CN110755428A - 骆驼蓬灵在制备降脂药物中的应用 - Google Patents
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Abstract
本发明涉及骆驼蓬灵在制备降脂药物中的应用,属于医药技术领域。本发明提供了骆驼蓬灵在制备降脂药物中的应用。本发明的骆驼蓬灵不仅能抑制脂肪细胞分化,而且能抑制脂肪合成,从而抑制脂肪积累。能用于制备降脂药物,为高血脂症、动脉粥样硬化、肥胖和非酒精脂肪肝的治疗提供了新的药物选择。
Description
技术领域
本发明涉及骆驼蓬灵在制备降脂药物中的应用,属于医药技术领域。
背景技术
高脂血症是指血脂水平过高,其可直接引起一些严重危害人体健康的疾病,如动脉粥样硬化、冠心病、胰腺炎等。高脂血症可分为原发性和继发性两类。原发性与先天性和遗传有关,是由于单基因缺陷或多基因缺陷,使参与脂蛋白转运和代谢的受体、酶或载脂蛋白异常所致,或由于环境因素(饮食、营养、药物)和通过未知的机制而致。继发性多发生于代谢性紊乱疾病(糖尿病、高血压、黏液性水肿、甲状腺功能低下、肥胖、肝肾疾病、肾上腺皮质功能亢进),或与其他因素年龄、性别、季节、饮酒、吸烟、饮食、体力活动、精神紧张、情绪活动等有关。
高脂血症的临床表现主要是脂质在真皮内沉积所引起的黄色瘤和脂质在血管内皮沉积所引起的动脉硬化。尽管高脂血症可引起黄色瘤,但其发生率并不很高;而动脉粥样硬化的发生和发展是一种缓慢渐进的过程。因此,在通常情况下,多数患者并无明显症状和异常体征。不少人是由于其他原因进行血液生化检验时才发现有血浆脂蛋白水平升高。
血脂异常者往往伴有多种心血管危险因素。血脂水平和下降会使得心血管疾病的发生率和死亡率随着血清总胆固醇和低密度脂蛋白胆固醇水平的下降而降低。因此,控制血脂水平,对于改善高血脂患者生活质量,延长患者寿命,具有十分重要的意义。
骆驼蓬(Peganum harmala L)是骆驼蓬属(Peganum L)多年生草本植物,在我国主要分布于西北部新、蒙、陕、甘、宁等干旱地区。该植物资源丰富,是我国维吾尔族、哈萨克族和蒙古族等民族沿用已久的民族药物。在中东和北非传统上用作调经药物和堕胎药。在巴基斯坦、印度等国家用其种子作为羊毛或丝绒的染料。骆驼蓬全草含有生物碱、甾体、黄酮、蒽醌、氨基酸等成分。骆驼蓬中的骆驼蓬灵(Harmaline)的结构式如下:
但目前,骆驼蓬灵使用后对脂肪合成的影响尚不清楚。因此,本项目通过考察骆驼蓬灵对3T3-L1细胞和RAW264.7细胞增殖的影响,研究骆驼蓬灵对脂肪合成和分化的影响。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供骆驼蓬灵在制备降脂药物中的应用,本发明的骆驼蓬灵能减少脂肪累积,抑制脂肪细胞分化,抑制脂肪合成。
为实现上述目的,本发明采取的技术方案为:骆驼蓬灵在制备降脂药物中的应用。
作为本发明所述应用的优选实施方式,所述降脂药物为减少脂肪累积的药物。
作为本发明所述应用的优选实施方式,所述降脂药物为抑制脂肪细胞分化的药物。
作为本发明所述应用的优选实施方式,所述降脂药物为抑制脂肪合成的药物。
作为本发明所述应用的优选实施方式,所述药物的剂型为胶囊剂、片剂、丸剂、颗粒剂、口服液体制剂或注射剂。
本发明还提供了一种降脂药物,所述药物含有骆驼蓬灵。
作为本发明所述降脂药物的优选实施方式,所述药物还含有药用载体。
作为本发明所述降脂药物的优选实施方式,所述药物的剂型为胶囊剂、片剂、丸剂、颗粒剂、口服液体制剂或注射剂。
与现有技术相比,本发明的有益效果为:本发明的骆驼蓬灵能减少脂肪累积,抑制脂肪细胞分化,抑制脂肪合成,能用于制备降脂药物。
附图说明
图1为不同浓度的骆驼蓬灵对3T3-L1前脂肪细胞、RAW264.7细胞增殖影响的统计图。
图2为不同浓度的骆驼蓬灵对3T3-L1前脂肪细胞中甘油三酯含量影响的统计图。
图3为不同浓度的骆驼蓬灵对3T3-L1前脂肪细胞中脂肪积累影响的油红O染色图。
图4为骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段影响的示意图。
图5为骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段的甘油三酯含量影响的统计图。
