CN113546073A - 毛蕊异黄酮作为tgfbr1抑制剂及在制备治疗心室重构、心肌纤维化药物中的应用 - Google Patents
毛蕊异黄酮作为tgfbr1抑制剂及在制备治疗心室重构、心肌纤维化药物中的应用 Download PDFInfo
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Abstract
本发明公开了毛蕊异黄酮作为TGFBR1抑制剂及在制备治疗心室重构、心肌纤维化药物中的应用,涉及医药技术领域。基于其天然、安全的特性,毛蕊异黄酮为因TGF‑β通路紊乱引起的疾病治疗提供了可能,特别是提供了响应于TGFBR1相关的病症的药物中的应用。
Description
技术领域
本发明涉及医药技术领域,特别是涉及毛蕊异黄酮作为TGFBR1抑制剂及在制备治疗心室重构、心肌纤维化药物中的应用。
背景技术
急性心肌梗死(Acute myocardial infarction,AMI)是指在冠状动脉病变的基础上,发生局部心肌急性坏死。心室重构(Ventricular Remodeling)是指由于前后负荷的增加或心肌损伤致使心肌结构和功能发生改变,包括病变的修复及心室整体代偿的动态病理生理过程。心肌梗塞后心肌纤维化是指心肌梗塞后心脏在受到损伤或超负荷状态下,出现复杂的分子信号改变和胚胎基因及蛋白再表达,从而造成心肌成纤维细胞增殖,心肌细胞外胶原沉积。心梗后心肌纤维化是导致心室重构的病理学基础之一。心室重构作为AMI的后续改变,包括左心室体积增大,形状改变及梗死节段心肌变薄和非梗死节段心肌增厚,是影响AMI预后的主要原因之一。尽管随着再灌注技术的发展,心梗患者的死亡率已明显下降,但仍有相当多患者正受到心梗后进展为心衰的威胁。
转化生长因子β(transforming growth factor-β,TGF-β)是一类可由多种细胞分泌的具有多种生物学效应的多肽生长因子,对细胞生长、分化和发育的调节发挥重要作用。在TGF-β信号通路转导中,TGF-β首先与 TGFBR2结合,形成异源二聚体复合物,将TGFBR1激酶的前段Gs结构域的丝氨酸/苏氨酸残基发生磷酸化,进而激活转化生长因子β受体1(Transforming growth factor beta receptor 1,TGFBR1),活化的TGFBR1 继而磷酸化其下游信号分子Smad2和Smad3,活化的Smad2/Smad3二聚体与Smad4结合成三聚体进入细胞核内,激活特定的靶基因,调控靶基因的转录,完成整个信号转导的过程。TGFBR1是TGF-β信号转导的关键节点。 TGF-β/Smad信号通路被认为参与了多种心血管疾病的发生发展,在高血压、动脉粥样硬化、冠心病、心肌梗死、心力衰竭、心肌病以及房颤等疾病中具有重要作用。大量研究表明TGF-β/Smad信号通路的异常激活在左室重构及心肌纤维化中起着重要作用。
据文献报道,毛蕊异黄酮(calycosin)可抑制平滑肌细胞钙内流,对内皮细胞具有显著的保护作用,可通过抗氧化、抗炎、抑制病理状态下的钙超载、改善血管微循环发挥心血管疾病治疗作用,此外,毛蕊异黄酮还具有显著的抗肿瘤、镇咳、祛痰、增强免疫力以及降低胆固醇含量、降血糖的作用。毛蕊异黄酮的药理机制涉及面广泛,但其对转化生长因子β受体 1(TGFBR1)的调控以及对心梗后心室重构的影响未见相关报道。
发明内容
本发明的目的是提供一种毛蕊异黄酮作为TGFBR1抑制剂及在制备治疗心室重构、心肌纤维化药物中的应用,从而有效防治TGF-β通路紊乱引起的疾病,特别是响应于TGFBR1相关的病症,防治心肌纤维化、心室重构。
为实现上述目的,本发明提供了如下方案:
本发明的技术方案之一是提供毛蕊异黄酮作为TGFBR1抑制剂的应用。
本发明的技术方案之二是提供一种TGFBR1抑制剂,所述TGFBR1抑制剂包含治疗有效量的毛蕊异黄酮。
进一步地,所述TGFBR1抑制剂包括药物、保健品、功能食品、医疗用途食品或生物制品。
本发明的技术方案之三是提供毛蕊异黄酮在制备治疗心室重构、心肌纤维化药物、保健品、功能食品、医疗用途食品或生物制品中的应用。
