CN115944612A - 胰高血糖素拮抗剂阿度格列凡的新用途 - Google Patents
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Abstract
本发明公开了一种胰高血糖素拮抗剂阿度格列凡作为保护心肌的药物的新用途。实验表明,胰高血糖素与反映心肌损伤最敏感的指标超敏肌钙蛋白I的水平具有相关性,能够显著增加心肌细胞凋亡比例并增加FOX01、Bax、cleaved‑Caspase 3的表达水平,而阿度格列凡能够显著减少心肌细胞凋亡比例,提示阿度格列凡在挖掘开发心肌保护药物制备中占有较大的潜力和远景。
Description
技术领域
本申请涉及生物医药技术领域,具体而言,涉及一种胰高血糖素拮抗剂阿度格列凡的新用途。
背景技术
心肌损伤是指由于缺血、代谢紊乱、炎症、药物副作用等因素引起的心肌细胞损伤,表现为细胞坏死、凋亡、溶解,临床上可观察到心肌独有的酶如肌钙蛋白等水平升高。目前保护心肌的药物种类以及发挥的效果有限。
胰高血糖素(GLC,glucagon)拮抗剂阿度格列凡(Adomeglivant,又名LY2409021)有效成分是分子式为C32H36F3NO4的化合物。该化合物的化学名称N-[4-[(1S)-1-[4'-(1,1-二甲基乙基)-2,6-二甲基[1,1'-联苯]-4-基]氧基]-4,4,4-三氟丁基]苯甲酰基]-β-丙氨酸(N-[4-[(1S)-1-[[4'-(1,1-dimethylethyl)-2,6-dimethyl[1,1'-biphe nyl]-4-yl]oxy]-4,4,4-trifluorobutyl]benzoyl]-β-Alanine),化学结构式如图1所示。阿度格列凡可以特异性拮抗胰高血糖素受体,阻断胰高血糖素的信号通路,发挥降低血糖的功能。但是现有技术中并没有阿度格列凡作为保护心肌药物的应用。
发明内容
本发明提供了胰高血糖素拮抗剂阿度格列凡的新用途。
具体的,本发明提供胰高血糖素拮抗剂阿度格列凡作为保护心肌的药物的新用途。所述保护心肌的表现为心肌损伤程度减轻。进一步,心肌损伤表现为生物标志物水平升高,心肌细胞凋亡增加。
糖尿病患者具有心肌损伤易感性,围术期心肌损伤发生风险较高。发明人前期研究发现,糖尿病以及手术应激都会导致胰高血糖素水平升高,可能与心肌损伤发生有关。心肌细胞表达有胰高血糖素受体,因此胰高血糖素拮抗剂阿度格列凡可以作用于心肌细胞的胰高血糖素受体,发挥保护心肌的作用。
本发明的有益效果包括:
本发明确定了阿度格列凡对心肌的保护作用。实验验证表明,胰高血糖素与反映心肌损伤最敏感的指标超敏肌钙蛋白I的水平具有相关性,能够显著增加心肌细胞凋亡比例并增加FOX01、Bax、cleaved-Caspase 3的表达水平,而阿度格列凡能够显著减少心肌细胞凋亡比例,提示阿度格列凡在挖掘开发心肌保护药物制备中占有较大的潜力和远景。
附图说明
图1为胰高血糖素拮抗剂阿度格列凡(Adomeglivant)有效成分化合物[C32H36F3NO4]的化学结构式;
图2为低温体外循环冠状动脉旁路移植术中胰高血糖素与cTNI散点图;
图3为蛋白印迹测定H9C2细胞凋亡相关蛋白表达水平;其中,A为H9C2细胞FOXO1、BAX、Cleaved-Caspase3及GAPDH的Western Blot条带图;B为FOXO1与GAPDH灰度比值;C为Cleaved-Caspase1与GAPDH灰度比值,D为BAX与GAPDH灰度比值;
图4为CCK-8测定H9C2细胞增殖活性;
图5为流式细胞学测定胰高血糖素与阿度格列凡(LY2409021)对心肌细胞H9C2凋亡比例的影响。
具体实施方式
