CN112190587A - 青钱柳皂苷及其衍生物和其盐或前体化合物的制药应用 - Google Patents
青钱柳皂苷及其衍生物和其盐或前体化合物的制药应用 Download PDFInfo
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Abstract
本发明属于生物医药领域,特别是涉及天然产物的医药用途领域,更为具体的说是涉及青钱柳皂苷及其衍生物、和其盐或前体化合物的应用。本发明为青钱柳这一传统中药材的现代用药提供了思路。青钱柳皂苷化合物中,特别是通式1‑通式5中所定义的化合物具有优秀的P‑AMPK、G6Pase、PEPCK的蛋白和基因表达调控能力,能够显著抑制肝脏糖异生(以化合物1‑5为例说明),在针对糖尿病、肥胖、非酒精性脂肪肝的治疗药物中具有极高的应用前景。
Description
技术领域
本发明属于生物医药领域,特别是涉及天然产物的医药用途领域,更为具体的说是涉及青钱柳皂苷及其衍生物、和其盐或前体化合物的应用。
背景技术
青钱柳为胡桃科青钱柳属植物,目前大部分研究都是针对青钱柳叶中的黄酮类、多糖类物质,对青钱柳叶中的皂苷类化合物的药理学研究则少有报道。
糖尿病是一种常见的慢性代谢性疾病。流行病学表明,2019年全球约有4.63亿成人患有糖尿病,而中国糖尿病患者人数和发病率位居世界第一。目前临床上治疗T2DM的降糖药包括双胍类、磺脲类、DPP-4抑制剂、SGLT2抑制剂、GLP-1受体激动剂和人工胰岛素等。然而,长期临床应用表明双胍类、磺脲类等对于糖尿病治疗都存在着局限性。双胍类药物主要临床不良反应为对消化系统的反应,如腹胀、腹泻、食欲减退、恶心,另外还可能引起乳酸酸中毒,所以有严重肾、心、肝以及肺功能不全的患者不宜使用双胍类药物。磺酰脲类可能引起低血糖,心血管不良反应,胃肠道损伤等。新型药物DPP-4、GLP-1受体激动剂等可以通过降低血浆胰高血糖素水平来发挥部分降糖作用,但其机制尚存争议,仍有待研究。
胰岛素和胰高血糖素共同维持体内葡萄糖稳态。从人类和动物研究中积累的证据表明,血浆胰高血糖素浓度在肥胖和/或糖尿病患者中异常升高,肝内胰高血糖素反应失调,肝糖异生功能明显增强。肝脏糖代谢紊乱是高血糖的主要成因。
正常状态下,机体通过进食获取能量或者在空腹状态下通过分解体内储存的糖原或通过糖异生途径将非糖物质转化为葡萄糖供能。病理条件下,糖异生异常导致内源性葡萄糖增加并导致高血糖症。Gastaldelli等人通过对37名2型糖尿病人研究发现,禁食15h后糖尿病人机体血糖约有64%来源于糖异生,远远大于正常人体的47%,因此2型糖尿病患者肝糖异生功能明显增强,肝糖异生不仅决定空腹血糖水平,而且对稳态维护起着关键作用。研究证据表明,肝脏糖异生异常与糖尿病、肥胖等疾病密切相关。抑制糖异生可以治疗糖尿病等代谢性疾病。
AMPK是调控能量稳态的重要激酶,不仅能引起急性代谢反应,还能调节特定的转录因子和相关酶。AMPK在糖代谢中起着重要作用,可通过影响胰高血糖素信号通路中G6Pase、PEPCK的表达调控肝脏糖异生。其具体分子机制尚需要进一步研究。
发明内容
本发明所要解决的技术问题是对青钱柳进行深入研究和药用开发,特别是对目前现有技术中并未关注的青钱柳中所含皂苷类化合物进行深入研究和开发。
为了解决上述技术问题,本发明公开了青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备抑制肝脏糖异生药物中的应用。
同时,在本发明中还公开了青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备对P-AMPK、G6Pase、PEPCK的蛋白和基因表达具有调控作用的药物中的应用。
进一步的,在本发明中还公开了青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备通过调控P-AMPK、G6Pase、PEPCK的蛋白和基因表达抑制肝脏糖异生药物中的应用。
同时,进一步的,在本发明中还公开了所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗肥胖的药物中的应用。以及所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗糖尿病的药物中的应用;和所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗非酒精性脂肪肝的药物中的应用。
