CN115487178A - 木犀草素在制备治疗或预防银屑病药物中的应用 - Google Patents
木犀草素在制备治疗或预防银屑病药物中的应用 Download PDFInfo
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Abstract
本发明公开了木犀草素在制备治疗或预防银屑病药物中的应用。属于医药健康技术领域。与现有技术相比，本发明取得的有益效果为：证明了木犀草素在皮肤炎症的治疗过程中展现出良好的抗炎活性，可用于银屑病的抗炎治疗。
Description
技术领域
本发明涉及医药健康技术领域，更具体的说是涉及木犀草素在制备治疗或预防银屑病药物中的应用。
背景技术
银屑病是一种最为常见的炎症性的皮肤病。银屑病的发病受遗传及环境因素的双重影响，其中饮食、气候、地理分布都是影响其发病率的重要因素。银屑病最主要的临床表现是在患者的皮肤上形成炎症皮损斑块，除此之外，该病也可对患者的指(趾)甲、关节等部位造成损害，甚至促使患者本身所具有的慢性疾病(如糖尿病、高血压、代谢疾病、抑郁症以及疲劳等)发作，极大地损害患者的健康。
银屑病的主要病理特征表现为表皮棘层增厚、皮肤角化异常以及以淋巴细胞为主的炎性细胞浸润，同时伴随新生血管的形成。在银屑病患者的皮损组织中，角质形成细胞的分裂周期明显缩短，表皮更替时间仅为3-4天，而正常的皮肤组织则需要约30天；同时，皮损部位还出现角化不全的现象，具体表现为皮肤组织中角蛋白的表达出现异常，尤其是角蛋白16和角蛋白17，这两种角蛋白在正常皮肤中并不常见。除此之外，银屑病患者的皮损组织中还能检测到淋巴细胞，尤其是CD4+T细胞的浸润，以及大量角质形成细胞调节因子如IL-6，IL-17，IL-20，IL-22等，这些细胞因子能够影响角质形成细胞的生长，分化以及凋亡水平。
由于致病机理的复杂性以及不确定性，对于银屑病的治疗也一直是困扰医学界的一个难题。目前临床上的治疗方法包括：1)物理治疗：如窄谱中波紫外线照射治疗以及淋浴疗法等；2)药物治疗：目前银屑病的全身治疗药物包括维A酸类，甲氨蝶呤，环孢素等，而外用药物则包括类固醇激素，钙调神经磷酸酶抑制剂他克莫司以及维生素D类衍生物等；3)免疫生物学治疗：如针对TNF-α及其受体、IL-1等相关分子的单抗；4)中医中药治疗。前三种治疗方式是目前应用比较成熟的治疗方式，针对银屑病的病情也有一定的治疗效果，但是因为疗效限制，不良反应过大或者治疗费用较高等因素，大大限制了这些药物的使用以及推广。中药是我国的民族瑰宝，针对我国丰富的中药资源，开发针对银屑病的治疗药物，具有重要的实用价值。
木犀草素，学名3′,4′,5,7-四羟基黄酮，是一种天然多酚羟基黄酮类化合物，在木犀科植物中分布广泛，存在于木犀草、金银花、菊花、荆芥、夏枯草、洋蓟、紫苏、黄芩等天然药材中。早在我国古代时期，富含木犀草素的草药就被用于多种疾病的治疗，例如用于止咳祛痰，消炎以及高血压等。由于木犀草素在多种植物中分布广，含量高，提取分离方法简单，因此来源丰富、易于制备，同时也具有良好的成药性。黄酮类植物化学物大都具有抗氧化生物活性，木犀草素也同样具备这样的特性，由于其良好的抗氧化生物活性，目前已被广泛应用于药品、保健品及化妆品等多个领域。木犀草素具有抗感染、抗氧化、保肝、利胆、抗炎、抗突变、抗肿瘤等多种生物学功能。临床主要用于止咳、祛痰、消炎、治疗心血管疾病、治疗呼吸道病毒感染以及肝炎等。但是目前，木犀草素是否可以用于银屑病的治疗，还有待于阐明。
发明内容
有鉴于此，本发明提供了木犀草素在制备治疗或预防银屑病药物中的应用。
为了实现上述目的，本发明采用如下技术方案：
木犀草素在制备治疗或预防银屑病药物中的应用。
进一步的，木犀草素可以抑制由IL-6或IL-22诱导的皮肤角质形成细胞的增殖，可以降低由IL-6/IL-22刺激引起的STAT3Thy705位点的磷酸化，可以抑制由IL-6/IL-22引起的STAT3活化。
木犀草素，化学名：3',4',5,7-四羟黄酮，别名：黄示灵、黄色黄素，CasNo:491-70-3，化学式：C15H10O6，分子量：286.23。物理性状：黄色针状结晶，熔点328-330℃。微溶于水，具弱酸性，可溶于碱性溶液中，正常条件下稳定。木犀草素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、紫苏含量较高。因此，可以按常规制剂方法，将木犀草素制备成临床适用的任何一种药剂，如膏剂、片剂、胶囊剂、颗粒剂及注射剂等形式。在制备上述任何一种制剂的过程中，可以将木犀草素与任何一种适用于制备成临床药剂的赋型剂混合使用，制备成药物制剂。通过本发明，木犀草素可以有效用于治疗银屑病或预防银屑病复发，且无明显毒副作用。