下面结合实施例对本发明进行进一步说明和描述,但所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明和实施例中,本领域普通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发明和实施例,都属于本发明保护的范围。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1、胰高血糖素拮抗剂阿度格列凡在制备用于保护心肌的药物中的用途的验证
验证方法包括如下步骤:
S101,测定体外循环冠状动脉旁路移植术患者术中胰高血糖素(Glucagon)水平和肌钙蛋白I(cTNI,是反映心肌损伤最敏感的指标)水平;
具体的,测定方法为:选择接受体外循环冠状动脉旁路移植术患者29例,于体外循环30分钟、体外循环60分钟以及停机后采集患者全血,快速离心,取上清液,使用Millipore试剂盒依照说明书测定胰高血糖素水平,采用Tropinin T hs STAT试剂盒依照说明书测定肌钙蛋白I水平,并对二者的测定结果进行皮尔逊相关分析,结果如图2所示。从图2中可以看出,cTNI与胰高血糖素水平具有显著相关性。此部分实验结果说明人体胰高血糖素水平与心肌损伤程度存在相关性,阿度格列凡能够拮抗胰高血糖素受体,因而可能抑制心肌损伤。
S102,细胞凋亡相关蛋白表达水平测定
将H9C2细胞接种于6孔板,使用含10%胎牛血清的DMEM培养基进行传代培养,当细胞密度生长至90%时,将细胞分为五组:①对照组(-):无药物干预;②棕榈酸150mmol/L组(PA150):在培养基中加入150mmol/L的棕榈酸处理24小时;③胰高血糖素0.1nmol/L组(PA150+GLCO.1):在组②的基础上额外添加0.1nmol/L的胰高血糖素处理24小时;④胰高血糖素0.2nmol/L组(PA150+GLCO.2):在组②的基础上额外添加0.2nmol/L的胰高血糖素处理24小时;⑤棕榈酸250mmol/L组(PA250):在培养基中加入250mmol/L的棕榈酸处理24小时。
干预24小时后使用Ripa裂解液于冰上裂解细胞并离心,获得蛋白溶液,采取Western Blot技术测定FOX01、Bax,cleaved-Caspase 3等细胞凋亡相关蛋白的表达水平,以GAPDH作为内参进行比较;结果如图3所示,其中,图3B-D中,“#”表示与对照组相比,p<0.05;“*”表示与PA150组相比,p<0.05。
图3B中,与不施加干预相比,PA150、PA250干预组FOXO1/GAPDH表达升高,与PA150mM干预组相比,PA150+GLC0.1、PA150+GLC0.2组4我方卷号FOXO1/GAPDH表达升高;图3C中,Cleaved-Caspase3/GAPDH:与不施加干预相比,PA150组Cleaved-Caspase3/GAPDH表达升高,与PA 150组相比,PA150+GLC0.1、PA150+GLC0.2组Cleaved-Caspase3/GAPDH表达升高;图3D中,与不施加干预相比,PA150组Bax/GAPDH表达升高,与PA 150组相比,PA150+GLC0.1、PA150+GLC0.2组Bax/GAPDH表达升高。
从图3中可以看出,150、250mmol/L的棕榈酸均可以引起H9C2细胞FOX01、Bax,cleaved-Caspase 3表达水平升高,提示模型构建成功;0.1和0.2nmol/L的胰高血糖素均导致FOX01、Bax,cleaved-Caspase 3的表达进一步升高,提示胰高血糖素加重高脂诱导的心肌凋亡。此部分实验结果说明胰高血糖素对心肌细胞具有损伤作用。
S103,采用CCK8测定细胞的增值活性;