本发明公开了以下技术效果:
本发明首次公开了毛蕊异黄酮在制备转化生长因子β受体1(TGFBR1) 抑制剂及制备治疗心室重构、心肌纤维化药物中的应用,通过实验证实其在体外SD乳鼠原代心肌成纤维细胞中具有抑制TGFBR1及其下游信号分子 Smad2/Smad3表达的作用,以及在体内C57小鼠心肌梗死后小鼠心脏中具有抗心室重构、心肌纤维化的作用,基于其天然、安全的特性,毛蕊异黄酮为因TGF-β通路紊乱引起的疾病治疗提供了可能,特别是提供了响应于 TGFBR1相关的病症的药物中的应用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例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,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为毛蕊异黄酮对TGFBR1抑制作用的分子对接图;
图2为calycosin-TGFBR1复合物晶体结构在0ns到80ns间的表面可视化模型;
图3为calycosin-TGFBR1复合物重原子的均方根偏差(RMSD)在0 ns到80ns间的演变过程中calycosin-TGFBR1结合部分的RMSD;
图4为毛蕊异黄酮与TGFBR1的体外结合亲和力;
图5为SB431542与TGFBR1的体外结合亲和力;
图6为毛蕊异黄酮改善心肌梗死后小鼠心脏结构及功能图;图6A为不同处理组的FS图、图6B为不同处理组的LVESD图、图6C为不同处理组的LVEDD图、图6D为不同处理组的LVEF图;
图7为各组小鼠心肌组织的Masson染色图;
图8为毛蕊异黄酮抑制乳鼠原代心肌成纤维细胞TGBFBR1及其下游 Smad2、Smad3的磷酸化水平;图8A:采用western blot检测p-TGFBR1, p-Smad2,p-Smad3,GAPDH蛋白的表达;图8B:p-TGFBR1的相对蛋白表达水平(n=3);图8C:p-Smad2的相对蛋白表达水平(n=3);图8D:p-Smad3 的相对蛋白表达水平(n=3)。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
本发明毛蕊异黄酮(calycosin)分子式为C16H12O5,分子量为284.26,购自成都曼思特生物科技有限公司,结构式如下所示:
实施例1分子模拟虚拟筛选
使用Autodock Vina软件对Calycosin与TGFBR1之间的相互结合进行模拟生成最优构象,该模拟提示Calycosin与TGFBR1之间具有较强的结合能力。
毛蕊异黄酮对TGFBR1抑制作用的分子对接图如图1所示,分子对接结果显示Calycosin-TGFBR1复合物的结合能为-9.267kcal/mol,表明了出了良好的结合力。由图1可以看出,毛蕊异黄酮可与TGFBR1的GLU-45、ASP-151、SER-80氨基酸残基发生氢键结合。图2的表面可视化模型可看出calycosin在0ns到80ns间均能稳定结合在TGFBR1的结合口袋中;图3为calycosin-TGFBR1复合物重原子的均方根偏差(RMSD)在0ns到 80ns间的演变过程中calycosin-TGFBR1结合部分的RMSD,均稳定维持在左右。
实施例2Calycosin与TGFBR1之间的体外结合能力
采用表面等离子体共振成像(SPRi)分子互作实验进行分析,选择3D Dextran芯片进行点样固定。具体操作流程如下:
(1)分别盛放0.765g EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)及0.115g NHS(N-N-羟基琥珀酰亚胺)于两支50ml专用离心管中,随后向离心管中各加入10ml双蒸水使其充分溶解混匀,使用时将两种溶液倒入方形盒中,使溶液没过需要活化芯片的表面,接着置于摇床上反应 15min。
