CN117323323A - 奇楠成分对ampk的激活作用 - Google Patents
奇楠成分对ampk的激活作用 Download PDFInfo
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- CN117323323A CN117323323A CN202311047909.8A CN202311047909A CN117323323A CN 117323323 A CN117323323 A CN 117323323A CN 202311047909 A CN202311047909 A CN 202311047909A CN 117323323 A CN117323323 A CN 117323323A
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- ampk
- hydrogen
- complications
- diabetes
- alkoxy
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Abstract
奇楠成分对AMPK的激活作用,本发明公开了一种式I的化合物或其药学上可接受的盐在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途,其中,R1为氢或C1‑12烷氧基,R2为氢或C1‑12烷氧基,R3为氢,R4为氢或C1‑12烷氧基。本发明所述的化合物能够显著激活AMPK的体外活性,并能够促进葡萄糖摄取,可应用在制备与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中。
Description
技术领域
本发明涉及医药技术领域,具体涉及奇楠成分对AMPK的激活作用。
背景技术
奇楠(沉香)(简称“奇楠”)是白木香(Aquilaria sinensis(Lour.)Gilg)的一种特殊种质所产沉香,在多个文献中作为优质的药用沉香记载,然而由于奇楠(沉香)的资源珍稀和历史原因,很长时间里奇楠(沉香)非常稀缺。近几年,随着奇楠人工培育技术逐渐成熟,奇楠(沉香)初步形成产业并且仍在蓬勃发展。然而奇楠(沉香)产业目前存在缺乏质量标准以及对其开发利用不足等情况。
AMPK(一磷酸腺苷激活的蛋白激酶,Adenosin 5'-monophosphate(AMP)-activated protein kinase)是一种丝氨酸/苏氨酸激酶,广泛存在于真核细胞中。AMPK已被发现是治疗各种疾病的重要药物靶点,它是治疗糖尿病的一线临床药物二甲双胍的主要效应物,也被认为是控制代谢综合征、癌症等人类疾病的重要治疗靶点。AMP激活的蛋白激酶(AMPK)激动剂长期以来一直作为研究肥胖、糖尿病等代谢性疾病的国际热点。
具体而言,AMPK信号通路是一种能量的传感器和调节器,在促进各种组织中ATP的产生并抑制ATP的消耗过程中发挥着重要的作用。该激酶在应对耗尽细胞ATP供应的应激时被激活,如低血糖、缺氧、缺血和热休克。AMPK作为能够对低ATP水平作出高效反应的细胞能量传感器,AMPK的激活可以积极调节和补充细胞ATP供应的信号通路。例如,AMPK的激活可以有效促进GLUT4转录和易位,进而会导致机体受胰岛素刺激而产生的葡萄糖摄取增加。
作为脂质和糖代谢的中央调节器,AMPK被认为是治疗肥胖、二型糖尿病和癌症的关键治疗靶点。AMPK负调节ATP消耗过程中的几个核心蛋白质,如CREB转录共激活因子(TORC2)和糖原合酶最终都可以导致糖异生、糖原、脂质和蛋白质合成的下调或抑制。AMP活化蛋白激酶(AMPK)在调节细胞能量稳态中起着重要作用。这种酶在低ATP条件下被激活,通常由各种应激引起,并调节增加可用ATP供应的信号通路。
近年来,人们对AMPK激活和AMPK信号通路都有了许多新的认识。新的发现认为,葡萄糖水平下降时,AMPK能够在ATP水平下降之前就被激活,及时补充了潜在ATP的不足。
目前已知的AMPK的间接激活方式,主要有两种。其中更重要的是升高细胞内AMP/ATP的比值,如盐酸小檗碱、二甲双胍就是通过抑制呼吸链来增加AMP/ATP的比值以达到间接激活AMPK的效果,从而产生疗效。
