CN101284001B - 芒果甙元在制备预防和治疗ii型糖尿病药物中的应用 - Google Patents
芒果甙元在制备预防和治疗ii型糖尿病药物中的应用 Download PDFInfo
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Abstract
本发明属于生物制药及分子生物学技术领域，具体涉及一种四羟基吡啶芒果甙元(norathyriol)在治疗II型糖尿病中的应用。293A细胞和芒果甙元共同孵育24小时后，293A细胞的UCP2(Uncoupling Protein 2，解偶联蛋白2)基因表达水平显著下调。本发明阐明了芒果甙元可以抑制293A细胞UCP2基因的表达，可在制备预防和治疗II型糖尿病药物中应用，并提出了一个治疗II型糖尿病药物的体外试验模型。
Description
一、技术领域
本发明属于生物制药及分子生物学技术领域，具体涉及芒果甙元在治疗II型糖尿病中的应用。
二、背景技术
II型糖尿病的病因主要包括胰岛细胞功能异常和胰岛素抵抗。胰岛细胞功能异常是一种复杂的现象，包括对葡萄糖感应的丧失，导致GSIS(glucose-stimulated insulin secretion)损害等。
UCP2(Uncoupling Protein 2，解偶联蛋白2)是解偶联蛋白家族的成员，为一种位于线粒体内膜上的阳离子载体蛋白。它可以引起质子的渗漏，使氧化磷酸化解偶联，ATP合成减少，能量以热的形式散失。UCP2是胰岛素分泌的负调节分子。首先，它介导了线粒体内膜的质子渗漏，这已被一系列的研究所证明，这些研究的对象涵盖了原脂质体、线粒体以及完整细胞(Proc.Natl.Acad.Sci.，99：118-122，2002)。胰岛β细胞中，如果ATP/ADP比值增高，会使ATP敏感的K+通道关闭，细胞膜去极化，Ca2+内流，从而导致胰岛素分泌。UCP2介导的质子渗漏会减少ATP合成，损害胰岛素分泌，从而负调节葡萄糖刺激的胰岛素分泌(glucose-stimulated insulin secretion，GSIS)。ob/ob小鼠是肥胖导致的糖尿病动物模型，在该小鼠胰岛中，UCP2表达显著升高。另外，高血糖也能导致胰岛内UCP2表达升高。更重要的是，在ob/ob小鼠中敲除UCP2，胰岛素分泌的第一相能得到恢复，并且血清中胰岛素含量升高，高血糖症状也得到改善(Cell，105：745-755，2001)。这些结果充分说明，UCP2在高血糖以及肥胖导致的胰岛功能异常中发挥了重要作用。因此，有效抑制UCP2基因在胰岛等组织中的表达对治疗II型糖尿病有较大意义，具有该作用特点的药物可应用于II型糖尿病的治疗。
芒果甙元(norathyriol)是一种四羟基吡啶，是芒果甙的甙元。芒果甙属双苯吡酮类化合物，在漆树芒果树(Mangifera indica)，扁桃树(Mangifera persiciformis)的叶、果实、树皮，龙胆科植物东北龙胆(Gentiana manshurica kitag)、川西瘴芽菜(Swertia mussotii franch)，百合科植物知母(Anmarrhena asphodeloides bge.)，水龙骨科植物光石韦(Pyrrosia calvata(Bak)chma)等多种植物中存在。药理学研究表明，芒果甙可降低糖尿病模型小鼠(KK-Ay mice)的血糖并提高其胰岛素耐量，对正常小鼠无明显作用(1.Biol Pharm Bull，21(12)：1389-90，1998；2.Phytomedicine，8(2)：85-7，2001)。有报道，人肠道内的一种厌氧菌会切断芒果甙的C-C糖甙键，生成芒果甙元(1.Biol Pharm Bull，28(9)：1672-78，2005；2.BiolPharm Bull，28(11)：2035-39，2005)。因此，我们以芒果甙元为研究对象，运用分子生物学手段，揭示芒果甙元可下调293A细胞UCP2基因的表达，提示芒果甙的降血糖和提高胰岛素耐量的作用可能是通过芒果甙元来实现的。
三、发明内容
本发明需要解决的问题是采用现代细胞生物学和分子生物学实验方法，研究芒果甙元作为一种治疗II型糖尿病的药物的应用及其分子作用机制，提出UCP2很有可能是中医寒热理论的一个重要效应分子，是芒果甙元作用的靶点。同时，建立一种治疗II型糖尿病的体外试验模型。
本发明的技术方案如下：
1.本发明采用芒果甙元进行体外试验。芒果甙元是一种四羟基吡啶，其结构式为：
