CN114907199B - 抗炎、止痒的蒲公英二萜类化合物、其制备方法及应用 - Google Patents
抗炎、止痒的蒲公英二萜类化合物、其制备方法及应用 Download PDFInfo
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- CN114907199B CN114907199B CN202210684012.5A CN202210684012A CN114907199B CN 114907199 B CN114907199 B CN 114907199B CN 202210684012 A CN202210684012 A CN 202210684012A CN 114907199 B CN114907199 B CN 114907199B
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Abstract
本发明公开了根据活性追踪法分离、富集并最终确定其结构的蒲公英二萜类化合物的制备方法;本发明还公开了含上述蒲公英二萜的组合物及其在抗炎、舒缓、止痒类化妆品和/或药品上的应用,这种应用是通过提高HaCaT细胞活力、抑制HaCaT细胞炎性细胞因子分泌、降低蛋白酶激活受体‑2含量、和/或降低Th2介导的IgE和IgG1以及Th1介导的IgG2a的血清水平而实现的。本发明的蒲公英二萜组合物可以作为抗皮肤瘙痒活性物使用,在化妆品或药物中具有广泛的应用前景。
Description
技术领域
本发明涉及蒲公英活性提取物(蒲公英二萜类化合物)、制备方法及其应用,更具体地讲,本发明涉及蒲公英二萜类化合物、其制备方法以及在制备具有抗炎、舒缓、止痒作用的化妆品/药品中的应用。
背景技术
小儿湿疹,即特应性皮炎(atopic dermatitis,AD),属于变态反应性皮肤疾病,是一种慢性、炎症性、复发性皮肤病。食入、吸入或接触不耐受或过敏等均可导致小儿湿疹的发生。目前西医治疗主要为内服抗组胺药和外用激素类药,主要包括糖皮质激素和免疫抑制剂,但西药通常治标不治本,其虽能缓解症状、缩短病程,但不能控制复发,治愈率低,较多的患儿在停药后会复发。
中医治疗小儿湿疹讲究标本兼治,针对不同的症型采取不同的治疗,主要有内服法,外洗法和外治法,在缓解、根治湿疹上具有很大的优势。中医外治对湿疹患儿治疗,不仅可以促进患儿体内的热毒、湿毒的排除,且由于选用的中药具有抗过敏、抗菌、解热、抗炎的作用,能够有效地对小儿湿疹病症进行治疗,防止感染状况的出现,达到根治的效果。
蒲公英又名黄花地丁、婆婆丁等,分布较广,几乎遍及全国多数地区,具有较高的药用价值、食用价值以及经济价值。全草皆可入药,是一味珍贵的中草药,具有清热解毒、消痛散结、消炎、凉血、利尿、利胆、轻泻、健冒、防癌等多种功能。蒲公英含有蒲公英甾醇、蒲公英赛醇、豆甾醇、谷甾醇、胆碱、有机酸、菊糖、橡胶等。
例如,中国专利201310744612.7公开了一种野菊花浸膏与蒲公英浸膏互配的浸膏类烟用香料及其制备方法和应用。野菊花中含有丰富的黄酮、挥发油及多种葡萄糖苷、萜烯类等成分,具有抗菌消炎、降血压及疏风清热、消肿解毒等功效;蒲公英是一种常用的中药材,有抗菌、利胆、通乳、抗肿瘤的功效。此烟用香料对吸烟引发的一系列咽喉炎症有一定的抑制作用。
中国专利申请201610343484.9公开了一种复方红豆杉免煎颗粒、其制备方法和用途。其利用含红豆杉、生薏米、丹参、黄柏、紫芍、败浆草、大青叶、蒲公英、知母、黄芩、金银花、泽泻、蜈蚣的物质为原料,经提取、精制、喷雾干燥制备成可用于药品或化妆品的免煎颗粒,对治疗粉刺痤疮可短时间达到理想效果。
中国专利申请201710298174.4公开了一种利用植物提取液防治菊花病虫害的制剂及制备方法。将香樟根、狼毒大戟根和蒲公英全草按重量比1∶1∶1的比例混合,用粉碎机加工成颗粒,过60目筛,放入提取釜中进行萃取,加入75%乙醇,在80~85℃的温度下蒸煮、浓缩,即成香樟根、狼毒大戟根和蒲公英全草复合提取物浓缩膏及结晶体,对菊花病虫害有较高的防治作用。