AMPK作为机体能量调控过程中的重要激酶通过感知机体内ATP的水平高低,来维持细胞自身能量供应和营养补给。在低能量供应条件下,AMPK磷酸化特异性的酶和位点,能增加ATP生成,降低ATP消耗。在哺乳动物体内,当AMPK被激活,它的调控几乎作用于生命体的整个生理代谢过程,在蛋白质代谢、脂质代谢、糖类代谢、自噬和线粒体稳态四大类生理代谢活动中具有不可或缺的重要作用。遗传学和药理学研究表明,AMPK是机体保持葡萄糖平衡所必需的。AMPK的激活能积极改善由二型糖尿病引起的代谢失衡,然而激活AMPK的分子机制十分复杂,通过药物分子激活AMPK,找到能够高效激活AMPK且低副作用的AMPK激活剂,是治疗糖尿病所面临的一个巨大挑战。
而奇楠中的巨盘木型-2-2苯乙基色酮类化合物(简称“FTPECs”)未见与AMPK激活相关的糖尿病、肥胖症和/或其并发症的相关报道。
发明内容
基于此,本发明提供了一种式I的化合物或其药学上可接受的盐在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途,
其中,R1为氢或C1-12烷氧基,R2为氢或C1-12烷氧基,R3为氢,R4为氢或C1-12烷氧基。
进一步地,R1为氢或C1-8烷氧基,R2为氢或C1-8烷氧基,R4为氢或C1-8烷氧基。
进一步地,R1为氢或C1-3烷氧基,R2为氢或C1-3烷氧基,R4为氢或C1-3烷氧基。
进一步地,该化合物具有选自由以下组成的组的结构:
根据本发明的另一个方面,提供了一种包含上述化合物或其药学上可接受的盐的组合物在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途。
进一步地,该组合物进一步包括一种或多种药物和/或提取物。
进一步地,该药物包含降糖药。
进一步地,该降糖药选自以下的一种或多种:格列吡嗪、格列齐特、格列本脲、格列波脲、格列美脲、格列喹酮、阿卡波糖、伏格列波糖、吡格列酮、西格列汀、沙格列汀、维格列汀、二甲双胍、罗格列酮和胰岛素。
根据本发明的另一个方面,提供了一种包含上述化合物或其药学上可接受的盐或者上述组合物的制剂在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途。
进一步地,该制剂进一步包括一种或多种药学上可接受的辅料。
进一步地,该辅料选自以下的一种或多种:分散剂、润湿剂、粘合剂、稀释剂、助流剂、润滑剂、缓释剂、增塑剂、崩解剂、包合剂、矫味剂、遮光剂和抗氧化剂。
进一步地,该制剂的剂型为片剂、滴丸剂、胶囊剂、散剂、注射液、膜剂、锭剂、颗粒剂或口服液。
进一步地,该糖尿病包括I型糖尿病和/或II型糖尿病。
进一步地,该并发症为急性并发症和/或慢性并发症。
进一步地,该急性并发症为糖尿病酮症酸中毒、高渗性非酮症糖尿病昏迷和/或乳酸性酸中毒。
进一步地,该慢性并发症为大血管并发症、微血管并发症、神经病变和/或糖尿病足。
进一步地,该大血管并发症为心脑血管病变、冠心病、脑卒中和/或下肢坏疽。
进一步地,该微血管并发症为糖尿病视网膜病变和/或糖尿病肾病。
进一步地,与AMPK激活相关的糖尿病和/或其并发症相关的细胞为人肾上皮细胞系细胞。
进一步地,该人肾上皮细胞系细胞为HEK293T细胞。
进一步地,该化合物从奇楠或奇楠提取物获得。
进一步地,该AMPK激活是间接激活机制。
进一步地,该AMPK包含α2亚基、β1亚基和γ1亚基。
进一步地,该AMPK的活化发生在肌肉、肝脏和/或肾脏组织中。
本发明的有益效果:
本发明所述的化合物能够显著激活AMPK的体外活性,并能够促进葡萄糖摄取,可应用在制备与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中。
附图说明
为了更清楚地说明本发明实施例中的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,还可以根据这些附图获得其他的附图,而并不超出本发明要求保护的范围。
图1为奇楠乙醇提取物在293T细胞中激活AMPK的体外活性结果示意图。其中,结果以平均值±SD(n=3)的形式呈现,与溶剂对照(DMSO)相比,**p<0.01,***p<0.001。
