CN111297848A - 山奈酚及其类似物的应用 - Google Patents
山奈酚及其类似物的应用 Download PDFInfo
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- CN111297848A CN111297848A CN201811509414.1A CN201811509414A CN111297848A CN 111297848 A CN111297848 A CN 111297848A CN 201811509414 A CN201811509414 A CN 201811509414A CN 111297848 A CN111297848 A CN 111297848A
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- kaempferol
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Abstract
山奈酚及其类似物的应用,用于与血管内皮生长因子结合而促进血管生成。本发明提出了山奈酚及其类似物的新的应用,首次发明了采用山奈酚促进血管内皮生长因子诱导的血管生成的手段,对人脐静脉内皮细胞增殖和细胞迁移均有显著的增强作用。在动物模型中,山奈酚可以显著增强斑马鱼肠下静脉血管的生成,进一步明确了其促进血管生成作用,可以用于缺血性心脏病的预防与防治。本发明的山奈酚及其类似物的应用设计科学,实用性强。
Description
技术领域
本发明涉及血管生成领域,尤其涉及山奈酚及其类似物的应用。
背景技术
血管生成(angiogenesis)是在原有血管网基础上,通过刺激内皮细胞芽出而形成周围组织的小血管生长和侧支循环,生成新生血管的复杂过程。该过程涉及血管内皮细胞外基质降解、内皮细胞向基质降解处迁移、增殖、伸展及管状结构形成和内皮细胞外基质膜产生等多个步骤,主要包括:激活期血管基底膜降解;血管内皮细胞的激活、增殖、迁移;重建形成新的血管和血管网,是一个涉及多种细胞和多种分子的复杂过程。血管形成是促血管形成因子和抑制因子协调作用的复杂过程,正常情况下二者处于平衡状态,一旦此平衡打破就会激活血管系统,使血管生成过度或抑制血管系统使血管退化。
血管内皮细胞(Vascular Endothelial Cell)具有多种生理功能,参与机体的凝血、免疫、物质转运和生物活性物质释放等生物活动。研究表明,内皮细胞的损伤及功能紊乱与多种疾病的发生密切相关,包括高血压、冠心病、糖尿病、慢性肾功能衰竭等。引起内皮细胞损伤是一个复杂的病理过程,参与的因素很多,如糖尿病、高血脂和高血压等多种疾病,氧化应激以及炎症反应等等。血管内皮细胞的损伤是多种血管性疾病的主要环节,保护血管内皮功能是防治血管性疾病的关键环节。因此,研究保护血管内皮功能的药物成为治疗血管性疾病的重要措施。针对内皮细胞损伤的不同环节进行的药物研究也在进行中,包括抑制黏附分子生成和释放、拮抗黏附分子作用的药物、作用于LOX-1受体的药物等等,都收到了研究人员的重视。目前的治疗性血管生成方法中最常用的是外源性促血管生成因子(如VEGF)的基因治疗与重组蛋白质治疗,促血管生成生长因子在促进内皮细胞增殖中表现为可刺激组织修复细胞增殖,趋化炎性细胞、表皮细胞和成纤维细胞向伤口聚集,加剧创面愈合,此生理效应可预防和治疗斑痕修复。但促血管生成生成因子转基因治疗存在免疫原性、调控困难;促血管生成生长因子重组蛋白静脉给药存在是否发生其他部位的血管异常生长,甚至发生肿瘤的风险;外源性促血管生成生长因子因半衰期短,难以通过血管屏障,要反复给药,易出现副作用等问题,限制了其应用。经过调研,未见我国学者对山奈酚促进血管生成的相关文献报道(自CNKI、维普中国期刊网),因此山奈酚在促进血管生成的药理、药效等研究领域尚处于空白阶段。本研究发现山奈酚具有促进内皮细胞生成的作用,为保护内皮细胞的相关疾病提供新的治疗方法与应用。
山奈酚(Kaempferol)是一种天然黄酮类化合物,分子式:C15H10O6,分子量:286.23,化学结构如下所示:
山奈酚不仅是可食用植物,包括西兰花、葡萄柚、苹果等在内的植源性物质,也是对传统中药材,如银杏叶,进行质量控制的指标成分之一。现代药理学研究表明,山奈酚具有广泛的药理活性,包括抗氧化、抗炎、抗菌、抗癌、保护心脏、抗糖尿病、抗雌激素、抗焦虑和抗过敏等作用,但目前还没有山奈酚可与血管内皮生长因子(vascular endothelialgrowth factor,VEGF)结合进而促进新生血管形成并作为血管形成增强剂使用的报道。
发明内容
本发明针对上述技术问题,提出山奈酚及其类似物的应用。
本发明所提出的技术方案如下:
本发明提出了一种山奈酚的应用,用于与血管内皮生长因子结合而促进血管生成。
本发明还提出了一种促进血管生成的药物,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。在这里,槲皮素以及山奈酚-3-O-芸香糖苷的结构与山奈酚类似,与山奈酚一样,能够促进血管生成。
本发明上述的促进血管生成的药物中,用于心血管接入术,或用于预防或治疗冠心病、心肌梗死后等缺血性心脏病,脑梗塞后、血管闭塞性血栓性脉管炎,以及伤口愈合中抑制斑痕形成中的至少一种。
本发明上述的促进血管生成的药物中,采用胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂以及软膏剂中任意一种形式。
本发明还提出了一种促进血管生成的保健品,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。
本发明还提出了一种有利于血管生成的化妆品,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。
本发明还提出了一种槲皮素的应用,用于与血管内皮生长因子结合而促进血管生成。
本发明还提出了一种山奈酚-3-O-芸香糖苷的应用,用于与血管内皮生长因子结合而促进血管生成。
本发明提出了山奈酚及其类似物的新的应用,首次发明了采用山奈酚促进血管内皮生长因子诱导的血管生成的手段,对人脐静脉内皮细胞增殖和细胞迁移均有显著的增强作用。在动物模型中,山奈酚可以显著增强斑马鱼肠下静脉血管的生成,进一步明确了其促进血管生成作用,可以用于缺血性心脏病的预防与防治。本发明的山奈酚及其类似物的应用设计科学,实用性强。
附图说明
下面将结合附图及实施例对本发明作进一步说明,附图中:
图1是银杏叶总提取物高效液相指纹图;
图2是山奈酚促进人脐静脉内皮细胞(HUVEC)增殖的结果示意图;
图3是山奈酚促进HUVEC的划痕迁移的照片;
图4示出了山奈酚促进HUVEC的划痕迁移的量化图;
图5是山奈酚促进斑马鱼肠下静脉血管形成的照片;
图6示出了山奈酚促进斑马鱼肠下静脉血管形成的量化图;
图7示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)磷酸化发挥其促血管生成作用的照片;
图8示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)磷酸化发挥其促血管生成作用随时间变化的量化图;
图9示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)磷酸化发挥其促血管生成作用随山奈酚浓度变化的量化图;
图10示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用的照片;
图11示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用随时间变化的量化图;
图12示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用随山奈酚浓度变化的量化图;
图13示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用的照片;
图14示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用随时间变化的量化图;