作为一种优选的技术方案,所述的青钱柳皂苷为式1、或式2、或式3、或式4、或式5所定义的化合物:
其中,R1、R2、R3、R4、R5独立地选自:-H、-Ara、-Glc、-Rha1-2Ara、-Glc1-6Glc。
最后,本发明还公开了一种药物,所述药物中含有青钱柳皂苷、和/或其衍生物、和/或其医药学上可接受的盐,和/或其前体化合物,所述的青钱柳皂苷是指式1、式2、式3、式4、式5所定义化合物中的一种或几种;
其中,R1、R2、R3、R4、R5独立地选自:-H、-Ara、-Glc、-Rha1-2Ara、-Glc1-6Glc。
同时,在本发明中还进一步公开了该药物中还包括有药学上可接受的载体或赋形剂,以及制备相应剂型所用的辅料。
药物的剂型可以根据选择为胶囊剂、片剂、颗粒剂、注射剂、丸剂、糖浆剂、散剂、膏剂等。
本发明为青钱柳这一传统中药材的现代用药提供了思路。青钱柳皂苷化合物中,特别是通式1-通式5中所定义的化合物具有优秀的P-AMPK、G6Pase、PEPCK的蛋白和基因表达调控能力,能够显著抑制肝脏糖异生,在针对糖尿病、肥胖、非酒精性脂肪肝的治疗药物中具有极高的应用前景。
附图说明
图1是5种青钱柳皂苷化合物结构式
图2是5种青钱柳皂苷对小鼠原代肝细胞糖异生的抑制作用结果示意图。
图3是小鼠原代肝细胞mRNA图。
图4是两种皂苷的蛋白印记法-免疫印迹实验(Western blot)图。
图5是图3的定量图。
图6是三种皂苷元的蛋白印记法-免疫印迹实验(Western blot)图。
图7是图5的定量图。
具体实施方式
为了更好的理解本发明,下面我们结合具体的实施例对本发明进行进一步的阐述。
实施例1青钱柳皂苷化合物的提取和纯化
取2.5kg青钱柳干燥粉末用80%乙醇回流提取(20L×3,每次2h)。合并提取物,减压浓缩无醇味后加适量水混悬,用石油醚脱脂并用氯仿分离,得到氯仿部位提取物171.9g。取部分氯仿提取物用3%NaOH水溶液提取后,水相部分用5%HCl溶液反复萃取3次,得到三萜酸富集部位84.7g(得率为3.39%)。主要化合物pterocaryoside B(化合物1)、cyclocarioside H(化合物2)、arjunolic acid(化合物3)、3β,23-dihydroxy-12-ene-28-ursolic acid(化合物4)、2a,3a,23-trihydroxyurs-12-en-28-oic(化合物5)经吴正凤等人综合运用UV、HPLC-MS、NMR等现代光谱学技术,进行分析和鉴定得出(如图1所示)。
实施例2青钱柳皂苷化合物肝脏糖异生抑制活性试验
分别以实施例1中获得化合物1、化合物2、化合物3、化合物4和化合物5作为给药试剂,以二甲双胍作为阳性对照药,考察青钱柳皂苷化合物对肝脏糖异生的抑制活性。
试验方法:
将原代肝细胞分为八组,按1.5*105个/ml接种于24孔板,贴壁4h后更换为无血清培养基培养,继续培养18h,分为正常对照组(NC组,2mM pyruvate+20mM乳酸)、模型组(M组,2mM pyruvate+20mM乳酸+100nM glucagon)、给药组(分别为10μM的化合物1、化合物2、化合物3、化合物4和化合物5)和二甲双胍组(Met组,150μM Metformin),共孵育6h后,取上清,4℃、10000rpm离心3min,葡萄糖测试盒测定上清中葡萄糖含量,同时用BCA试剂盒检测各孔中蛋白浓度以校正葡萄糖含量。
试验结果如图2所示,图中由左至右分别为:正常对照组、模型组、化合物1-5组和二甲双胍组的抑制活性结果示意,其中化合物1-5对肝糖异生的抑制率分别为21.63%、15.86%、16.25%、19.11%、14.92%,二甲双胍对肝糖异生的抑制率为28.85%(与模型组比较,##P<0.05,##P<0.01)。
由图2可以看出,以化合物1、化合物2、化合物3、化合物4、化合物5为代表的青钱柳皂苷具有很高的肝脏糖异生抑制作用。
实施例3青钱柳皂苷化合物PEPCK、G6Pase mRNA抑制活性试验
分别以实施例1中获得化合物1、化合物2、化合物3、化合物4和化合物5作为给药试剂,以二甲双胍作为阳性对照药,考察青钱柳皂苷化合物对肝脏糖异生的抑制活性。
试验方法:
将原代肝细胞接种于6孔板,按实施例2处理细胞后,用Trizol试剂抽提细胞总RNA,酶标仪测定A260/280及其浓度,A260/280在1.8~2.0视为提取纯度合适,按照逆转录试剂盒将RNA逆转录为cDNA。按照PCR试剂盒进行后续PCR反应。
