CN113679715A - 3-芳基香豆素类化合物的应用、胰岛素抵抗制剂 - Google Patents
3-芳基香豆素类化合物的应用、胰岛素抵抗制剂 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物生产领域,具体提供一种3-芳基香豆素类化合物的应用、胰岛素抵抗制剂。
背景技术
糖尿病是一种慢性的、多因素的代谢紊乱,以高血糖、胰岛素抵抗和胰岛β细胞功能障碍为特征的一种疾病。糖尿病患者极易并发心血管疾病,心血管并发症是糖尿病患者最主要的死亡原因。糖尿病目前已是继心脑血管疾病和恶性肿瘤之后的第三大威胁人类健康的非传染性疾病,给社会和经济带来了沉重的负担,严重威胁人类的健康。糖尿病本身并不可怕,可怕的是它的并发症。糖尿病并发症涉及全身各个器官,是导致血脑血管疾病、肾病、失明、足坏死等严重疾病的主要原因。国内外现有药物对于治疗糖尿病和糖尿病引起的并发症表现出了较好疗效。但具有较好协同生物活性的药物还亟待开发,这就需要我们对此类化合物进行深入活性研究,开发出具有预防和治疗糖尿病及其并发症的新药物。
Ⅱ型糖尿病的主要特征包括高血糖、胰岛素抵抗。胰岛素抵抗会导致PI3K/AKT信号通路调控的糖异生功能紊乱,导致高血糖的发生。持续高血糖会导致机体产生过量ROS,导致氧化应激现象的发生。
发明内容
本发明是针对上述现有技术的不足,提供一种3-芳基香豆素类化合物的应用。
本发明解决其技术问题所采用的技术方案是:结构式(I)所示的3-芳基香豆素类化合物在制备胰岛素抵抗制剂中的应用,
作为优选,所述胰岛素抵抗制剂用于促进HepG2细胞的葡萄糖吸收和糖原合成。
作为优选,所述胰岛素抵抗制剂用于促进AKT(Ser473)、GSK-3β(Ser9)的磷酸化,激活HepG2细胞胰岛素抵抗模型的PI3K/AKT信号通路。
作为优选,所述胰岛素抵抗制剂用于促进AMPK的Thr172磷酸化,激活AMPK信号通路。
作为优选,所述胰岛素抵抗制剂用于Nrf2-Keap1信号通路,促进Nrf2的表达,抑制Keap1的表达,改善抗氧化系统,从而改善胰岛素抵抗。
本发明进一步的技术任务是提供一种胰岛素抵抗制剂。
所述胰岛素抵抗制剂的有效成分包括结构式(I)所示的3-芳基香豆素类化合物。
作为优选,胰岛素抵抗制剂中结构式(I)所示的3-芳基香豆素类化合物的摩尔百分比含量为25-50uM,优选为30uM。
所述胰岛素抵抗制剂为药品或保健品。
所述胰岛素抵抗制剂还包括一种或多种药学上可以接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
所述胰岛素抵抗制剂可以经口服或非口服等形式使用,如可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
用于口服时,可以将其制成常规的固体制剂,如片剂、粉剂、颗粒剂、胶囊、膏剂、霜剂等;制成液体制剂如水或油悬浮剂或其它液体制剂,如口服液等。用于非口服时,可将其制成注射液等。
Nrf2参与抗氧化的信号通路,维持氧化还原的内环境稳态。Keap1与Nrf2相互作用,使Nrf2向细胞核转移过程受阻,抑制抗氧化基因转录。AMPK磷酸化也能够降解Keap1,产生Nrf2,Nrf2积累又会促进AMPK磷酸化。AKT激活能磷酸化Keap1释放Nrf2,Nrf2减少会抑制PI3K/AKT信号通路,所以Nrf2-Keap1信号通路在改善胰岛素抵抗和氧化应激方面起关键作用。申请人建立了葡萄糖胺诱导的HepG2细胞胰岛素抵抗模型,并从细胞水平探讨结构式(I)化合物改善肝脏胰岛素抵抗的机制。发现结构式(I)化合物可以改善葡萄糖胺引起的细胞损伤,促进HepG2细胞的葡萄糖吸收以及糖原合成。通过Western Blot结果可以发现,结构式(I)化合物能够促进AKT(Ser473)、GSK-3β(Ser9)的磷酸化,激活HepG2细胞胰岛素抵抗模型的PI3K/AKT信号通路。还能够促进AMPK的Thr172磷酸化,激活AMPK信号通路。结构式(I)化合物还能够作用于Nrf2-Keap1信号通路,促进Nrf2的表达,抑制Keap1的表达,改善抗氧化系统,从而改善糖尿病病人的胰岛素抵抗,使胰岛素能够正常发挥作用,达到降血糖、治疗糖尿病的目的。