(2)TGFBR1蛋白点样,根据生物点样仪的操作流程将芯片放置于点样仪上设置好程序后即可进行点样操作,将点样完成的芯片贴上cover的同时标记好芯片编号后放置于生化试剂盒内(湿度应大于50%)4℃冰箱孵育过夜。
(3)在SPR仪器上装载孵育完成的芯片,准备流通小分子化合物。
(4)将母液浓度为100mM的毛蕊异黄酮用PBS分别配制成浓度为10mM, 20mM,40mM的,体积为各1mL的不同浓度梯度的流通相及将母液浓度为 100mM的阳性对照SB431542用PBS分别配制成浓度为5mM、10mM、20mM、 40mM,体积为各1mL的不同浓度梯度的流通相备用。
(5)将固定好靶标蛋白TGFBR1样品的芯片,不同浓度梯度毛蕊异黄酮及SB431542的流通样品及缓冲液、重生液在PlexArray HT A100生物分子相互作用仪上加载安放好后,参照《PlexArray HT高通量分子间相互作用筛选系统使用SOP》操作流程,进行生物分子间相互作用实验。
由TGFBR1和毛蕊异黄酮、SB431542结合和解离过程可见,不同浓度毛蕊异黄酮、SB431542均能与TGFBR1迅速结合。毛蕊异黄酮与TGFBR1间相互作用的动力学参数,分别为ka=414(1/Ms),kd=0.0167(1/s), KD=4.03e-05(M)。SB431542与TGFBR1间相互作用的动力学参数,分别为 ka=1.26e+03(1/Ms),kd=0.0311(1/s),KD=2.47e-05(M)。分子间结合能力的大小由KD值表示,KD越小,表明结合力或亲和力越大。由KD值可看出,TGFBR1与毛蕊异黄酮、SB431542均具有强的亲和力。
不同浓度毛蕊异黄酮calycosin及SB431542与TGFBR1的体外结合亲和力的表面等离子共振成像图如图4-5所示,其中,图4为毛蕊异黄酮与 TGFBR1的体外结合亲和力,图5为SB431542与TGFBR1的体外结合亲和力。
实施例3毛蕊异黄酮改善心肌梗死后小鼠心脏结构及功能、改善心室重构
小鼠心肌梗死模型建立:选取8周龄的小鼠,分为假手术组(Sham),模型组(左冠状动脉前降支结扎),毛蕊异黄酮低剂量组(左冠状动脉前降支结扎+25mg/kg毛蕊异黄酮),毛蕊异黄酮高剂量组(左冠状动脉前降支结扎+50mg/kg毛蕊异黄酮),每组5只。左冠状动脉前降支结扎术:术前禁食禁水,使用2%戊巴比妥钠以50mg/kg剂量腹腔注射麻醉小鼠,待小鼠麻醉后(夹趾反射消失),将小鼠呈仰卧位用医用胶布将其四肢及尾巴固定于解剖台上,备皮,用规格为20号的留置针进行气管插管,成功后,连接呼吸机,完成人工气道建立。呼吸机潮气量应保持1mL,每min呼吸频率保持120次。胸骨左缘3-4肋间开胸,暴露心脏,小心剥离心包,找到左心耳,于左心耳下方约2mm处用8-0眼科带针缝合线结扎左冠状动脉前降支,即从左心耳根部下方2mm处入针,进针深度以0.5mm为宜,从心肌表层穿出,肉眼可见结扎处至心尖的组织变白;然后逐层关闭胸腔。假手术组开胸,但不结扎左冠状动脉前降支,其余步骤同手术组。
术后给药组每天分别灌胃0.2ml药物,假手术组及模型组给予等量溶剂对照,连续灌胃4周。
通过多普勒超声心动图评估心肌梗死后小鼠心脏结构及功能。术后4 周,采用异氟烷麻醉小鼠,使用超声仪进行二维M型超声心动图,在胸骨旁左心室长轴观察心脏。采用MS400(18-38MHZ)探头检测来自3个连续心动周期的左心室形态,记录左心室收缩末期直径(LVED)、左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD),根据以上数值测量缩短分数(FS)和左室射血分数(EF)。
通过上述的实验证明:结扎术后4周,超声心动图结果显示模型组 (Model)小鼠与假手术组(Sham)比较,冠脉结扎后LVEDD、LVESD显著升高(P<0.01),而LVEF、FS显著降低(P<0.01),而接受毛蕊异黄酮治疗的低剂量组(25mg/kg)和高剂量组(50mg/kg),LVEDD、LVESD均有不同程度的降低,LVEF、FS均有升高(P<0.05)。