图15示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2 (VEGFR2)介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用随山奈酚浓度变化的量化图;
图16示出了山奈酚可与VEGF结合的示意图。
具体实施方式
本发明所要解决的技术问题是:促血管生成生成因子转基因治疗存在免疫原性、调控困难;促血管生成生长因子重组蛋白静脉给药存在是否发生其他部位的血管异常生长,甚至发生肿瘤的风险;外源性促血管生成生长因子因半衰期短,难以通过血管屏障,要反复给药,易出现副作用等问题,限制了其应用。本发明就该技术问题而提出的技术思路是:采用山奈酚及其类似物来促进血管内皮生长因子诱导的血管生成。
为了使本发明的技术目的、技术方案以及技术效果更为清楚,以便于本领域技术人员理解和实施本发明,下面将结合附图及具体实施例对本发明做进一步详细的说明。
本发明的目的是要开发和利用可与血管内皮生长因子结合的山奈酚药物。通过对山奈酚进行深入细致研究,首次发明了采用山奈酚促进血管内皮生长因子诱导的血管生成的手段,对人脐静脉内皮细胞增殖和细胞迁移均有显著的增强作用。在动物模型中,山奈酚可以显著增强斑马鱼肠下静脉血管的生成,进一步明确了其促进血管生成作用,可以用于缺血性心脏病的预防与防治。为进一步充分说明本发明的药物应用,现通过以下实施例来说明。
实施例1:银杏叶总提取物的制备和银杏叶总提取物的高效液相指纹图谱
1、方法
将银杏叶药材粉碎,称取50g,至于容量瓶中,用1000mL、50%乙醇浸泡提取三天,提取液60℃真空浓缩至30mL后真空冻干,即得银杏叶总提取物,冻干粉真空保存。
称取冻干粉100mg,置于15mL的离心管中,加入4mL、50%甲醇,超声 15分钟后,1000x g条件下离心5分钟,得上清液,上清液进样前,使用0.45μm 的微孔滤膜过滤,取续滤液,进样分析。使用的分析仪器为带有自动进样器和二元泵的安捷伦液相,色谱柱为安捷伦,Grace VisionHT C18柱(4.6x 250mm, 5μm),流动相为乙腈(溶剂A)和0.2%甲酸水溶液(溶剂B),流速为1mL/min,柱温为室温,梯度洗脱,流动相比例如下:0-12分钟,8-18%溶剂A;12-36 分钟,18-24%溶剂A;36-41分钟,24-25%溶剂A;41-56分钟,25-40%溶剂A;56-96分钟,40-75%溶剂A。进样体积为10μL,检测波长为360纳米。山奈酚作为该银杏叶总提取物的指标成分。
2、结果与结论
请参照图1,在上述分析条件下,银杏叶的乙醇提取物中的各化学成分均达到基本分离,可作为银杏叶药材质量控制方法应用。在该银杏叶的乙醇提取物中,山奈酚的含量为0.49mg/g。
需要说明的是,银杏叶总提取物也可以是利用水或95%乙醇提取得到,或者可以通过有机溶剂,如甲醇、丙酮、异丙醇等等,其它现有的任何可以针对银杏叶提取的方法所得到的银杏叶总提取物,均可以实现本发明的药物应用,均在本发明的保护范围之内,其它提取方法的银杏叶总提取物这里就不再详细赘述。其中,利用水提取银杏叶总提取物参见如下过程:将银杏叶药材粉碎,称取50g,至于容量瓶中,用1000mL、水浸泡过夜,超声提取1小时,重复提取两次,取上清液真空冻干,即得银杏叶水提取物,冻干粉真空保存。利用95%乙醇提取银杏叶总提取物参见如下过程:将银杏叶药材粉碎,称取50g,至于容量瓶中,用1000mL、95%乙醇浸泡过夜,超声提取1小时,重复提取两次,合并两次提取的上清液,60℃真空浓缩后真空冻干,即得银杏叶醇提取物,冻干粉真空保存。
实施例2:山奈酚促进人脐静脉内皮细胞的(HUVEC)增殖实验
采用四唑盐(MTT)比色法观察阳性对照组癌思停(Avastin)组对HUVEC 的增殖抑制作用和不同给药浓度的山奈酚对HUVEC的增殖促进作用,表明山奈酚具有良好地促进HUVEC增殖的作用,并存在浓度依赖关系。
1、方法