图2为用不同浓度的PECs单体处理HEK 293T细胞并利用SDS-PAGE和Western Blot检测细胞裂解液中pAMPK和AMPK水平结果示意图。与溶剂对照(DMSO)相比,**p<0.01,***p<0.001。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
除非另外说明,本文所用的所有技术和科学术语和缩略语具有本发明领域或该术语应用领域中普通技术人员通常所理解的含义。虽然本发明实施过程中可使用类似于或等价于本文公开的那些的任何方法、条件、物质或材料,但本文描述了优选的方法、条件物质或材料。
本发明有预期地涵盖所有的选择余地、变体和同等物,这些可能如权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质,这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。
说明书和所附权利要求中所用的单数形式“一个”,“一种”和“所述”包括复数指示物,除非上下文另有明确规定。
在本发明中,术语“包括”与“包含”同义。本文中所用的术语“包含”、“包括”、“具有”、“含有”或其任何其它变形,意在覆盖非排它性的包括。例如,包含所列要素的组合物、步骤、方法、制品或装置不必仅限于那些要素,而是可以包括未明确列出的其它要素或此种组合物、步骤、方法、制品或装置所固有的要素。
正如背景技术部分所描述的,奇楠中的巨盘木型-2-2苯乙基色酮类化合物未见与AMPK激活相关的糖尿病、肥胖症和/或其并发症的相关报道的问题。为了解决上述问题,本发明提供了一种式I的化合物或其药学上可接受的盐在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途,
其中,R1为氢或C1-12烷氧基,R2为氢或C1-12烷氧基,R3为氢,R4为氢或C1-12烷氧基。
在一种优选的实施方式中,R1为氢或C1-8烷氧基,R2为氢或C1-8烷氧基,R4为氢或C1-8烷氧基。
在一种优选的实施方式中,R1为氢或C1-3烷氧基,R2为氢或C1-3烷氧基,R4为氢或C1-3烷氧基。
在一种优选的实施方式中,该化合物具有选自由以下组成的组的结构:
根据本发明的另一个方面,提供了一种包含上述化合物或其药学上可接受的盐的组合物在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途。
在一种优选的实施方式中,该组合物进一步包括一种或多种药物和/或提取物。
在一种优选的实施方式中,该药物包含降糖药。
在一种优选的实施方式中,该降糖药选自以下的一种或多种:格列吡嗪、格列齐特、格列本脲、格列波脲、格列美脲、格列喹酮、阿卡波糖、伏格列波糖、吡格列酮、西格列汀、沙格列汀、维格列汀、二甲双胍、罗格列酮和胰岛素。
根据本发明的另一个方面,提供了一种包含上述化合物或其药学上可接受的盐或者上述组合物的制剂在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途。
在本发明中,术语“治疗”也包括“预防”,除非存在与此相反的具体说明。术语“治疗(的)”和“治疗(地)”应该作相应的理解。
在本发明中,术语“治疗”,包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善或预防潜在代谢综合症;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防或治疗由疾病或症状引起的征兆。如本文所用,某一组合物或某一制剂,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
在一种优选的实施方式中,该制剂进一步包括一种或多种药学上可接受的辅料。
在一种优选的实施方式中,本发明的制剂含有相对于制剂的重量计算总量为0.00001至50wt.%、或0.0001至10wt.%、或0.0001至5wt.%、或0.005至1wt.%、或0.1至20wt.%、或0.5至15wt.%、或1至5wt.%的至少一种药学上可接受的辅料。
