CN110934860A - 木犀草素在制备抑制视网膜病变药物中的应用 - Google Patents
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Abstract
本发明公开了木犀草素在制备预防和治疗视网膜病变药物中的应用，为视网膜病变的预防和治疗提供新的可能性药物，为木犀草素在视网膜病变防治中的应用，以及天然黄酮资源的开发和功能研究提供一定的实验依据。所述的木犀草素通过抑制视网膜色素上皮细胞(RPE)存活率降低、细胞形态学损伤和细胞凋亡水平的升高，来有效抑制环境污染物丙烯醛诱导的细胞凋亡，维持细胞内环境稳态。木犀草素存在于多种植物中，来源广泛，价格低廉，具备可深入开发潜力。
Description
技术领域
本发明涉及木犀草素的应用，具体地说，涉及木犀草素在制备抑制环境污染物丙烯醛诱导的视网膜病变药物中的应用。
背景技术
视网膜病变是导致失明的主要因素之一。其中，年龄相关性黄斑变性(age-related macular degeneration,AMD)是导致老年人群失明的最常见的视网膜病变。AMD已经成为我国老年人主要致盲性眼病，患者表现为双眼同时或先后不可逆的，渐进性的视力下降。随着人口老龄化进程的推进，50岁以上人群中AMD的发病率已经从1987年的6.41％上升至2005年的15.5％，15年的时间，发病率上升高达约2.4倍；仅2005年一年，在50岁以上的人群中，AMD就造成106.4万的低视力患者和21.7万的盲人。预计到2040年，全球的AMD患者将会达到2.8亿，成为严重威胁公共健康的疾病之一。AMD给患者的身心带来了沉重的压力与痛苦，导致患者生活质量严重下降。繁重的医疗负担，伴随着治疗药物的副作用以及治疗的长期性，不仅严重影响患者健康，也不断加重患者的经济压力。因此，探究AMD的发生、发展机制，采取相应措施进行相关预防和治疗，改善AMD患者视力，提高患者生活质量，具有重要的临床和社会意义。
AMD的确切病因及发病机制暂未明确，国内外学者发现它可能与长期黄斑的慢性光损伤、环境、代谢、饮食、遗传与种族等多种因素有关，而这些外界因素均可以导致视网膜色素上皮细胞(retinal pigment epithelium,RPE)的损伤。RPE细胞是位于神经视网膜和脉络膜之间的单层多边形细胞，RPE细胞在眼的发育和视觉功能中发挥着重要作用，例如：组成视网膜生理组织的重要部分即血-视网膜屏障，同时也能够分泌多种生长因子，参与视循环代谢和维持感光细胞的正常生理功能和降解其外节所脱落膜盘碎片的作用等。因此，维持RPE细胞的完整性对正常的视网膜功能至关重要。
环境污染物通过多种途径进入大气和水体中，并对机体有一定的毒害作用，多种常见慢性疾病与之密切相关。虽然目前对AMD病因的认识还未明确，但是吸烟已被国内外学者公认为首要危险因素。群组研究统计表明：吸烟者发生晚期AMD的相对危险度是未吸烟者的2.4倍，补体因子402HCC基因组吸烟者的相对危险度是未吸烟者的34倍。烟雾中的醛类和氧化氮类等毒性物质，不仅可以显著降低RPE细胞中的抗坏血酸水平和硫化氢蛋白的含量，也可引起脂肪和蛋白的氧化。随着吸烟剂量的增大，患者黄斑色素的浓度逐渐降低，血浆中烟碱和可铁宁的浓度增加，进一步导致炎性介质的产生，最终导致细胞凋亡。目前在香烟中已发现有六种毒性醛类物质，丙烯醛就是其中的一种，与其余5种醛类物质相比丙烯醛具有更高的危险指数，它的毒性大约是甲醛的10倍，乙醛的100倍。鉴于丙烯醛对RPE细胞的高毒性作用，制备一种能够有效抑制丙烯醛的药物已经成为研究者们面临的重要课题。