HUVEC细胞以5.0×103个/mL的密度接种于96孔培养板培养,每孔 100μL,待细胞生长达到80%融合后,将5ng/mL VEGF或不同浓度的山奈酚加入孔中,作用48小时后每孔加入MTT溶液10μL,37℃继续培养4小时后终止培养,弃去培养上清液,每孔加150μL DMSO,振荡10min充分溶解,选择490nm波长,在酶标仪上测定各孔吸光度(OD)值。以未加药的孔作为对照,按如下公式计算细胞活力:
细胞活力(%)=(OD样品-OD对照品)/OD对照品×100%
2、结果与结论
请参照图2,图2是山奈酚促进人脐静脉内皮细胞(HUVEC)增殖的结果示意图;如图2所示,山奈酚对HUVEC的增殖促进作用呈剂量依赖关系。
实施例3:山奈酚促进人脐静脉内皮细胞(HUVEC)划痕迁移实验
1、方法
HUVEC细胞以20×104个/孔的密度接种于12孔板中培养,过夜让细胞贴壁,待细胞生长达到80%融合后,使用200μL吸管尖,在每孔中间划伤一个横向的伤口,弃培养基,PBS洗一遍,于培养液中分别单独加入5ng/mL的人血管内皮细胞生长因子(VEGF)、200μg/mL的癌思停和不同浓度的山奈酚,并设置一个未加药的空白实验。利用配有摄影机的显微镜在50倍放大率下于 0和8小时后拍下每孔内细胞层覆盖率的变化。再利用TScratch软件把恢复生长速度数据化,按照下式计算细胞恢复生长速度:
回复率%=(At0-At8)/At0×100%,
其中,At0:给药0小时后所测的划痕面积;
At8:给药8小时后所测的划痕面积。
2、结果与结论
请参照图3-图4,图3是山奈酚促进HUVEC的划痕迁移的照片;图4示出了山奈酚促进HUVEC的划痕迁移的量化图。如图3-图4所示,山奈酚对 HUVEC的划痕迁移抑制作用呈剂量依赖关系。
实施例4:山奈酚促进斑马鱼肠下静脉血管(SIV,subintestinal vessel) 形成实验
斑马鱼肠下静脉血管(SIV,subintestinal vessel)生长在卵黄囊两侧,其形状似一个篮子,肠下静脉血管(SIV)由体节腹侧向下延伸的长度约为 50~100μm。
1、方法
实验分组及胚胎处理:取70只发育良好的斑马鱼胚胎,胚胎发育时相为受精后23hpf(hour-postfertilization,hpf),随机分为7组,每组胚胎数量为10只。操作时将胚胎均匀分配至12孔细胞培养板中,每孔10只胚胎,每孔胚胎饲养用水1mL。
药物处理:用移液器(量程100~1000μL,Eppendorf)迅速将预先配置好的5ng/mL的人血管内皮细胞生长因子(VEGF)、200μg/mL的癌思停和不同浓度的山奈酚加入12孔细胞培养板对应的孔中,每孔1mL。加药液之前,用移液器(量程100~1000μL,Eppendorf)将12孔细胞培养板中孵育胚胎的饲养用水尽力移出,此操作需在短时间内预先完成,以防止胚胎干燥。实验环境温度控制在28.5℃左右,相对湿度40~70%。将12孔板包裹号,做好实验标记,迅速放置于斑马鱼培养箱中继续培养48小时(培养箱温度控制在 28.5℃)。48小时后,使用4%多聚甲醛于4℃环境中固定斑马鱼胚胎20小时后,依次使用PBST(0.1%吐温)、50%甲醇、甲醇,每次清洗胚胎5分钟,将斑马鱼胚胎浸于甲醇中,置于-20℃环境中脱水两小时;脱水后,使用 PBST(0.1%吐温)洗去多余的甲醇,使用nitro-blue tetrazolium/5-bromo-4-chloro-3-indol-yl-phosphate(NBT/BCIP)对斑马鱼胚胎进行染色后,在倒置光学显微镜下观察血管形成。
2、结果与结论
请参照图5-图6,图5是山奈酚促进斑马鱼肠下静脉血管形成的照片;图 6示出了山奈酚促进斑马鱼肠下静脉血管形成的量化图。如图5-图6所示,山奈酚对斑马鱼肠下静脉血管形成的抑制作用呈剂量依赖关系。
实施例5:山奈酚特异性增强血管内皮生长因子受体2(VEGFR2)介导的信号通路发挥其促进血管生成作用
1、方法
采用western-blot实验评价山奈酚对VEGF依赖性血管生成的作用。将 HUVEC细胞接种于12孔板内(20×104细胞/孔),置于37℃培养箱孵育24 小时。采用无血清培养基饥饿培养1小时后,分别加入5ng/mL的人血管内皮细胞生长因子(VEGF)、200μg/mL的癌思停和不同浓度的山奈酚,给药。使用低浓度裂解液对HUVEC细胞进行裂解,收集细胞裂解液,于8%-10% SDS-PAGE胶上样。采用分子结合软件(Molecular Docking,Vina,PhyMol) 山奈酚和血管内皮生长因子之间的分子相互作用。