图6为骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段中脂肪积累影响的油红O染色图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点,下面将结合附图和具体实施例对本发明作进一步说明。
下述实施例中,若未特别指明,所用的技术手段为本领域技术人员所熟知的常规手段,本申请中的试剂和材料均可从市场上或其它公共渠道获得。
实施例1骆驼蓬灵对3T3-L1前脂肪细胞、RAW264.7细胞毒性的影响
为了确定骆驼蓬灵在不同活性浓度下对3T3-L1前脂肪细胞的抑制不是由于细胞毒性引起的,采用MTT方法对3T3-L1前脂肪细胞和RAW264.7细胞进行不同浓度的细胞活力测试。
1.实验方法
(1)骆驼蓬灵对3T3-L1前脂肪细胞增殖的影响
3T3-L1前脂肪细胞以1×104个/mL接种于96孔板,用完全培养液培养过夜后,加入不同浓度的骆驼蓬灵完全培养液孵育3天。组合浓度设置如下:50μM、40μM、30μM、20μM和10μM,每组设置3个平行复孔。
48h后,每孔加入20μL 5mg/mL MTT溶液,放置于37℃培养箱中孵育4小时。小心吸去孔中液体,每孔加入150μL DMSO溶剂,轻轻振荡培养板10min后,于酶标仪490nm处检测吸光度。
(2)骆驼蓬灵对RAW264.7细胞增殖的影响
RAW264.7细胞以1×105个/mL接种于96孔板,用完全培养液培养过夜后,加入不同浓度的骆驼蓬灵完全培养液孵育3天。组合浓度设置如下:50μM、40μM、30μM、20μM和10μM,每组设置3个平行复孔。
48h后,每孔加入20μL 5mg/mL MTT溶液,放置于37℃培养箱中孵育4小时。小心吸去孔中液体,每孔加入150μL DMSO溶剂,轻轻振荡培养板10min后,于酶标仪490nm处检测吸光度。
2.实验结果
图1为骆驼蓬灵对3T3-L1前脂肪细胞、RAW264.7细胞毒性的影响,实验结果如图1所示。由图1可知,与对照组对比,骆驼蓬灵在不同浓度下对3T3-L1前脂肪细胞、RAW264.7细胞均无明显毒性,排除了细胞毒性引起的假阳性。实施例2骆驼蓬灵对3T3-L1前脂肪细胞脂质积累的影响
为了评价骆驼蓬灵抑制3T3-L1前脂肪细胞分化成脂的能力,考察不同浓度骆驼蓬灵对3T3-L1前脂肪细胞分化以及脂肪累积的影响。为了研究骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段的影响,分别考察不同时期骆驼蓬灵对3T3-L1前脂肪细胞内甘油三酯含量的影响。
1.实验方法
(1)骆驼蓬灵对3T3-L1前脂肪细胞分化的影响
(a)所需缓冲液、药物溶液的配制方法
将骆驼蓬灵溶于二甲亚砜(DMSO,dimethylsulfoxide),配成10mM浓度,-20℃低温冰箱保存,临用时用相应培养液稀释至所需浓度,使DMSO终浓度小于或等于0.1%。
100×IBMX储存液(500mM,111.12mg/ml):称取适量IBMX粉末,溶于DMSO中,使其配成111.12mg/ml的溶液,储存于-20℃待用。
2000×胰岛素储存液(4mg/ml):称取适量胰岛素粉末,溶于含1当量的HCl的灭菌ddH2O中,使其浓度为4mg/ml,然后用0.22μm的滤膜过滤,储存于-20℃待用。
10000×地塞米松储存液(2.5mM,1mg/ml):称取适量地塞米松粉末,溶于乙醇中,使其浓度为1mg/ml,然后用0.22μm的滤膜过滤,储存于4℃待用。
基础培养基:DMEM高糖培养基+10%新生牛血清+105IU/L青霉素+105IU/L链霉素。
分化培养基:基础培养基中添加三联诱导剂0.5mM异丁基-甲基-黄嘌呤,1ng/ml地塞米松,2μg/mL胰岛素。
分化后培养基:基础培养基中添加2μg/mL/mL胰岛素。
(b)实验过程
3T3-L1前脂肪细胞接种于48孔培养板中,先用基础培养基培养,直至细胞100%融合;两天后,换成分化培养基(此时设定为分化的起始Day 0),诱导分化培养3天(至Day 3),如需加药,骆驼蓬灵用分化培养基稀释到相应浓度后加入;换成分化后培养基再培育3天(Day 6);设立分化对照组(即Vehicle组),在相应培养基中添加相同体积的DMSO作为对照,空白对照组(即Control组),以含0.1%DMSO的基础培养基培养,作为不分化的对照。
(2)骆驼蓬灵对3T3-L1前脂肪细胞内甘油三酯含量的影响
(a)所需缓冲液的配制方法