在本发明中,术语“药学上可接受”这里指一种物质,如载体或稀释液,不会使化合物的生物活性或性质消失,且相对无毒,如,给予个体某物质,不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
在本发明中,术语“药学上可接受的辅料”是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂,其是本领域公知的(参见例如Remington's PharmaceuticalSciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)。
在一种优选的实施方式中,该辅料选自以下的一种或多种:分散剂、润湿剂、粘合剂、稀释剂、助流剂、润滑剂、缓释剂、增塑剂、崩解剂、包合剂、矫味剂、遮光剂和抗氧化剂。
本领域技术人员将知晓如何选择具体的在上述辅料类别范围内的化学物质。例如,该分散剂可选自以下的一种或多种:交联羧甲基纤维素钠、淀粉甘醇钠和预明胶化的玉米淀粉。该润湿剂可选自以下的一种或多种:硬脂酸聚甲醛、泊洛沙姆、聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯烷基醚、聚山梨醇酯如聚山梨醇酯80、鲸蜡醇、甘油脂肪酸酯(如三醋精、甘油单硬脂酸酯和类似物)、聚氧乙烯脂肪酸酯、聚乙二醇脂肪酸酯、十二烷基硫酸钠、山梨醇脂肪酸酯、蔗糖脂肪酸酯、聚氧乙烯醚、苯扎氯铵、聚氧乙烯蓖麻油和多库酯钠。该粘合剂可选自以下的一种或多种:聚乙烯吡咯烷酮、羟丙基纤维素、聚乙二醇和甲基纤维素。该稀释剂可选自以下的一种或多种:糖粉、淀粉、可压性淀粉、乳糖、糊精、甘露醇、山梨醇、微晶纤维素、硫酸钙和碳酸钙。该助流剂为微粉硅胶。该润滑剂可选自以下的一种或多种:硬脂酸钙、滑石粉、硬脂酸镁、硬脂酸和胶态二氧化硅。该缓释剂可选自以下的一种或多种:羧甲基纤维素钠、低取代的羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、羟乙基纤维素、阿拉伯胶、明胶和紫胶。该增塑剂可以是二丁基癸二酸酯和/或各种柠檬酸酯。该崩解剂可选自以下的一种或多种:羧甲基纤维素、羧甲基纤维素钙盐和羧甲基纤维素钠。该包合剂为羟丙基倍他环糊精。该矫味剂可选自以下的一种或多种:山梨醇、葡萄糖、甘露糖、蔗糖和乳糖。该遮光剂为二氧化钛。该抗氧化剂可选自以下的一种或多种:亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠和硫代硫酸钠。
这些辅料优选为药物惰性的,或者可以具有协同或增加作用,以增强药物组合物的治疗活性,并且上述辅料仅是列举式的,本发明实际使用的辅料并不限于上述辅料,可根据实际情况进行调整,均能实现本发明的效果。
在一种优选的实施方式中,该制剂的剂型为片剂、滴丸剂、胶囊剂、散剂、注射液、膜剂、锭剂、颗粒剂或口服液。
在一种优选的实施方式中,该糖尿病包括I型糖尿病和/或II型糖尿病。
在一种优选的实施方式中,该并发症为急性并发症和/或慢性并发症。
在一种优选的实施方式中,该急性并发症为糖尿病酮症酸中毒、高渗性非酮症糖尿病昏迷和/或乳酸性酸中毒。
在一种优选的实施方式中,该慢性并发症为大血管并发症、微血管并发症、神经病变和/或糖尿病足。
在一种优选的实施方式中,该大血管并发症为心脑血管病变、冠心病、脑卒中和/或下肢坏疽。
在一种优选的实施方式中,该微血管并发症为糖尿病视网膜病变和/或糖尿病肾病。
在一种优选的实施方式中,与AMPK激活相关的糖尿病和/或其并发症相关的细胞为人肾上皮细胞系细胞。
在一种优选的实施方式中,该人肾上皮细胞系细胞为HEK293T细胞。
在一种优选的实施方式中,该化合物从奇楠或奇楠提取物获得。
在一种优选的实施方式中,该AMPK激活是间接激活机制。
在一种优选的实施方式中,该AMPK包含α2亚基、β1亚基和γ1亚基。
在一种优选的实施方式中,该AMPK的活化发生在肌肉、肝脏和/或肾脏组织中。
根据本发明的另一个方面,提供了一种上述化合物、上述组合物或上述制剂,用于预防和/或治疗受试者中的与AMPK激活相关的糖尿病、肥胖症和/或其并发症。
根据本发明的另一个方面,提供了一种预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的方法,包括向该受试者施用有效量的上述化合物、上述组合物或上述制剂。