2、结果与结论
请参照图7-图15;图7示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)磷酸化发挥其促血管生成作用的照片;图8示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)磷酸化发挥其促血管生成随时间变化的量化图;图9示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)磷酸化发挥其促血管生成随山奈酚浓度变化的量化图;图10示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用的照片;图11示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用随时间变化的量化图;图12示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)介导的下游信号通路eNOS发挥其促细胞增殖和细胞迁移作用随山奈酚浓度变化的量化图;图13示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用的照片;图14示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2)介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用随时间变化的量化图;图15 示出了山奈酚与VEGF结合特异性增强血管内皮生长因子受体2(VEGFR2) 介导的下游信号通路Erk发挥其促细胞增殖和细胞迁移作用随山奈酚浓度变化的量化图;图16示出了山奈酚可与VEGF结合的示意图。
实施例6:山奈酚制剂
将山奈酚与合适的辅料混合,可按照不同工艺制成不同的剂型如:胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂或软膏剂,作为制备用于治疗和预防冠心病、脑梗塞后、血管闭塞性血栓性脉管炎等新生血管依赖性和新生血管相关性疾病的药物制剂,各个剂型的制备方法均是现有技术中常用的制备方法,这里不再进行赘述。
上面结合附图对本发明的实施例进行了描述,但是本发明并不局限于上述的具体实施方式,上述的具体实施方式仅仅是示意性的,而不是限制性的,本领域的普通技术人员在本发明的启示下,在不脱离本发明宗旨和权利要求所保护的范围情况下,还可做出很多形式,这些均属于本发明的保护之内。
Claims (8)
1.一种山奈酚的应用,其特征在于,用于与血管内皮生长因子结合而促进血管生成。
2.一种促进血管生成的药物,其特征在于,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。
3.根据权利要求2所述的促进血管生成的药物,其特征在于,用于心血管接入术,或用于预防或治疗冠心病、心肌梗死后等缺血性心脏病,脑梗塞后、血管闭塞性血栓性脉管炎,以及伤口愈合中抑制斑痕形成中的至少一种。
4.根据权利要求2所述的促进血管生成的药物,其特征在于,采用胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂以及软膏剂中任意一种形式。
5.一种促进血管生成的保健品,其特征在于,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。
6.一种有利于血管生成的化妆品,其特征在于,包括山奈酚、槲皮素以及山奈酚-3-O-芸香糖苷中的至少一种。
7.一种槲皮素的应用,其特征在于,用于与血管内皮生长因子结合而促进血管生成。
8.一种山奈酚-3-O-芸香糖苷的应用,其特征在于,用于与血管内皮生长因子结合而促进血管生成。
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