附图说明
附图1是活性检测中葡萄糖吸收效果图;
附图2是活性检测中糖原合成效果图;
附图3是western blot检测中蛋白条带图;
附图4是western blot检测中AMPK的磷酸化效果图;
附图5是western blot检测中GSK-3β的磷酸化效果图;
附图6是western blot检测中AKT的磷酸化效果图;
附图7是western blot检测中Nrf2的表达效果图;
附图8是western blot检测中Keap1的表达效果图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,但不作为对本发明的限定。
如无特别说明,下述所用各成分的含量为重量百分比含量;所使用的实验方法均为常规方法;所用的试剂、生物材料等均可从商业途径得到。
本发明实施例中涉及的化合物编号及结构式如下:
【制备实施例】
化合物I即3-(4'-羟基苯基)-6-羟基香豆素的制备过程如下:
在100mL的三口反应瓶中,加入1.52g(10mmol)4-羟基苯乙酸,1.38g(10mmol)2,5-二羟基苯甲醛,5.56g(55mmol)三乙胺和6.12g(60mmol)乙酸酐,然后加入磁子,置于微波反应器中,设置微波功率100W和反应时间70min,在搅拌下反应。在反应完毕后趁热立即倒入50ml水中,搅拌,此时析出大量固体,静置,抽滤,滤饼用水洗涤至洗液近中性,待晾干后再用乙酸乙酯/石油醚重结晶即可得淡黄色针状固体。
将所得固体加入100mL的三口反应瓶中,加入10ml乙醇加热搅拌至固体全部溶解,然后加入10%盐酸40ml,搅拌均匀,加热至80℃回流反应3h。TCL监测反应完成后将反应液倒入50ml冰水中,搅拌,析出大量固体,静置后抽滤,滤饼用乙醇/水重结晶,真空干燥,得到化合物I。
【活性测定】
1.葡萄糖吸收检测
HepG2细胞以4×105个/孔/2ml铺于6孔板中,孵育24h,弃去原培养基,加入2ml新鲜培养基配制的盐酸葡萄糖胺,处理18h,构建胰岛素抵抗模型。
实验分为对照组、模型组、实验组,并按照如下方法处理。对照组:2ml新鲜培养基。模型组:同对照组。实验组:加入2ml新鲜培养基配制化合物I,化合物I浓度配置为30uM。空白组:不铺细胞,其他同模型组。
每孔设置3个复孔,继续处理24h。然后用含100nmol/l的无血清无酚红的DMEM培养基处理15min,用葡萄糖含量检测试剂盒检测上清中葡萄糖含量,见图1。葡萄糖吸收值=空白孔中葡萄糖含量-实验组中上清中葡萄糖含量。
2.糖原合成检测
HepG2细胞以4×105个/孔/2ml铺于6孔板中,孵育24h,弃去原培养基,加入2ml新鲜培养基配制的盐酸葡萄糖胺,处理18h,构建胰岛素抵抗模型。实验分为对照组、模型组、实验组,并按照如下方法处理。对照组:2ml新鲜培养基。模型组:同对照组。实验组:加入2ml新鲜培养基配制化合物I,化合物I浓度配置为30uM。空白组:不铺细胞,其他同模型组。
每孔设置3个复孔,继续处理24h。