图6为毛蕊异黄酮改善心肌梗死后小鼠心脏结构及功能图;图A为不同处理组的FS图、图B为不同处理组的LVESD图、图C为不同处理组的 LVEDD图、图D为不同处理组的LVEF图。其中:*与control相比,P< 0.05,有统计学差异;**与control相比,P<0.01,有统计学差异。
实施例4毛蕊异黄酮抑制心肌梗死后小鼠心脏胶原沉积、改善心肌纤维化及心室重构
采用Masson染色观察心肌组织胶原变化:
术后4周完成心脏超声后第二天,将小鼠麻醉,眼球采血后,打开小鼠胸腔,将心脏取出,放于PBS中浸泡,轻轻挤压去除残留于心脏的血液,修剪组织,浸泡于4%多聚甲醛溶液中固定24h,后续进行石蜡切片制作:
(1)浸洗:将固定好的心脏组织用流水冲洗去除固定液,随后置于滤纸吸干,擦镜纸包埋并标记。
(2)梯度脱水、透明:将标记好的组织块依次放入80%乙醇3h,90%乙醇3h,95%乙醇过夜。然后再分别用无水乙醇(Ⅰ,Ⅱ,Ⅲ)浸泡3次,每次各30min。二甲苯(Ⅰ,Ⅱ,Ⅲ)浸泡3次,每次各30min。
(3)浸蜡:将脱水透明完成的组织块,用滤纸去除多余二甲苯后,依次浸入已提前融化的石蜡Ⅰ及石蜡Ⅱ中各30min,石蜡Ⅲ中90min。
(4)包埋:制作大小合适的石蜡包埋模具,用加热的镊子将浸蜡完成的组织从杯蜡中取出,迅速放入已倒入石蜡的模具中(确保石蜡可没过组织),调整组织位置,排尽气泡,置于室温(或冰上)冷却凝固。
(5)切片:去掉模具及多余石蜡,将含有组织的蜡块固定于切片机上切成厚约3-5μm的薄片。(注意切片不宜过厚,否则染色效果不佳)。
(6)贴片:将切片放入恒温池(36.5℃)中,使切片展平,随后用已标记的载玻片将悬浮于恒温池水面的切片小心贴附到载玻片上,贴片过程应在恒温池中进行。
(7)烤片:将切片小心放置切片盒中,置于60℃烘箱内烘干水分。最后放置室温内使其温度平衡,室温保存备用。
MASSON染色步骤:
试剂:MASSON染色套装(Servicebio,货号G006);无水乙醇(国药集团化学试剂有限公司,货号100092683)、二甲苯(国药集团化学试剂有限公司,货号10023418)、中性树胶(国药集团化学试剂有限公司,货号 10004160)。
(1)石蜡切片脱蜡至水:依次将切片放入二甲苯Ⅰ20min-二甲苯Ⅱ 20min-无水乙醇Ⅰ5min-无水乙醇Ⅱ5min-75%酒精5min,自来水洗。
(2)切片浸入Masson A液中浸泡过夜,自来水洗。
(3)切片入Masson B液及Masson C液等比混合的染液,浸染1min,自来水洗,1%盐酸酒精分化,自来水洗。
(4)切片入Masson D液浸染6min,自来水漂洗。
(5)Masson E液浸染1min。
(6)不水洗,稍沥干直接入Masson F液染2-30s。
(7)切片用1%冰醋酸漂洗分化,两缸无水乙醇脱水。
(8)透明封片:切片放入第三缸无水乙醇5min,二甲苯5min透明,中性树胶封片。
(9)显微镜镜检,图像采集分析。
结果提示:Masson染色观察心肌组织胶原变化,蓝色区域为胶原纤维组织,红色为心肌细胞、纤维细胞和红细胞。与假手术组比较,模型组鼠心肌组织梗死区及非梗死区均可见大片蓝染区域,呈网状纤维结缔组织增生, 提示模型组小鼠已发生心室重构,心脏组织出现明显纤维化,而毛蕊异黄酮低剂量及高剂量用药组心肌组织中蓝染区域显著减少,提示毛蕊异黄酮治疗能有效减轻冠脉结扎引起的心肌纤维化。
图7为Masson染色的各组小鼠心肌组织,其中:*与control相比, P<0.05,有统计学差异;**与control相比,P<0.01,有统计学差异。
实施例5毛蕊异黄酮抑制乳鼠原代心肌成纤维细胞TGBFBR1及其下游 Smad2、3的磷酸化水平
实验原料:
将Calycosin溶于无菌二甲基亚砜DMSO中,配置成所需浓度。
细胞株:
从SD乳鼠心脏分离心肌成纤维细胞(CFs)进行体外培养。
培养条件:含10%FBS(GIBCO)的DMEM高糖型培养基(Gibco公司), 37℃、5%CO2饱和湿度培养箱。
