CN117462568A - 一种薯蓣皂苷在制备药物中的应用 - Google Patents
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Abstract
本发明涉及一种薯蓣皂苷在制备药物中的应用,薯蓣皂苷可降低小鼠(HFD小鼠)的体重,改善糖脂代谢,增加基础代谢率,但并不影响小鼠的进食量;薯蓣皂苷能减少皮下和内脏白色脂肪组织及棕色脂肪组织的脂滴大小,并促进脂肪组织棕色化,减少脂肪合成,增加脂肪酸氧化;薯蓣皂苷能减少肝脏脂质合成,降低肝脏的脂质沉积。
Description
技术领域
本发明属于生物医药领域,特别涉及一种薯蓣皂苷在制备药物中的应用。
背景技术
传统中药(Traditional Chinese Medicine,TCM)经过数千年的临床实践,为保护我国人民的生命健康发挥了不可磨灭的作用。中草药还是天然的化合物库,目前,越来越多的研究聚焦在草药提取物或天然产物上。
薯蓣皂苷来源于山药属植物,如日本山药和山药。
发明内容
本发明所要解决的技术问题是提供一种薯蓣皂苷在制备药物中的应用。
本发明的一种薯蓣皂苷在制备改善糖耐量水平和胰岛素抵抗药物中的应用。
本发明的一种薯蓣皂苷在制备抑制皮下白色脂肪组织脂肪合成药物中的应用。
本发明的一种薯蓣皂苷在制备抑制棕色脂肪的脂质合成药物中的应用。
本发明的一种薯蓣皂苷在制备预防或治疗脂肪肝药物中的应用。
本发明的一种薯蓣皂苷在制备促进内脏白色脂肪组织脂肪酸氧化并抑制炎症反应药物中的应用。
本发明的一种薯蓣皂苷在制备减少肝脏脂质合成药物中的应用。
所述药物为单方制剂或复方制剂。
所述药物为片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
有益效果
薯蓣皂苷可降低小鼠(HFD小鼠)的体重,改善糖脂代谢,增加基础代谢率,但并不影响小鼠的进食量;薯蓣皂苷能减少皮下和内脏白色脂肪组织及棕色脂肪组织的脂滴大小,并促进脂肪组织棕色化,减少脂肪合成,增加脂肪酸氧化;薯蓣皂苷能减少肝脏脂质合成,降低肝脏的脂质沉积。
附图说明
图1薯蓣皂苷抑制HFD小鼠体重增长;其中高脂喂养小鼠对照组和薯蓣皂苷干预组,两组小鼠的体重(A);体重净增长量(B);大体照片(C);进食量(D);小鼠的体脂率(E)。数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图2为薯蓣皂苷改善肥胖小鼠的基础代谢率和能量代谢;其中利用CLAMS代谢监测系统,观察薯蓣皂苷处理组与对照组小鼠相比,24h(早上7点至次日早上7点为一昼夜)内:氧气消耗量(A、B);CO2呼出量(C、D)。数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图3为薯蓣皂苷增加肥胖小鼠的胰岛素敏感性;其中葡萄糖耐量实验(A、C);胰岛素耐量试验(B、D)。实验数据用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图4为薯蓣皂苷对皮下白色脂肪组织的影响;薯蓣皂苷干预后,两组小鼠皮下脂肪组织(IWAT)大体照片(A)及脂肪组织体重比(B);HE染色观察脂滴大小(C);免疫组织化学的方法观察皮下脂肪组织UCP1的表达变化(D);薯蓣皂苷治疗后小鼠皮下脂肪组织线粒体的电镜形态学观察(E);线粒体拷贝数的定量检测(F);Real-time PCR检测组织中各类基因表达水平:脂肪棕色化(G);脂质合成(H);脂肪酸氧化(I)、炎症因子(J);数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图5为薯蓣皂苷对棕色脂肪组织的影响;薯蓣皂苷干预后,两组小鼠棕色脂肪组织(BAT)大体照片(A)及脂肪组织体重比(B);HE染色观察脂滴变化(C);Real-time PCR检测组织中各类基因表达水平:脂肪棕色化(D);脂质合成(E);脂肪酸氧化(F);内质网应激(G);炎症因子(H);免疫印迹实验蛋白的表达(I)。