(1)细胞培养、孵育方法及处理：
293A细胞用含10％胎牛血清的DMEM高糖培养液，在95％空气+5％CO2的环境下培养于60mm培养皿中，细胞铺满培养皿80％左右时，弃去上清，加入含胎牛血清低于2％的DMEM高糖培养液和终浓度分别为10、50、100μM芒果甙元(用DMSO溶解，DMSO终浓度为0.1％)，对照组细胞不加芒果甙元。孵育24小时后弃去上清，加入Trizol 1mL，充分吹打后转入eppendoff管中，放置于-70℃冰箱中保存。
(2)细胞RNA的提取、RT-PCR和real-time PCR：
按RNA提取试剂盒操作，从细胞中提取总RNA，然后将RNA反转录成cDNA。然后用cDNA样品进行Q-PCR，内参为β-Actin(使用定量PCR引物、Eva Green染料)，比较对照组和给药组293A细胞中UCP2基因表达(其中具体分子生物学操作参照《分子克隆实验指南第三版上册》，2002，科学出版社)。
结果表明，本发明药物可显著降低293A细胞UCP2基因表达水平(p＜0.01)(图1)，提示芒果甙元可抑制293A细胞中UCP2表达。
本发明研究证明，芒果甙元可降低293A细胞UCP2基因表达水平，因而可以改善胰岛细胞的功能和胰岛素分泌，可制备成预防和治疗II型糖尿病的药物。
2.模型评价：
本发明研究提出了一种治疗II型糖尿病药物的体外试验模型，用待测药物芒果甙元和293A细胞孵育24小时，然后以UCP2为靶点，以定量PCR手段来测量组织中UCP2基因的表达水平。此模型优点在于其采用分子生物学手段，从mRNA水平上用定量的方法来判断药物的有效性，直接从分子水平揭示药物的作用靶点，较普通的定性方法更深入、更准确，对药物药效和毒性的综合评价提供了一个有益线索。
本发明与现有技术相比，其有益效果在于为中医药治疗II型糖尿病提供了现代分子生物学的体外试验模型，揭示了一些以芒果甙元为有效成分的中药治疗II型糖尿病的作用靶点，证明芒果甙元可作为一种治疗II型糖尿病的药物。
四、附图说明
图1为293A细胞UCP2基因的表达水平(定量PCR结果)。
对照组不加芒果甙元，其他条件同给药组；给药组与芒果甙元(终浓度分别为10、50、100μM)孵育24小时。注：各浓度给药组与对照组比较均p＜0.01。
五、具体实施方式
下面结合具体实施例对本发明做进一步的阐述，但不对其有任何限制。
材料与来源：
试剂：Trizol购自Invitrogen公司；逆转录酶和Taq酶购于大连宝生物工程有限公司；DMEM高糖培养液购自GIBICO公司；DMSO购自AMRESCO公司。本发明中芒果甙元由国家新药筛选中心南发俊教授实验室提供。
器材：OLYMPUS IX71显微镜；REVCO ELITE II细胞培养箱；AIR TECH超净工作台；BIO-RAD PTC-100 Programmable Thermal Controller；ABI 7300 RealTime PCR System。
实施例是将芒果甙元用无菌DMSO配制成浓度为50mM的溶液，每个60mm的培养皿加6mL的培养液和6μL的药液，对照组只加6mL培养液。
实施例1细胞培养、孵育方法
293A细胞用含10％胎牛血清的DMEM高糖培养液，在95％air+5％CO2的环境下培养于60mm培养皿中，细胞铺满培养皿80％左右时，弃去上清，加入含胎牛血清低于2％的DMEM高糖培养液6mL和芒果甙元药液6μL(浓度分别为10、50、100mM，芒果甙元用DMSO溶解，DMSO终浓度为0.1％)，对照组细胞不加芒果甙元，孵育24小时。
实施例2细胞RNA的提取、RT-PCR和real-time PCR
孵育24小时后弃去上清，每个培养皿加入1mL Trizol，充分吹打后转入1.5mL eppendoff管中，加入200μL氯仿，13200rpm离心10分钟，小心吸取上清至另一洁净的1.5mL eppendoff管中，加入等体积的异丙醇，13200rpm离心10分钟，弃上清，用75％乙醇洗涤沉淀，室温干燥。然后用20μL DEPC水溶解该沉淀，紫外分光法检测总RNA的浓度和纯度。
2μg RNA用于逆转录，反应体系为20μL，含2μg RNA，1mM dNTP，RNA酶抑制剂1U/μL，Olig(dT)18引物2.5pmol/μL，AMV逆转录酶0.5U/μL，轻轻混匀，42℃孵育1小时，70℃孵育10分钟，冰上放置2分钟。所得cDNA可用于real-time PCR。