在本发明中,术语“受试者”是哺乳动物。哺乳动物可以是人、非人灵长类动物、小鼠、大鼠、狗、猫、马或牛,但不限于这些实例。除人以外的哺乳动物可以有利地用作代表与AMPK激活相关的糖尿病、肥胖症和/或其并发症模型的受试者。优选地,所述受试者是人。
本发明所用的组合物或制剂的“有效量”可以获得所需要的治疗和/或预防效果。对此用途有效的量将取决于例如药物组合物、给药方式、治疗的疾病的阶段和严重性、个体体重和总体健康状况、以及处方医师的判断。剂量的给予可以每周一次,或两天或每天一次,或甚至每天几次。可以在短期(例如数周至数月)或更长时间段(数月至数年)给予剂量单元。
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。下列实施例中未注明具体条件的实验方法,通常按照常规条件或制造厂商所建议的条件。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
实施例
1.材料与仪器
1.1材料
人源肾胚上皮细胞株HEK293T细胞(清华大学生命科学学院保藏,原购自AmericanType Culture Collection,ATCC)和3T3-L1小鼠脂肪前体细胞(购自American TypeCulture Collection,ATCC);抗AMPK磷酸化和抗AMPK总量抗体(美国Cell Signalling公司);抗β-actin的抗体(北京BI公司);PBS磷酸盐缓冲液(Hyclone);南美胎牛血清(Gibco);青链霉素双抗混合液(Hyclone);胰蛋白酶(trypsin);PVDF膜(美国Millipore公司);葡萄糖摄取试剂盒(Promega);DMEM高糖培养基(Gibco);OPTI-MEM培养基(Hyclone);支原体抑制剂(ScienCell);地塞米松(DEX)、二甲基亚砜(DMSO)、胰岛素(Insulin)、1-甲基-3-异丁醇黄嘌呤(IBMX)、5'-ATP二钠盐、5'-AMP二钠盐、5'-ADP二钠盐、二甲双胍(Met)、盐酸小檗碱(BBR)和Compund C均来源于美国Sigma公司。奇楠样品经中国中医科学院中药研究所张志杰研究员鉴定后,保存于中药所生药中心药材储藏室。
4’-甲氧基沉香四醇(批号:AF21042706,纯度≥98%,MW:348.3g/mol,编号A131)购自于成都埃法生物科技有限公司。
2-(2-苯乙基)色酮(批号:PS020524,纯度>98%,MW:250.29g/mol,编号A82)购自于成都普思生物科技股份有限公司。
6,7-二甲氧基-2-(苯乙基)色酮(批号:AF22030801,纯度≥98%,MW:310.3g/mol,编号A87)购自于成都埃法生物科技有限公司。
2-[2-(4’-甲氧基苯)乙基]色酮(纯度≥98%,MW:280.3g/mol,编号A102)购自于中国热带农业科学院。
1.2仪器
Scientz-IID型超声波细胞破碎仪(宁波新芝生物公司),DYCZ-24DN型电泳仪(北京六一仪器厂),ELITE II型二氧化碳恒温培养箱(Revco公司)。
2.实验方法
2.1药物制备
精密称取奇楠样品5g,加入500ml 95%乙醇,室温浸泡半小时后微沸回流提取1小时。提取结束冷却后用8层纱布和0.45μm微孔滤膜过滤,滤液旋转蒸发去除溶剂,加入DMSO溶解,制备成250mg/ml奇楠提取液,冰箱冷藏保存备用。细胞给药时,奇楠的提取物溶于DMSO,DMSO的最终浓度为0.1%对细胞无毒性。
精密称取各单体化合物(A131、A82、A87、A102、BBR)10mg,加入DMSO溶液溶解,并定容至10ml容量瓶,配制成1mg/ml供试品。
2.2人肾上皮细胞系HEK293T细胞的培养和药物处理
HEK293T细胞在提前配制的含有10%胎牛血清和1%双抗的DMEM完全培养基中进行培养,CO2细胞培养箱中温度37℃、二氧化碳含量5%,细胞培养过程中每隔24h更换培养基,待细胞密度达80%左右即可进行药物处理。处理细胞时,将不同浓度各单体化合物(A131、A82、A87、A102、BBR)加入提前配制的完全培养基(DMEM+0.5%不含脂肪酸牛血清白蛋白(BSA)+1%双抗)中培养1h后收集细胞。