试验结果如图3所示,图中由左至右分别为:正常对照组、模型组、化合物1-5组和二甲双胍组的G6Pase、PEPCK基因表达结果示意,其中化合物1-5对基因G6Pase的抑制率分别为26.28%、23.12%、35.65%、38.13%、32.96%,二甲双胍对基因G6Pase的抑制率为60.75%,化合物1-5对基因PEPCK的抑制率分别为38.05%、34.18%、46.04%、46.00%、49.62%,二甲双胍对基因PEPCK的抑制率为53.09%(与模型组比较,#P<0.05,##P<0.01)。
由图3可以看出,以化合物1、化合物2、化合物3、化合物4、化合物5为代表的青钱柳皂苷具有很好的G6Pase、PEPCK基因表达抑制作用。
实施例4青钱柳皂苷化合物PEPCK、G6Pase蛋白抑制活性试验
分别以实施例1中获得化合物1、化合物2、化合物3、化合物4和化合物5作为给药试剂,以二甲双胍作为阳性对照药,考察青钱柳皂苷化合物对肝脏糖异生关键酶G6Pase、PEPCK的蛋白抑制活性。
试验方法:
将原代肝细胞接种于6孔板,按实施例2处理细胞后,每孔加入150μL RIPA裂解液(含1%PMSF),在冰上裂解5min,刮下细胞,转移到1.5ml EP管,4℃13000rpm离心20min,收集上清液,用BCA试剂盒测定蛋白浓度。将蛋白质样品稀释至相同浓度,配制10%分离胶及5%浓缩胶,进行SDS-PAGE电泳,经半干转到PVDF膜上,用含5%脱脂奶粉的TBST溶液室温封闭2h,加入一抗孵育,4℃过夜。TBST洗涤3次,然后加入二抗37℃孵育1h,TBST洗涤3次,电化学发光检测法显色,Image pro plus 6.0软件扫描蛋白条带灰度值并进行灰度值分析。
试验结果如图4-图7所示。
其中,图5中由左至右分别为:正常对照组、模型组、化合物1-2组和二甲双胍组的G6Pase、PEPCK蛋白表达结果示意,其中化合物1-2对蛋白G6Pase的抑制率分别为35.61%、26.54%,二甲双胍对蛋白G6Pase的抑制率为32.07%,化合物1-2对蛋白PEPCK的抑制率分别为36.18%、37.28%,二甲双胍对蛋白PEPCK的抑制率为34.30%(与模型组比较,#P<0.05,##P<0.01)。
图7中由左至右分别为:正常对照组、模型组、化合物3-5组和二甲双胍组的G6Pase、PEPCK蛋白表达结果示意,其中化合物3-5对蛋白G6Pase的抑制率分别为24.73%、28.23%、26.04%,二甲双胍对蛋白G6Pase的抑制率为31.81%,化合物3-5对蛋白PEPCK的抑制率分别为28.19%、31.68%、38.24%,二甲双胍对蛋白PEPCK的抑制率为48.97%(与模型组比较,#P<0.05,##P<0.01)。
根据图4-图7可以看到,以化合物1、化合物2、化合物3、化合物4、化合物5为代表的青钱柳皂苷具有很好的PEPCK、G6Pase蛋白抑制作用。
以上所述是本发明的具体实施方式。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为本发明的保护范围。
Claims (10)
1.青钱柳皂苷及其衍生物和其医药学上可接受的盐或前体化合物在制备抑制肝脏糖异生药物中的应用。
2.青钱柳皂苷及其衍生物和其医药学上可接受的盐或前体化合物在制备对P-AMPK、G6Pase、PEPCK的蛋白和基因表达具有调控作用的药物中的应用。
3.青钱柳皂苷及其衍生物和其医药学上可接受的盐或前体化合物在制备通过调控P-AMPK、G6Pase、PEPCK的蛋白和基因表达抑制肝脏糖异生药物中的应用。
4.根据权利要求3所述的应用,其特征是,所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗肥胖的药物中的应用。
5.根据权利要求3所述的应用,其特征是,所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗糖尿病的药物中的应用。
6.根据权利要求3所述的应用,其特征是,所述青钱柳皂苷及其衍生物、和其医药学上可接受的盐或前体化合物在制备治疗非酒精性脂肪肝的药物中的应用。
9.根据权利要求8所述的药物,其特征是,还包括有药学上可接受的载体或赋形剂,以及制备相应剂型所用的辅料。
10.根据权利要求8所述的药物,其特征是,所述药物为胶囊剂、片剂、颗粒剂、注射剂、丸剂、糖浆剂、散剂、膏剂等。
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