分组:将心肌成纤维细胞(CFs)分为对照组、模型组、毛蕊异黄酮低剂量组(10μM)、毛蕊异黄酮中剂量组(20μM)、毛蕊异黄酮高剂量组(40 μM)。根据实验分组,在没有(模型组)或不同浓度的毛蕊异黄酮(10、 20、40μM)的情况下孵育24h后,使用TGF-β1(10ng/ml)刺激心肌成纤维细胞30min,然后通过蛋白质印迹法(western blot)检测phospho- Smad2、phospho-Smad3、phospho-TGFBR1的表达。
蛋白质印迹法(western blot):用含有PMSF(碧云天生物技术有限公司)和磷酸酶抑制剂(碧云天生物技术有限公司)的RIPA裂解液(碧云天生物技术研究所)裂解细胞后,提取总蛋白。细胞蛋白取15ug,经10%SDS- PAGE胶电泳后,转移至PVDF膜,该膜与特异性抗体(一抗)4℃孵育过夜。洗涤3遍,与过氧化物酶标记的二抗(anti-rabbit IgG 1:2000浓度)稀释,室温孵育1h后,洗涤3遍,浸泡于HRP-ECL化学发光液(美国Millipore 公司,将A液、B液以1:1比例充分混匀)后放入曝光仪中拍摄成像。
所用特异性抗体(一抗)如下:
Rabbit anti-p-Smad2 antibody(1:1000浓度稀释;美国Abcam公司);Rabbitanti-p-Smad3 antibody(1:1000浓度稀释;美国Abcam公司);Rabbit anti-p-TGFBR1antibody(1:1000浓度稀释;美国Cell Signaling公司);Rabbit anti-GAPDH antibody(1:1000浓度稀释;美国 Affinity公司)。
Image J图像分析软件分析
用Image J图像分析软件对曝光后条带的灰度值进行分析,分别计算 phospho-Smad2、phospho-Smad3、phospho-TGFBR1分别与GAPDH进行灰度值比。
统计分析
采用spss 22.0统计软件进行分析,结果均采用以均数±标准差 (Mean±SD)表示。多组间比较使用one-way ANOVA,方差齐时采用LSD 法,方差不齐时采用Welch稳健估计,再用Tamhane T2法两两比较,以P <0.05认为有统计学意义。
结果提示与对照组相比,模型组的TGFBR1及其下游Smad2、Smad3的磷酸化水平显著升高,而不同剂量组的毛蕊异黄酮能浓度依赖性地抑制 TGFBR1及其下游Smad2、Smad3的磷酸化水平(P<0.05)。
图8为毛蕊异黄酮calycosin抑制乳鼠原代心肌成纤维细胞TGBFBR1 及其下游Smad2、Smad 3的磷酸化水平。图A:采用western blot检测p- TGFBR1,p-Smad2,p-Smad3,GAPDH蛋白的表达;图B:p-TGFBR1的相对蛋白表达水平(n=3);图C:p-Smad2的相对蛋白表达水平(n=3);图D:p- Smad3的相对蛋白表达水平(n=3)。数据以平均值±标准差表示。与对照组相比,*P<0.05,**P<0.01。其中:*与control相比,P<0.05,有统计学差异;**与control相比,P<0.01,有统计学差异。
通过上述的实验证明:毛蕊异黄酮能显著地抑制转化生长因子β受体 1(TGFBR1),抑制TGFBR1-Smad信号通路中Smad2及Smad3的磷酸化水平,进而调控其下游信号基因的表达及转录。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (4)
1.毛蕊异黄酮作为TGFBR1抑制剂的应用。
2.一种TGFBR1抑制剂,其特征在于,所述TGFBR1抑制剂包含治疗有效量的毛蕊异黄酮。
3.根据权利要求2所述的TGFBR1抑制剂,其特征在于,所述TGFBR1抑制剂包括药物、保健品、功能食品、医疗用途食品或生物制品。
4.毛蕊异黄酮在制备治疗心室重构或心肌纤维化药物、保健品、功能食品、医疗用途食品或生物制品中的应用。
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