给药24h后,用PBS将胰酶消化下来的细胞洗三次。然后按照如下方法处理细胞:①每5×106个细胞加入0.5mL糖原提取液,以“200W功率、超声3s、间隔10s”的方式,循环超声30次,直至溶液变得透明;②将溶液转移到15mL离心管中,置于95℃水浴锅中恒温水浴20min(为防止溶液蒸发影响结果,保持离心管密闭)。为使水浴均匀,每5min振荡一次离心管;③待离心管冷却后,用超纯水定容到5mL,振荡混匀,8000g室温离心10min;④取出上清,并用糖原含量检测试剂盒检测糖原含量;⑤用BCA试剂盒检测上清中的总蛋白含量对各实验组细胞糖原含量进行标定,见图2。
3.结果分析
根据图1、2可知,与正常细胞相比,盐酸葡萄糖胺处理过的胰岛素抵抗模型细胞的葡萄糖吸收和糖原合成水平显著降低,但经过化合物Ⅰ作用,可以发现给药组的葡萄糖吸收和糖原合成水平明显上升。表明,化合物Ⅰ具有很好地促进葡萄糖吸收和糖原合成的作用。
【Western Blot检测】
1.实验方案
HepG2细胞以4×105个/孔/2ml铺于6孔板中,孵育24h,弃去原培养基,加入2ml新鲜培养基配制的盐酸葡萄糖胺,处理18h,构建胰岛素抵抗模型。
实验分为对照组、模型组、实验组,并按照如下方法处理。对照组:2ml新鲜培养基。模型组:同对照组。实验组:加入2ml新鲜培养基配制化合物I,化合物I浓度配置为30uM。空白组:不铺细胞,其他同模型组。
每孔设置3个复孔,继续处理24h。
给药24h后,用PBS将胰酶消化下来的细胞洗三次。将提取到的细胞沉淀加入含1μg/mL PMSF和1μL磷酸化酶抑制剂的RIPA裂解液中冰上裂解45min,离心后取上清用PierceTMBCA蛋白定量试剂盒进行蛋白定量。将上清与5×上样缓冲液混合均匀,100℃煮10min,上样20μg蛋白,调节电压至80V,待溴酚兰刚跑出分离胶底部即可终止电泳。然后将PAGE凝胶放于半干式转膜仪(BioRad,美国),恒压15V条件下转膜2h,5%奶粉封闭2h,TBST缓冲液洗3次,每次5min。分别加入抗体稀释液稀释的一抗(p-AMPK,1:1000;AMPK,1:1000;p-AKT,1:1000;AKT,1:1000;p-GSK3β,1:1000;GSK3β,1:1000;Keap1,1:1000;Nrf2,1:1000和GAPDH,1:1000),4℃条件下孵育过夜。TBST清洗后加入辣根过氧化物酶标记的二抗(HRP-IgG,1:2000),室温孵育2h,TBST洗涤后,加入ECL显影液,在化学发光成像系统(BioRad,美国)曝光显影并利用该凝胶图象处理系统分析其灰度值(如附图3所示)。
2.结果分析
根据图3-8可知,化合物Ⅰ能够促进AKT(Ser473)、GSK-3β(Ser9)的磷酸化,激活HepG2细胞胰岛素抵抗模型的PI3K/AKT信号通路;能够促进AMPK的Thr172磷酸化,激活AMPK信号通路;能够作用于Nrf2-Keap1信号通路,促进Nrf2的表达,抑制Keap1的表达,改善抗氧化系统,从而改善胰岛素抵抗现象,达到治疗糖尿病的目的。
Claims (7)
2.根据权利要求1所述的应用,其特征在于,所述胰岛素抵抗制剂用于促进HepG2细胞的葡萄糖吸收和糖原合成。
3.根据权利要求1所述的应用,其特征在于,所述胰岛素抵抗制剂用于促进AKT(Ser473)、GSK-3β(Ser9)的磷酸化,激活HepG2细胞胰岛素抵抗模型的PI3K/AKT信号通路。
4.根据权利要求1所述的应用,其特征在于,所述胰岛素抵抗制剂用于促进AMPK的Thr172磷酸化,激活AMPK信号通路。
5.根据权利要求1所述的应用,其特征在于,所述胰岛素抵抗制剂用于Nrf2-Keap1信号通路,促进Nrf2的表达,抑制Keap1的表达,改善抗氧化系统,从而改善胰岛素抵抗。
7.根据权利要求6所述的胰岛素抵抗制剂,其特征在于:结构式(I)所示的3-芳基香豆素类化合物的摩尔百分比含量为25-50uM。
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