2.3SDS-聚丙烯酰胺凝胶电泳和蛋白质印迹检测
给药后收集细胞后加入含有蛋白酶抑制剂和磷酸酶抑制剂的细胞裂解液在4℃下进行裂解2小时,然后将细胞裂解液离心后取上清液,用β-巯基乙醇处理样品30分钟,并煮沸5分钟使蛋白质变性。将细胞裂解液进行SDS-PAGE凝胶电泳分离,以湿转法将分离后的蛋白转移PVDF膜上,接着用5%脱脂奶粉的TBST溶液室温封闭2h,再用抗AMPK抗体(CellSignaling)和抗p-AMPK抗体(Cell Signaling)在4℃下孵育过夜,然后用山羊抗兔辣根过氧化物酶标记的二抗(Santa Cruz)在室温下孵育1小时,充分洗膜后加入发光物,放入暗室曝光感光胶片,再拍照并处理图谱数据。
其中AMPK总量作为参照,使用NIH Image J软件分析并获取不同浓度点pAMPK和AMPK蛋白免疫印迹条带灰度值,以pAMPK/AMPK比值代表AMPK磷酸化水平,利用GraphPadPrism 6.0对pAMPK/AMPK进行统计分析,**即p<0.01以及***即p<0.001表明差异具有显著统计学意义。
2.4葡萄糖摄取-生物体外分析
葡萄糖摄取检测实验通过Promega葡萄糖摄取检测试剂盒完成,用试剂盒对各单体化合物各单体化合物(A131、A82、A87、A102)处理后的成熟的3T3-L1脂肪细胞葡萄糖摄取能力进行检测。试剂盒从-20℃冰箱中取出解冻。按照试剂盒的使用说明,试剂盒中的中和缓冲液和终止缓冲液于4℃保存,其余组分在-20℃保存。实验方法如下:
(1)细胞处理
3T3-L1细胞诱导至第7天成为成熟的脂肪细胞。换液,除去维持液,加入含有药物的全培养基处理24h,在37℃,5% CO2的细胞培养箱培养。
(2)脱糖处理
对细胞进行24h各单体化合物(A131、A82、A87、A102)处理后,移除培养基,加入含有各单体化合物(A131、A82、A87、A102)的无糖无血清无抗培养基饥饿处理2-3h,于37℃,5% CO2细胞培养箱培养。
(3)胰岛素激活
移除(2)中培养基,加入含有10μg/mL胰岛素的PBS溶液,于37℃、5% CO2的细胞培养箱中激活10min,移除胰岛素,用PBS清洗2-3次。
(4)配制2DG6P检测反应液
提前1h配制该反应液。按照100μL/样品的体积,根据试剂盒说明书提供的各组比例配制。
(5)配制细胞反应液
用PBS小心清洗胰岛素处理过的细胞以及未激活的细胞。用1mM2DG溶液于37℃,5% CO2细胞培养箱中处理20分钟,加入2DG一半体积的终止缓冲液终止细胞的葡萄糖摄取反应并裂解细胞。振摇数次,细胞彻底裂解后,加入与终止缓冲液相同体积的中和缓冲液。把上述全部液体收集到离心管中,在室温下离心机5000g离心5min,收集上清液,作为实验所需的细胞反应液。
(6)葡萄糖摄取的检测
取100μL细胞反应液与100μL 2DG6P检测反应液放入96孔板中充分混合,避光孵育1h(室温),在EnSpire多模式微孔板检测仪上检测各实验组的荧光强度。
2.5数据处理及统计学分析
蛋白质印迹法条带分析采用NIH Image J图像分析软件,采用GraphPad Prism6.0进行统计学分析包括单因素方差分析(ANOVA)和均值比较。**表示p<0.01以及***表示p<0.001说明结果具有显著的统计学差异。
3.结果
3.1奇楠活性验证
为了检测奇楠提取物是否能够激活AMPK,我们用不同浓度的奇楠醇提物处理HEK293T细胞1小时,然后用SDS-PAGE和Western Blot(蛋白免疫印迹)检测细胞裂解液中pAMPK(Thr-172)及AMPK水平。如图1所示,经奇楠醇提物处理后,细胞中pAMPK水平呈剂量依赖性升高。Western Blot分析结果展示奇楠醇提物均能够在体外HEK293T细胞中激活AMPK,均具有AMPK激活活性并且以活性-剂量依赖的方式激活。在120μg/ml的浓度下奇楠乙醇提取物的AMPK激活能力甚至强于阳性药物二甲双胍。
3.2FTPECs类与THPECs类单体成分活性验证及比较