数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图6为薯蓣皂苷对内脏白色脂肪的影响;薯蓣皂苷干预后,两组小鼠内脏脂肪组织(EWAT)大体照片(A)及脂肪组织体重比(B);HE染色观察脂滴大小(C);免疫组织化学的方法观察皮下脂肪组织UCP1的表达变化(D);EWAT线粒体的电镜形态学观察(E);线粒体拷贝数的测定(F)。Real-time PCR检测组织中各类基因表达水平:脂肪棕色化(G);脂质合成(H);脂肪酸氧化(I);内质网应激(J);炎症因子(K);免疫印迹实验检测蛋白的表达(L)。数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图7为薯蓣皂苷减少肝脏脂质沉积;薯蓣皂苷作用与肥胖小鼠,两组小鼠肝脏组织较体重比(A);肝脏总胆固醇含量(B);甘油三酯含量(C);HE染色观察脂滴变化(D)。Real-time PCR检测组织中各类基因表达水平:脂质合成(E);内质网应激(F);脂肪酸氧化(G);炎症因子(H)。免疫印迹实验检测蛋白的表达(I)。数据均用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图8.薯蓣皂苷减少肝原代细胞脂质沉积用游离脂肪酸处理肝原代细胞,观察油红O染色结果(A);Real-time PCR分析各类基因的表达(B)。实验数据用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001;
图9.薯蓣皂苷减少脂原代细胞脂质合成,Real-time PCR分析在IWAT和BAT各类基因的表达(A、B);油红O染色(C);免疫印迹结果观察脂质合成基因的表达(D)。实验数据用均数±标准误表示,*P<0.05,**P<0.01,***P<0.001。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
7周龄SPF级C57BL/6J小鼠购于江苏华创信诺医药科技有限公司,饲养在瑞金医院内分泌研究所动物房。小鼠的饲养条件为:环境温度(20-22℃),昼夜节律(12h-12h),自由进食及饮水。对照组小鼠所用的普通饲料成分为4.5%脂肪,4%纤维素,21%蛋白质,热量1.404kcal/g,订购于上海斯莱克公司(中国)。高脂饲料订购于帆泊生物医药(中国,无锡)有限公司,高脂饲料成分组成为60%脂肪,20%蛋白质,20%碳水化合物。高脂加薯蓣皂苷饲料也订购于帆泊生物医药(中国,无锡)有限公司。按照前期试验结果中显示的小鼠体重与进食量的关系,将薯蓣皂苷(纯度大于99%)添加至上述高脂饲料中,充分混匀,保证每1kg小鼠体重进食约150mg的薯蓣皂苷
实施例1
动物模型的建立与分组:
HFD小鼠:24只7周龄正常C57BL/6J小鼠按照随机原则分为实验组与对照组,适应性喂养一周后,更换为高脂饮食及高脂加薯蓣皂苷(150mg/kg)饮食,喂养周期3个月,记录体重及进食量。
ABX小鼠:24只7周龄正常C57BL/6J小鼠将其随机分为实验组与对照组,将氨苄青霉素、硫酸粘杆菌素、万古霉素、硫酸链霉素按比例溶解于水中,保证小鼠能够自由饮水,且抗生素需及时更换,一般一周更换1-2次。抗生素清菌10天后,将普通饲料替换为高脂饲料及高脂加薯蓣皂苷(150mg/kg)喂养3个月,期间保持抗生素持续供给,记录体重及进食量。
实验方法:
胰岛素耐量试验(ITT);葡萄糖耐量试验(IPGTT);小鼠体脂检测;代谢笼测定能量消耗;组织取材;
小鼠血清的获取及血脂指标的检测:小鼠血清的获取;血清TG测定(甘油磷酸氧化酶法);血清TC测定(氧化酶法);血清HDL测定(酶直接法);血清LDL-c(直接法);
肝脏代谢指标测定:肝脏甘油三酯(TG)含量测定;肝脏TC测定;
小鼠组织蛋白提取、Western blot;
粪便DNA提取;油红O染色;小鼠组织DNA提取;
实验中的所有数据均采用均数±标准误来表示,使用GraphPad Prism9.0和EXCEL软件对数据进行分析及作图。在不同组间进行比较时,采用双尾t检验方法进行统计学分析,认为在P<0.05时,差异有统计学意义。