具体的增值活性测定方法为:将细胞种植于96孔板,使用含10%胎牛血清的DMEM培养基进行传代培养,当细胞密度生长至90%时,将细胞分为四组:①对照组(-):无药物干预;②棕榈酸150mmol/L组(PA150):在培养基中加入150mmol/L的棕榈酸处理24小时;③胰高血糖素0.1nmol/L组(PA150+GLCO.1):在组②的基础上额外添加0.1nmol/L的胰高血糖素处理24小时;④胰高血糖素0.2nmol/L组(PA150+GLCO.2):在组②的基础上额外添加0.2nmol/L的胰高血糖素处理24小时。
每孔加入CCK8试剂10ul,放置培养箱培养0.5-1小时,置于酶标仪进行测定,结果如图4所示,其中,PA,棕榈酸;GLC,胰高血糖素。“#”表示与对照组相比,p<0.05;“*”表示与PA150组相比,p<0.05。
从图4中可以看出,与不施加干预的对照组相比,PA150组细胞增值活性显著下降,与PA150组相比,PA150+GLC0.1、PA150+GLC0.2干预组细胞增殖活性显著下降。此部分实验结果说明胰高血糖素对心肌细胞具有损伤作用。
S104,构建棕榈酸诱导的心肌细胞凋亡模型并进行药物干预实验
具体方法为:使用含10%胎牛血清的DMEM培养基对H9C2细胞系进行传代培养,将细胞接种于6孔板中,当细胞密度生长至90%时,将细胞分为四组:①对照组(Control):无药物干预;②棕榈酸组(PA 150mM):在培养基中加入150mmol/L的棕榈酸(购于西安鲲创有限公司KT001)处理24小时;③胰高血糖素组(PA 150mM+GLCO.1nM):在组②的基础上额外添加0.1nmol/L的胰高血糖素处理24小时;④阿度格列凡组(PA150mM+GLCO.1Nm+LY2409021):在组③的基础上添加1umol/L的阿度格列凡处理24小时。
采用流式细胞学测定细胞凋亡比例:
于药物干预24小时后,将六孔板中格孔的培养基吸走,PBS清洗3次,每孔加入0.25%不含EDTA的胰酶500ul,置于37℃细胞培养箱中1分钟后取出,加入新鲜的培养基中和胰酶反应,轻柔吹打六孔板底部促进细胞脱落,将各组细胞悬液吸入离心管中,置于离心机中4℃1000转/分离心5分钟,吸走培养基,使用Annexin V-FITC细胞凋亡检测试剂盒(碧云天C1062M)依照说明书对细胞进行染色,使用流式细胞仪测定和分析细胞的染色情况,通道选择FL1和FL2,计算细胞的凋亡比例,结果如图5所示。图5中四个小图分别代表1组,共4组,凋亡率=UR(图5中各图的右上象限)+LR(图5中各图的右下象限)。其中,对照组的H9C2细胞凋亡率为5%;PA 150mM组的H9C2细胞凋亡率升高为29.6%;PA150mM+GLCO.1nM组的H9C2细胞凋亡率进一步升高为57.6%;而在PA150mM+GLCO.1nM组的基础上同时给予1μMLY2409021干预(阿度格列凡组),凋亡率降低至35.9%。可见,使用胰高血糖素刺激后,细胞凋亡比例显著升高,而加用阿度格列凡则凋亡比例显著下降。说明阿度格列凡具有抑制心肌细胞凋亡的作用。
Claims (4)
1.胰高血糖素拮抗剂阿度格列凡作为保护心肌的药物的新用途。
2.根据权利要求1所述的用途,其特征在于,所述保护心肌的表现为心肌损伤程度减轻。
3.根据权利要求2所述的用途,其特征在于,所述心肌损伤表现为生物标志物水平升高,心肌细胞凋亡增加。
4.根据权利要求3所述的用途,其特征在于,所述生物标志物为肌钙蛋白I、FOX01、Bax和/或cleaved-Caspase 3。
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