进一步的，无论是将木犀草素作为活性组份单独使用，还是与其他活性成份配合使用制备成相应的制剂，用于银屑病的治疗/预防，都在本发明的保护之列。
进一步的，所述银屑病为寻常型、关节型、红斑型或脓疱型。
经由上述的技术方案可知，与现有技术相比，本发明取得的有益效果为：证明了木犀草素在皮肤炎症的治疗过程中展现出良好的抗炎活性，可用于银屑病等皮肤疾病的抗炎治疗。
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，下面将对实施例或现有技术描述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，还可以根据提供的附图获得其他的附图。
图1附图为木犀草素的分子结构；
图2附图为本发明实施例1中木犀草素抑制IL-6/IL-22诱导的角质形成细胞增殖，其中，*代表p<0.05；
图3附图为本发明实施例2中在皮肤角质形成细胞中，木犀草素抑制IL-6/IL-22诱导的Stat3通路的活化，其中a为IL-6结果，b为IL-22结果；
图4附图为本发明实施例3中木犀草素处理后IMQ小鼠模型背部皮损变化及HE染色图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，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实施例，都属于本发明保护的范围。
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实验例1木犀草素对皮肤角质形成细胞增殖功能的影响
1)实验材料：
木犀草素购自中国医学科学院药用植物研究所(分子结构如图1所示)。溶解于DMSO中制备成50μM的储存浓度，用0.2μm的滤膜过滤除菌，分装后贮存于4℃冰箱。
IL-6及IL-22均购自美国Peprotech公司，溶解于超纯水中制备成50μg/ml的储存浓度，用0.2μm的滤膜过滤除菌，分装后贮存于-20℃冰箱。
2)试验方法：
生长状态良好的HaCaT细胞培养于DMEM培养基(含10％胎牛血清，青霉素50U/ml，硫酸链霉素50μg/m)用胰酶消化并按2×104个/孔，共200μl的数量接种于96孔板中，于5％CO2培养箱中培养24小时，细胞达到60％以上汇合率后弃去培养基，再分别加入100ml含浓度为25ng/ml的IL-6/IL-22或/和25μM的木犀草素的新鲜培养基中，对照组加入相同体积的溶剂(具体实验分组如下)，继续于5％CO2培养箱中继续培养。24小时后，利用细胞增殖检测试剂(盒购自美国Promega公司)，按产品说明书中方法测定细胞的增殖水平，具体方法是，每孔加入10μl的MTS试剂，于5％CO2培养箱中孵育1.5个小时后，利用酶标仪在490nm波长条件下检测其吸光度，计算细胞增殖率。
细胞增殖率＝[1-(Ac-As)/(Ac-Ab)]×100％，其中，
As代表实验孔吸光度，Ac代表对照孔吸光度，Ab代表空白孔吸光度。
具体分组：
对照组：仅溶剂；
实验组1：加入25μM的木犀草素；
实验组2：加入25ng/ml的IL-6；
实验组3：加入25ng/ml的IL-6和25μM的木犀草素；
实验组4：加入25ng/ml的IL-22；
实验组5：加入25ng/ml的IL-22和25μM的木犀草素；
3)结果：
如图2所示，木犀草素可以效地抑制由IL-6或IL-22诱导的皮肤角质形成细胞的增殖。
实验例2木犀草素对皮肤角质形成细胞Stat3炎症通路活化的影响
炎症反应中IL-6的产生和持续刺激能激活STAT3通路，进而诱导IL-21表达，形成IL-21/STAT3自分泌环路，从而引起STAT3持续激活，上调ROR-γt丰度，使前体细胞向Th17分化。Th17细胞是银屑病发病中的关键细胞，因此STAT3对银屑病发病有重要作用。
1)试验方法：
生长状态良好的HaCaT细胞培养于DMEM培养基(含10％胎牛血清，青霉素50U/ml，硫酸链霉素50μg/m)用胰酶消化并按2×104个/孔，共2ml的数量接种于6孔板中，于5％CO2培养箱中培养24小时，细胞达到60％以上汇合率后弃去培养基，再分别加入1ml含浓度为25μM的木犀草素的新鲜培养基，对照组加入相同体积的溶剂DMSO，继续于5％CO2培养箱中继续培养24小时。再利用Th17相关细胞因子处理角质形成细胞，取上述用木犀草素处理24小时后的HaCaT细胞，弃去培养基，处理孔加入1ml含浓度为25ng/ml的IL-6或者IL-22的新鲜培养基，于5％CO2培养箱中继续培养30分钟(用于测定Stat3通路活化即PY-Stat3)或24小时(用于测定Stat3的下游调控基因表达)后，收集细胞，利用Westernblot法对细胞的蛋白成份进行测定。具体方法是：