木犀草素作为一种天然黄酮类化合物，具有抗炎、抗过敏、抗病毒及抗氧化等多种生物学活性，多以糖苷的形式存在于多种植物中，这些植物以全叶青兰、辣椒、野菊花、金银花及紫苏含量较高。目前已有报道表明黄酮类化合物在体内和体外对RPE细胞均具有保护作用，作为黄酮类化合物之一的木犀草素也对心脏、肝脏、神经及心血管疾病均存在有益效果，但目前木犀草素对丙烯醛诱导的RPE细胞损伤的保护作用尚未明确。因此，本发明通过探究木犀草素在制备抑制环境污染物丙烯醛诱导的视网膜病变药物中的应用，对木犀草素的生物学活性进行进一步的探索，为视网膜病变的预防和治疗提供理论基础和实验依据。
发明内容
本发明目的是提供一种含有木犀草素的药物，在制备抑制环境污染物丙烯醛诱导的视网膜病变药物中的应用。木犀草素能够抑制丙烯醛诱导的细胞凋亡，本发明从细胞存活率、细胞形态学观察及细胞凋亡角度出发，为木犀草素在视网膜病变的预防和治疗的应用中提供理论基础及实验依据。
本发明采用的技术方案为：木犀草素单用或与其他药物联用在制备抑制视网膜病变药物中的应用。
优选地，上述的应用，木犀草素单用或与其他药物联用在制备抑制环境污染物丙烯醛诱导的视网膜病变药物中的应用。
优选地，上述的应用，木犀草素通过抑制细胞凋亡，抑制视网膜病变。
优选地，上述的应用，所述的抑制细胞凋亡，包括抑制细胞存活率的降低、细胞形态学损伤及细胞凋亡水平的升高。
优选地，上述的应用，以木犀草素为有效成分，还包括药学上可接受的辅料或辅助性成分。
优选地，上述的应用，所述的视网膜病变为：年龄相关性黄斑变性。
优选地，上述的应用，所述的药物为片剂、胶囊剂或颗粒剂；注射制剂为注射液。
优选地，上述的应用，木犀草素的剂量为0.1～0.2mg/(kg·d)。
上述的环境污染物丙烯醛广泛存在于日常生活中，按来源可分为内源性及外源性，内源性主要源于脂质过氧化的分解，外源性主要是通过工业排放、机动车尾气排放、烟草燃烧及厨房油烟等途径。
附图说明
图1为木犀草素对丙烯醛诱导的RPE细胞存活率的影响。
图2为木犀草素对丙烯醛诱导的RPE细胞形态学的影响。
其中，a：空白；b：200μM丙烯醛；c：200μM丙烯醛+20μM木犀草素；d：200μM丙烯醛+40μM木犀草素；e：200μM丙烯醛+80μM木犀草素。
图3为木犀草素对丙烯醛诱导的RPE细胞凋亡水平的影响
其中，a：空白；b：200μM丙烯醛；c：200μM丙烯醛+20μM木犀草素；d：200μM丙烯醛+40μM木犀草素；e：200μM丙烯醛+80μM木犀草素。
本发明的有益效果：
本发明克服了现有视网膜病变预防和治疗药物的局限，为其提供新的可能性药物，利用木犀草素及以其为主要活性成分，在制备预防和治疗年龄相关性黄斑变性药物(或保健食品)中的应用。发现了木犀草素能够预防和治疗环境污染物丙烯醛所诱导的视网膜病变，抑制其诱导的RPE细胞凋亡。木犀草素来源广泛，价格低廉，具备可深入开发潜力。
具体实施方式
本实施例选用RPE细胞为研究对象，检测木犀草素对环境污染物丙烯醛诱导的RPE细胞凋亡的抑制作用，具体实验步骤如下：
一)细胞存活率检测实验