结果:
7周龄雄性C57BL/6J小鼠正常饮食适应性喂养一周后,8周龄给予高脂饮食喂养。按照随机原则把小鼠分为对照组和薯蓣皂苷干预组,期间监测小鼠的体重生长曲线和进食量。结果显示薯蓣皂苷组与对照组相比,小鼠的体重明显减轻,并且高脂喂养时间越久,两组间体重的差异越明显(图1A);两组小鼠的体重净增长量也提示给药组比对照组体重明显降低(图1B);小鼠大体照片也能直观表现出给药组相较于对照组体重的下降(图1C);但是对照组和给药组小鼠在进食量上没有差异(图1D),说明薯蓣皂苷组体重的减少并不是由于进食量减少导致的。检测体脂成分结果表明,两组差异明显,与对照组相比,给药组小鼠体脂含量明显降低(图1E)。
薯蓣皂苷对小鼠能量代谢的影响:
利用动物综合监测系统(CLAMS)对肥胖小鼠的几项能量代谢指标进行检测。分析数据发现,与对照组相比,薯蓣皂苷干预的肥胖小鼠每个时间点的氧气消耗量和二氧化碳呼出量均高于对照组小鼠(图2A、C),且薯蓣皂苷处理组昼夜二氧化碳呼出量和昼夜氧气消耗量也都高于对照组小鼠(图2B、D)。上述结果表明,薯蓣皂苷可以增加饮食诱导的肥胖小鼠的基础代谢率和能量消耗。
薯蓣皂苷增加肥胖小鼠的胰岛素敏感性:
胰岛素抵抗/高胰岛素血症是肥胖症中最常见的代谢紊乱,也是血脂异常发生的主要驱动力。在给小鼠给药8周时,对其进行了葡萄糖耐量实验(IPGTT)。结果显示,腹腔注射10%葡萄糖水后,对照组高脂小鼠各个监测节点的血糖均明显高于薯蓣皂苷组小鼠(图3A),对应的血糖曲线下面积也具有统计学差异(图3C)。待小鼠休息一周后,接着对小鼠进行了胰岛素耐量实验(ITT),目的在于观察薯蓣皂苷对饮食诱导的高脂小鼠的胰岛素敏感性的影响。实验结果显示,在注射胰岛素后,薯蓣皂苷组高脂小鼠每个监测点的血糖较对照组小鼠明显降低(图3B),同样对应的血糖曲线下面积也具有统计学差异(图3D)。说明饮食诱导的肥胖小鼠对胰岛素的敏感性在经过薯蓣皂苷干预后得到了明显改善。以上结果均证明薯蓣皂苷能够改善高脂诱导的肥胖小鼠的糖耐量水平和胰岛素抵抗。
薯蓣皂苷对小鼠代谢相关组织的作用:
薯蓣皂苷对皮下白色脂肪组织的影响:
对照组和给药组两组小鼠皮下白色脂肪(Inguinal white adipose tissues,IWAT)大体照片(图4A)和IWAT质量较体重比(图4B)都显示,薯蓣皂苷干预后小鼠IWAT体积明显小于对照组。取两组小鼠的IWAT组织进行HE染色,结果显示,与对照组相比,薯蓣皂苷组IWAT的细胞变多,脂滴明显减小(图4C)。UCP1的免疫组化显示,给药组脂肪细胞中UCP1的表达增加(棕色染色)(图4D)。IWAT电镜结果可见,薯蓣皂苷增加了小鼠IWAT的线粒体的大小及数目(图4E)。同时我们利用线粒体拷贝数实验定量了线粒体的变化(图4F)。在RNA水平上,测定了IWAT组织棕色化相关基因(UCP1、PGC1a、COX8b、Cidea)(图4G)、脂质合成相关基因(FAS、SREBP-1c、ChREBP)(图4H)、脂肪酸氧化(PPARa、PDK4、MRC1、FGF21)(图4I)、炎症相关基因(TNFa、IL-10、CCr2)水平变化(图4J)。结果显示,薯蓣皂苷增加了脂肪棕色化、脂肪酸氧化基因的表达,抑制了脂质合成基因、内质网应激和炎症反应基因水平的表达。上述实验结果证明,薯蓣皂苷可以抑制皮下白色脂肪组织脂肪合成,促进其棕色化水平。
薯蓣皂苷对棕色脂肪组织的影响:
观察对照及加药两组小鼠棕色脂肪(BAT)大体照片(图5A)和BAT重量较体重比(图5B)显示,薯蓣皂苷干预后小鼠BAT体积明显小于对照小鼠。取两组小鼠BAT组织进行HE染色,结果显示,与对照组脂滴体积相比,给药组BAT脂滴明显减小(图5C)。基因水平上,发现一些棕色化基因如Cidea、Prdm16和Dio2的表达被调控升高(图5D)。薯蓣皂苷同时也抑制了脂质合成基因的表达(FAS、SCD1)(图5E),抑制了内质网应激相关基因表达(ATF4、ATF6、ACC1、ACLY)(图5G),增加了脂肪酸氧化相关基因表达(FGF21、PPARa)(图5F),抑制了炎症因子(如TNFa、IL-1β、CCr2)的表达(图5H)。蛋白水平上,也证实了FAS、SREBP-1c的降低(图5I)。上述实验结果证明,薯蓣皂苷可以抑制棕色脂肪的脂质合成。
