Thermo 8000
3.3实验方法
3.3.1细胞铺板
1)培养细胞至融合度为70%。
2)吸除培养基,加10ml 1XPBS,轻轻晃动培养皿,吸除PBS。
3)加1ml 0.25%的胰酶,轻轻晃动培养皿,使胰酶均匀铺满皿底,显微镜下看细胞消化情况。
4)消化完全后,加5ml完全培养基(DMEM+10%FBS+10%双抗)终止消化,用枪头轻轻吹打细胞悬液。
5)用血球计数板计数细胞密度,用完全培养基将细胞稀释成1x106个/ml。
6)将稀释好的细胞悬液加入六孔板中,每孔2ml。前后或左右晃动几次,使细胞分布均匀。
7)37℃,5%CO2恒温培养16h,此时细胞融合度约为80%。
3.3.2细胞转染
1)在六孔板盖上做好标记。
2)吸除六孔板中的培养基,每孔加入2ml opti-MEM,放入37℃,5%CO2恒温培养箱中继续培养。
3)取质粒4μg与0.5ml的opti-MEM混匀。
4)取10μl lipofectmin2000转染试剂与0.5ml的opti-MEM混匀。
5)将质粒混合物与转染试剂混合物混匀,静置20min。
6)将上述混合物均匀滴加到标记好的六孔板中。
7)37℃,5%CO2恒温培养6h,将含有混合试剂的opti-MEM吸除,加入2ml完全培养基,37℃,5%CO2恒温培养培养24h。
3.3.3 luciferase测定
1)将六孔板的培养基吸除,PBS洗两遍,加0.25%胰酶消化,消化完全后,加完全培养基终止消化。
2)细胞计数板计数细胞,将细胞稀释成1x105个/ml。
3)向每个96孔板中加入100ul荧光底物,再加入100ul细胞悬液。
4)每隔10分钟,紫外分光光度计测量OD490。
5)选取荧光值较高的数值进行分析。
采用上述实验方法对转染质粒后的细胞荧光强度进行检测,以及不同浓度的光辉霉素处理组和对照组的细胞中的PSRC1表达水平进行检测,其中,光辉霉素处理组为:THP-1细胞使用无血清培养基饥饿6-8h后,分别以终浓度100nM、200nM、300nM加入光辉霉素处理24h;对照组的细胞不进行光辉霉素处理;测试结果参见图7-9,通过测试表明,SP1能够与PSRC1开放区结合并抑制PSRC1基因的表达,经过光辉霉素处理后能够上调PSRC1基因的表达,进而有效治疗高血脂疾病。
最后应说明的是:上述实施方式仅为本发明的优选实施例方式,不能以此来限定本发明保护的范围,本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (4)
1.光辉霉素或其药学上可接受的盐在制备治疗高血脂症疾病药物中的用途。
2.根据权利要求1所述的用途,其特征在于,所述药物为口服固体制剂、口服液体制剂或注射剂。
3.根据权利要求2所述的用途,其特征在于,所述口服固体制剂为片剂、胶囊剂、颗粒剂、丸剂或粉剂。
4.根据权利要求1所述的用途,其特征在于,所述药物为缓释制剂。
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