本实验进一步对成分分析筛选获得的奇楠FTPECs类成分以及THPECs成分进行活性差异比较,选取了其中3个FTPECs单体成分以及1个THPECs进行AMPK激动活性的体外活性验证,按照“2.2、2.3”项下方法将选定的FTPECs类单体成分分别处理细胞,用SDS-PAGE和Western Blot(蛋白免疫印迹)检测细胞裂解液中pAMPK(Thr-172)及AMPK水平,如图2所示,化合物A82、A87、A102均呈现剂量依赖关系,给药浓度越高,AMPK172位苏氨酸的磷酸化水平越高,这表明这些化合物均具有显著的AMPK激活能力,而化合物A131未表现出AMPK激活能力。
3.3葡萄糖摄取-生物体外分析
本发明的化合物A82、A87和A102在1~600mM浓度下能够促进3T3-L1脂肪细胞的葡萄糖摄取,相对于DMSO对照组而言,葡萄糖摄取率(%)大于100%,小于350%。
以上对本发明实施例进行了详细介绍,本文中应用了具体个例对本发明的原理及实施方式进行了阐述,以上实施例的说明仅用于帮助理解本发明的方法及其核心思想。同时,本领域技术人员依据本发明的思想,基于本发明的具体实施方式及应用范围上做出的改变或变形之处,都属于本发明保护的范围。综上所述,本说明书内容不应理解为对本发明的限制。
Claims (10)
1.一种式I的化合物或其药学上可接受的盐在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途,
其中,R1为氢或C1-12烷氧基,R2为氢或C1-12烷氧基,R3为氢,R4为氢或C1-12烷氧基。
2.根据权利要求1所述的用途,其特征在于,R1为氢或C1-8烷氧基,R2为氢或C1-8烷氧基,R4为氢或C1-8烷氧基;
优选地,R1为氢或C1-3烷氧基,R2为氢或C1-3烷氧基,R4为氢或C1-3烷氧基。
3.根据权利要求1所述的用途,其特征在于,所述化合物具有选自由以下组成的组的结构:
4.一种包含权利要求1至3中任一项所述的化合物或其药学上可接受的盐的组合物在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途;
优选地,所述组合物进一步包括一种或多种药物和/或提取物;
更优选地,所述药物包含降糖药;
又优选地,所述降糖药选自以下的一种或多种:格列吡嗪、格列齐特、格列本脲、格列波脲、格列美脲、格列喹酮、阿卡波糖、伏格列波糖、吡格列酮、西格列汀、沙格列汀、维格列汀、二甲双胍、罗格列酮和胰岛素。
5.一种包含权利要求1至3中任一项所述的化合物或其药学上可接受的盐或者权利要求4所述的组合物的制剂在制备用于预防和/或治疗与AMPK激活相关的糖尿病、肥胖症和/或其并发症的药品、食品、饮料或饮食补充剂中的用途;
优选地,所述制剂进一步包括一种或多种药学上可接受的辅料;
更优选地,所述辅料选自以下的一种或多种:分散剂、润湿剂、粘合剂、稀释剂、助流剂、润滑剂、缓释剂、增塑剂、崩解剂、包合剂、矫味剂、遮光剂和抗氧化剂;
又优选地,所述制剂的剂型为片剂、滴丸剂、胶囊剂、散剂、注射液、膜剂、锭剂、颗粒剂或口服液。
6.根据权利要求1至5中任一项所述的用途,其特征在于,所述糖尿病包括I型糖尿病和/或II型糖尿病;
优选地,所述并发症为急性并发症和/或慢性并发症;
更优选地,所述急性并发症为糖尿病酮症酸中毒、高渗性非酮症糖尿病昏迷和/或乳酸性酸中毒;
又更优选地,所述慢性并发症为大血管并发症、微血管并发症、神经病变和/或糖尿病足;
尤其优选地,所述大血管并发症为心脑血管病变、冠心病、脑卒中和/或下肢坏疽;
特别优选地,所述微血管并发症为糖尿病视网膜病变和/或糖尿病肾病。
7.根据权利要求1至5中任一项所述的用途,其特征在于,与AMPK激活相关的糖尿病和/或其并发症相关的细胞为人肾上皮细胞系细胞,例如HEK293T细胞。
8.根据权利要求1至5中任一项所述的用途,其特征在于,所述化合物从奇楠或奇楠提取物获得。
9.根据权利要求1至5中任一项所述的用途,其特征在于,所述AMPK激活是间接激活机制;
优选地,所述AMPK包含α2亚基、β1亚基和γ1亚基。
10.根据权利要求1至5中任一项所述的用途,其特征在于,所述AMPK的活化发生在肌肉、肝脏和/或肾脏组织中。
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