10×磷酸盐(PBS)缓冲液配制:于800mL水中加入81.816g NaCl、2.013g KCl、11.491g Na2HPO4和2.042g KH2PO4,用HCl调节溶液的pH值至7.4,加水定容至1L,高压蒸汽灭菌,保存于室温,使用时稀释。
1M氢氧化钾溶液(100ml)配制:称取5.6g KOH粉末,加ddH2O配成100ml溶液,摇匀即可。
(b)实验过程
将分化至第六天的3T3-L1前脂肪细胞弃去培养基,用PBS清洗2次;加入1M氢氧化钾溶液在60℃加热10min,4℃离心10min,使细胞充分裂解;匀浆细胞悬液,按甘油三酯测定试剂盒的使用说明测定甘油三酯的含量;甘油三酯含量分析的最终结果以“倍数对照”方式表示(即是(药物组的甘油三酯含量/对照组的甘油三酯的含量)*1),实验结果为三次独立实验的平均值。以此作图,与分化对照组比较,甘油三酯含量降低表示骆驼蓬灵对脂肪细胞的分化成脂有抑制作用。
(3)细胞成像实验
(a)试剂准备
油红O染液:称取0.5g油红O粉末,加入100mL异丙醇于烘箱中60℃充分溶解,静置过夜后滤纸过滤,在滤液中按1:1加入双蒸水混匀,再过滤两次,室温避光保存。
(b)油红O染色
诱导分化9天后,弃培养液,用PBS缓冲液清洗两次,每孔加入2mL 10%甲醛等渗磷酸缓冲液,室温下固定1h;吸去孔板内液体,PBS缓冲液洗两次,通风条件下晾干30min;每孔加入1mL油红O溶液,染色1h;吸去油红O溶液,PBS缓冲液清洗三次,37℃下干燥细胞,倒置显微镜下观察;细胞成像:将固定好的染色板置于细胞成像系统下,调整视野,拍照,每孔拍摄三张。
2.实验结果
在分化的第六天(Day 6)用甘油三酯含量测定试剂盒检测细胞内甘油三酯的含量。结果如图2所示,可以看到骆驼蓬灵能浓度依赖性地抑制3T3-L1前脂肪细胞中的脂肪累积。骆驼蓬灵的浓度为1μM时能产生显著性抑制甘油三脂积累的作用。此外,油红O染色实验也印证了甘油三酯含量测定的结果。如图3所示,不诱导分化的3T3-L1前脂肪细胞(Control)几乎没有脂滴累积,所以油红O染色后细胞不着色;而正常分化的脂肪细胞(Vehicle,MDI)有大量的脂滴蓄积,所以被染成了红色;与空白组(Vehicle)相比,骆驼蓬灵能不同程度地减少脂肪的累积。
考察骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段的影响。如图4所示,在脂肪细胞分化的过程中,分别加入10μM骆驼蓬灵孵育不同时间段,分别是分化的第一个三天(Days0-3),第二个三天(Days 3-6),第三个三天(Days 6-9),第一个六天(Days 0-6),第二个六天(Days 3-9),以及分化的全9天(Days 0-9),最后统一在第九天收集细胞,检测细胞内的甘油三酯含量,所得结果如图5所示。可以看到与正常分化的脂肪细胞(Control)比较,骆驼蓬灵在各个阶段皆能显著性地减少3T3-L1前脂肪细胞的脂滴蓄积,表明骆驼蓬灵不但可以抑制脂肪细胞的分化,同时也能抑制脂肪合成。
骆驼蓬灵对3T3-L1前脂肪细胞分化的不同阶段中脂肪积累影响的油红O染色图如图6所示。由图6可知,加药孵育第一个三天时(Days 0-3)油滴较少,而第二个三天时(Days3-6)油滴有所增加,到第三个三天(Days 6-9)时油滴更多。但与空白组(Vehicle)比较,所有加药组的油滴都减少了。这些结果再次证实了骆驼蓬灵能够在分化的各个阶段抑制脂肪细胞的分化以及脂肪的生成。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (8)
1.骆驼蓬灵在制备降脂药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述降脂药物为减少脂肪累积的药物。
3.如权利要求1所述的应用,其特征在于,所述降脂药物为抑制脂肪细胞分化的药物。
4.如权利要求1所述的应用,其特征在于,所述降脂药物为抑制脂肪合成的药物。
5.如权利要求1~4任一项所述的应用,其特征在于,所述药物的剂型为胶囊剂、片剂、丸剂、颗粒剂、口服液体制剂或注射剂。
6.一种降脂药物,其特征在于,所述药物含有骆驼蓬灵。
7.如权利要求6所述的降脂药物,其特征在于,所述药物还含有药用载体。
8.如权利要求6或7所述的降脂药物,其特征在于,所述药物的剂型为胶囊剂、片剂、丸剂、颗粒剂、口服液体制剂或注射剂。
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