real-time PCR为20μl反应体系，含1μL cDNA，1μL Eva Green染料，2mMMgCl2，0.2mM dNTP，1pmol/μl上、下游引物，0.025U/μL Taq酶，混匀。PCR反应条件：95℃5分钟，95℃30秒，60℃60秒(40个循环)72℃延伸3分钟。目的基因UCP2和内参β-Actin的引物序列：
定量PCR引物序列：
UCP2-sense：5’-CCGGTTACAGATCCAAGGAGAA-3’
UCP2-antisense：5’-TCAGAATGGTGCCCATCACA-3’
β-Actin-sense：5’-ACCGAGCGCGGCTACAG-3’
β-Actin-antisense：5’-CTTAATGTCACGCACGATTTCC-3’
结果用ABI 7300 SDS Software分析，见图1。
Claims (1)
1.芒果甙元其结构式为
在制备预防和治疗胰岛细胞功能异常引起的II型糖尿病药物中的应用。
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| CN2008100187690A CN101284001B (zh) | 2008-01-23 | 2008-01-23 | 芒果甙元在制备预防和治疗ii型糖尿病药物中的应用 |
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| CN2008100187690A CN101284001B (zh) | 2008-01-23 | 2008-01-23 | 芒果甙元在制备预防和治疗ii型糖尿病药物中的应用 |
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| CN101284001A CN101284001A (zh) | 2008-10-15 |
| CN101284001B true CN101284001B (zh) | 2010-07-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102657640A (zh) * | 2009-08-21 | 2012-09-12 | 南京大学 | 芒果苷元对ptp1b的抑制活性及其应用 |
| CN101669934B (zh) * | 2009-08-21 | 2013-05-29 | 南京大学 | 芒果苷元在制备治疗肥胖症的药物中的应用 |
| CN101693730B (zh) * | 2009-10-16 | 2012-07-18 | 天津中医药大学 | 芒果叶苷及其制备方法与应用 |
| CN102153536B (zh) * | 2011-03-03 | 2013-03-13 | 上海长征医院 | 一种芒果苷元衍生物及其制备方法和用途 |
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Non-Patent Citations (4)
| Title |
|---|
| Kanjana Sanugul et al.Isolation of a human intestinal bacterium thattransformsmangiferin to norathyriol and inducibility of theenzymethatcleaves a C-glycosyl bond.Biol Pharm Bull28 9.2005,28(9),1672-1678. |
| Kanjana Sanugul et al.Isolation of a human intestinal bacterium thattransformsmangiferin to norathyriol and inducibility of theenzymethatcleaves a C-glycosyl bond.Biol Pharm Bull28 9.2005,28(9),1672-1678. * |
| 杨璐.解偶联蛋白2与2型糖尿病.中国医师进修杂志29 4.2006,29(4),70-73. |
| 杨璐.解偶联蛋白2与2型糖尿病.中国医师进修杂志29 4.2006,29(4),70-73. * |
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