薯蓣皂苷对内脏白色脂肪的影响:
比较单纯高脂喂养和薯蓣皂苷处理组小鼠内脏白色脂肪(Epididymal whiteadipose tissues,EWAT)照片(图6A)和重量比(图6B)显示,薯蓣皂苷干预后小鼠的EWAT体积明显小于对照小鼠。EWAT组织的HE染色结果显示,与对照组相比,薯蓣皂苷组EWAT细胞内脂滴体积明显减小(图6C)。UCP1的免疫组化结果显示,给药组脂肪细胞中UCP1的表达增加(棕色染色)(图6D)。取EWAT组织做电镜切片,结果显示薯蓣皂苷组线粒体数目增多(图6E)。线粒体拷贝数实验结果也与其一致(图6F)。RNA水平上,测定了脂肪棕色化基因(PGC1a、UCP1、COX8b、Cidea)(图6G)、脂质合成相关基因(SREBP-1c、SCD1)(图6H)、内质网应激基因(ACC1、ACLY、ATF6、ATF4)(图6J)、脂肪酸氧化基因(PPARa、FGF21)(图6I)以及炎症因子水平(图6K)。分析结果发现,薯蓣皂苷抑制了脂质合成基因和内质网应激基因水平的表达,增加了脂肪棕色化基因、脂肪酸氧化基因的表达。蛋白水平的表达也一致(图6L)。上述实验结果证明,薯蓣皂苷促进了内脏白色脂肪组织脂肪酸氧化,抑制了其炎症反应。
薯蓣皂苷减少肝脏的脂质沉积:
对照组和薯蓣皂苷处理组小鼠肝脏较体重比(图7A)显示,给药组小鼠肝脏体积减小;脂肪肝一般是由于肝内酯类沉积引起的,而甘油三酯是其中最重要的指标。虽然肝脏总胆固醇显示两组没有显著性差异,但是肝脏甘油三酯的结果显示,薯蓣皂苷减少了肝脏甘油三酯的含量(图7B、C);HE染色的结果显示,给药组肝细胞中的脂滴数目显著减少(图7D);RNA水平上,我们发现薯蓣皂苷抑制了脂肪酸合成基因(ChREBP、SCD1、CEBPb、FAS、SREBP-1c)表达(图7E),增加了脂肪酸氧化基因(CPT1a、FGF21)表达(图7G),抑制了内质网应激基因(ACC1、ATF6)的表达(图7F),抑制了炎症因子(IL-10)的表达(图7H)。蛋白水平上同样显示,脂质合成相关基因如FAS、SREBP-1C的表达降低(图7H)。上述结果表明,薯蓣皂苷减少肝脏的脂质沉积,说明脂肪肝得到一定程度的改善。
薯蓣皂苷抑制肝原代细胞脂质合成:
用1mM的FFA处理小鼠肝原代细胞,并且用薯蓣皂苷干预;通过油红O染色可以看出,FFA处理组相对于对照组,脂滴增加,FFA+Dio处理组相对于FFA处理组,脂滴明显减少(图8B)。RNA水平上,分析显示脂质合成基因等相关基因的表达均减少(图8A)。上述结果表明,薯蓣皂苷可以减少肝脏脂质合成。
薯蓣皂苷抑制脂肪细胞脂质合成:
对成功诱导脂滴的小鼠脂肪原代细胞(IWAT、BAT)进行薯蓣皂苷干预,24h处理后收细胞。油红O染色结果显示,薯蓣皂苷加入后能明显减少细胞的脂滴(图9C)。从RNA水平上看,不论是IWAT还是BAT,薯蓣皂苷都能减脂质合成基因、内质网应激的基因表达,增加脂肪酸氧化基因水平(图9A、B)。蛋白水平同样佐证了这个结果(图9D)。
Claims (8)
1.一种薯蓣皂苷在制备改善糖耐量水平和胰岛素抵抗药物中的应用。
2.一种薯蓣皂苷在制备抑制皮下白色脂肪组织脂肪合成药物中的应用。
3.一种薯蓣皂苷在制备抑制棕色脂肪的脂质合成药物中的应用。
4.一种薯蓣皂苷在制备预防或治疗脂肪肝药物中的应用。
5.一种薯蓣皂苷在制备促进内脏白色脂肪组织脂肪酸氧化并抑制炎症反应药物中的应用。
6.一种薯蓣皂苷在制备减少肝脏脂质合成药物中的应用。
7.一种权利要求1-6任一所述应用,其特征在于,所述药物为单方制剂或复方制剂。
8.根据权利要求1-6任一所述应用,其特征在于,所述药物为片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
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