RPE细胞接种于96孔板，细胞分组情况为Control组，丙烯醛损伤组，不同浓度的木犀草素保护组。根据预实验结果，选定丙烯醛损伤浓度为200μM，木犀草素保护浓度为20μM、40μM和80μM，损伤组单独加入200μM丙烯醛，保护组同时加入200μM丙烯醛及不同浓度的木犀草素共同孵育细胞，处理24h后每孔加入20μL MTT溶液，置于5％CO2、37℃细胞培养箱中继续培养4h。之后吸出培养基每孔加入150μL的DMSO溶液，置于摇床上摇10min，使甲瓒晶体完全溶解，检测490nm处的吸光度值，计算RPE细胞的存活率。
从图1可以看出，丙烯醛处理后，RPE细胞的存活率相对于Control组出现显著(P＜0.01)降低，将Control组细胞存活率设为100％，丙烯醛损伤组细胞存活率降低到65.69％，加入木犀草素共孵育后，细胞存活率相对于丙烯醛损伤组呈现升高的趋势，40μM及80μM的木犀草素能够使细胞存活率分别上升到84.13％及93.63％，显著(P＜0.01)抑制丙烯醛诱导的细胞存活率的降低。结果表明，木犀草素能够抑制丙烯醛诱导的RPE细胞存活率的降低。
二)细胞形态学观察
通过观察细胞形态和数量判定细胞生长状态，将RPE细胞接种于6孔板中培养，细胞分组情况同上，处理结束后，于显微镜下进行观察并拍照。
实验结果如图2，Control组细胞呈梭形生长，细胞轮廓分明，生长状态良好且具有光泽，细胞数量也相对较多。加入丙烯醛后，细胞形态出现明显的变化，由梭形向圆形转变，胞体出现皱缩，贴壁细胞数量显著减少。观察不同浓度木犀草素组(20、40和80μM)细胞可见，与丙烯醛损伤组相比，80μM的木犀草素使得细胞形态发生明显改善，细胞皱缩现象得到明显缓解。
三)Hoechst33258细胞凋亡检测
Hoechst33258是一种可以穿透细胞膜的蓝色荧光染料，对细胞的毒性较低，常用于细胞凋亡检测。这种染料可以将死细胞立即染色，而对活细胞的染色却是逐步进行，而且在10min内染色会达到饱和。在紫外光340nm波长激发的荧光显微镜下观察，活细胞呈现均匀且较弱的蓝色荧光，而凋亡细胞内会出现明亮的蓝色荧光斑块。
将细胞接种于12孔板中，处理结束后，参照试剂盒说明加入Hoechst33258染料，避光温育10min。孵育结束后，使用PBS进行轻轻淋洗，5min/次，共3次。清洗后使用4％多聚甲醛室温固定30min，然后进行封片，置于倒置荧光显微镜下观察并拍照。
从图3可以看出，对照组细胞呈现微弱荧光，丙烯醛损伤组细胞染色呈强蓝色荧光。加入木犀草素共孵育后，随着浓度的增加，蓝色荧光强度显著减弱，呈浓度依赖性。结果表明，木犀草素能够抑制丙烯醛诱导的RPE细胞凋亡。
Claims (8)
1.木犀草素单用或与其他药物联用在制备抑制视网膜病变药物中的应用。
2.如权利要求1所述的应用，其特征在于，木犀草素单用或与其他药物联用在制备抑制环境污染物丙烯醛诱导的视网膜病变药物中的应用。
3.如权利要求1所述的应用，其特征在于，木犀草素通过抑制细胞凋亡，抑制视网膜病变。
4.如权利要求3所述的应用，其特征在于，所述的抑制细胞凋亡，包括抑制细胞存活率的降低、细胞形态学损伤及细胞凋亡水平的升高。
5.如权利要求1所述的应用，其特征在于，以木犀草素为有效成分，还包括药学上可接受的辅料或辅助性成分。
6.如权利要求1所述的应用，其特征在于，所述的视网膜病变为：年龄相关性黄斑变性。
7.如权利要求1所述的应用，其特征在于，所述的药物为片剂、胶囊剂或颗粒剂；注射制剂为注射液。
8.如权利要求1所述的应用，其特征在于，木犀草素的剂量为0.1～0.2mg/(kg·d)。
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