将处理后的HaCaT细胞置于冰上，用PBS洗涤每孔加入200μlRIPA裂解液，后用细胞刮刮下细胞转移至1.5ml离心管中，于冰上裂解15分钟后在4℃，12000RPM离心15分钟，收集上清，按照BCA蛋白定量试剂盒(购自美国PI公司)说明书进行操作，测定上清中的总蛋白量；调整蛋白总量，加入5×LoadingBuffer，95℃加热5分钟，再进行Westernblot试验。按照要求配置好SDS-PAGE分离胶(10％)和浓缩胶(5％)，每孔加入100ug的蛋白总量，稳压(浓缩胶60V，分离胶120V)电泳使蛋白分离。将胶放于转膜缓冲液中浸泡10分钟，然后剪切与胶大小相同的膜和滤纸，按照正确方向铺好，确保层与层之间没有气泡，恒压100V将蛋白条带转印至0.45μmPVDF膜上，膜在使用前先用100％甲醇预处理约15秒，使膜活化。转膜完成后用5％BSA封闭1小时以上。然后分别用含有合适稀释倍数的一抗Rabbitanti-P-Stat3(Tyr705)antibody，Rabbitanti-T-Stat3antibody(均购自英国Abcam公司)，以及anti-GAPDHantibody(均购自美国CST公司)于4℃冰箱过夜，使用TBST缓冲液洗涤三次，每次10分钟，然后室温孵育后，再用含1％BSA的经稀释的HRP-Goatanti-RabbitIgG酶标抗体对其进行孵育1小时后，使用ECL化学发光液均匀涂在膜上，在WesternBlot曝光系统中获得图像。
2)结果：
细胞学实验表明，如图3的检测结果表明木犀草素处理能够明显降低由IL-6/IL-22刺激引起的STAT3Thy705位点的磷酸化。木犀草素能够明显抑制由IL-6/IL-22等炎性因子引起的STAT3活化，并且由此达到对角质形成细胞过度增殖的抑制作用并改善皮肤的异常分化。
实施例3木犀草素能够改善小鼠模型中银屑病皮损
1)实验方法及动物分组：
咪喹莫特(IMQ)是一种TLR7/8激动剂，具有免疫激活作用，已经被证实能够引起银屑病样皮损。咪喹莫特诱导的银屑病小鼠模型被认为是目前最适合作为银屑病研究的模型之一。
咪喹莫特软膏(5％)(Aldara
)购自于德国MedaPharma公司。
6周大的BALB/C雌鼠购自于南京大学模式动物研究所，饲养在SPF级别动物房中，给与正常饮水、饮食及周期性光照。
小鼠称重并背部脱毛后被随机分成三组，每组5只。除对照组外，每只小鼠每天用62.5mg的咪喹莫特软膏涂抹于皮肤表面，对照组用同剂量凡士林作为对照。Luteolin组在接受咪喹莫特处理外，每天腹腔注射的方式给与5mg/kg的木犀草素，其余两组用生理盐水作为对照。在处理5天后，小鼠在接受背部拍照后被处死，取背部皮肤组织，投入4％多聚甲醛固定。
小鼠背部皮肤HE染色：固定后的组织制作成4mm厚度的石蜡切片，取上述小鼠皮肤切片，在60℃烘箱中烘烤15分钟后，置于二甲苯中脱蜡15分钟。脱蜡完成后，置于梯度酒精中水化。水化完成滴加苏木素染色液染色5分钟后用蒸馏水冲洗；放入95％乙醇5秒钟后滴加伊红染色液1分钟；用70％乙醇清洗后放入梯度酒精脱水，脱水完成放入二甲苯透明后封片，放于显微镜下观察拍照。以每组样本随机选取5～10视野进行拍照观察以考察皮损处改变。
2)结果：
结果如图4所示。动物实验表明，在银屑病中角质形成细胞过度增殖导致表皮增厚，木犀草素能够明显改善银屑病样皮损的形成，有效抑制了角质形成细胞的过度增殖。说明银屑病经木犀草素治疗后症状有所减轻。
本说明书中各个实施例采用递进的方式描述，每个实施例重点说明的都是与其他实施例的不同之处，各个实施例之间相同相似部分互相参见即可。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (2)
1.木犀草素在制备治疗或预防银屑病药物中的应用，其特征在于，木犀草素可以抑制由IL-6或IL-22诱导的皮肤角质形成细胞的增殖，可以降低由IL-6/IL-22刺激引起的STAT3Thy705位点的磷酸化，可以抑制由IL-6/IL-22引起的STAT3活化。
2.如权利要求1所述的应用，其特征在于，所述银屑病为寻常型、关节型、红斑型或脓疱型。
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| CN113768917A (zh) * | 2021-08-17 | 2021-12-10 | 南方海洋科学与工程广东省实验室(湛江) | 木犀草素在抑制nlrp3炎症小体活化中的应用 |
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