中国专利201710413443.7公开了一种含有核桃青皮提取物的抗氧化组合物,该抗氧化组合物由以下重量份数的原料制成:核桃青皮提取物35~65份、丹参提取物15~45份、小红参提取物5~35份和蒲公英提取物1~10份。其优点是:具有抗氧化,除皱和保湿的功效。
中国专利201810387780.8公开了一种祛痘复方精油制剂及其制备方法和应用,该祛痘复方精油制剂包括连翘精油1-5份、荆芥精油0.1-1份、蛇床子精油0.1-1份、石菖蒲精油0.1-1份、薄荷精油0.05-0.5份、薰衣草精油0.1-1份、蒲公英精油1-2份、蛇油5-10份、葡萄籽油20-30份、玉米胚芽油20-30份、茶树油10-20份和荷荷巴油10-25份,其改善了现有西药祛痘药物毒副作用大且成本高、单方精油作用单一、疗效不显著的技术问题,不仅能调节皮脂分泌平衡、抗炎杀菌、激活细胞自我修护,而且能淡化痘印、舒缓肌肤。
中国专利201811593435.6公开了一种护肤复合水果植物抗敏提取液、其制备方法和应用,该提取液原料包括:板蓝根、粉防己、茯苓、苦参根、蒲公英、中华猕猴桃,其中,板蓝根、粉防己、茯苓、苦参根、蒲公英、中华猕猴桃的质量比为(1~5):(5~10):(2~5):(1~5):(1~3):(0.1~0.5)。所得提取液具有保湿、预防、缓解敏感性皮肤过敏炎症的功能。
萜类化合物是蒲公英中含有的重要生物活性成分。然而,蒲公英萜类化合物是否具有抗炎、舒缓、止痒的功效却未见报道。
因此,有必要对蒲公英二萜类化合物进行有区别的分离、富集,以开发具有抗炎、舒缓、止痒的蒲公英二萜类化合物或其组合物应用于化妆品或药品具有重要的应用价值。
发明内容
本发明的发明目的之一是提供利用活性追踪法制备的蒲公英二萜类化合物;本发明的另一发明目的是提供制备蒲公英二萜类化合物的制备方法;本发明的再一发明目的是提供上述蒲公英二萜类化合物或其组合物在制备消炎、舒缓、止痒类化妆品或药品中的应用。
一方面,为了实现上述的发明目的,本发明提供了由干蒲公英通过活性追踪法制备的、下述结构式中式I-式III所示的蒲公英二萜类化合物,其中:
式I所示的蒲公英二萜命名为蒲公英二萜-1,简写为PET-1,结构式如下所示:
式II所示的蒲公英二萜命名为蒲公英二萜-2,简写为PET-2,其结构式如下所示:
式III所示的蒲公英二萜命名为蒲公英二萜-3,简写为PET-3,其结构式如下所示:
另一方面,为了实现上述的发明目的,本发明还提供了一种制备上述蒲公英二萜类化合物的方法,该方法包括如下的过程制备:
(1)将干蒲公英粉碎;
(2)粉碎后的蒲公英用乙醇-水进行渗漉提取;
(3)合并减压浓缩步骤(2)所得的提取液,得到浸膏;
(4)用水混悬步骤(3)所得的浸膏,得到混悬液;
(5)步骤(4)所得的混悬液用乙酸乙酯进行萃取,萃取液浓缩后得乙酸乙酯萃取物;
(6)将乙酸乙酯萃取物通过硅胶柱层析分离,采用石油醚-乙酸乙酯混合溶剂进行梯度洗脱,得到若干馏分;
(7)构建2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)的损伤模型,评价步骤(6)所得各馏分的活性;
(8)将步骤(7)中具有最佳保护活性的馏分先后采用凝胶柱、ODS反向柱层析、以及制备型HPLC分离纯化得如式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3。
在本发明的制备方法中,步骤(1)所使用的蒲公英可以是半干的或干燥的,优选所使用的蒲公英是干燥的。
在本发明的制备方法中,步骤(2)中蒲公英与酒精-水的质量比可以为1:(20-100)。
在本发明的制备方法中,步骤(2)中所采用的乙醇-水为30%-75%的乙醇,优选为35%-75%的乙醇,更优选为40%-60%的乙醇,例如45%的乙醇。此处,所说的乙醇浓度为体积浓度,例如45%的乙醇是指乙醇与水的体积比为45:65。
其中,步骤(5)中选用乙酸乙酯进行萃取也是在活性分析的基础上选择的:第一步,先将步骤(4)所得的混悬液依次用石油醚、乙酸乙酯、正丁醇进行萃取,将各萃取液浓缩后分别得石油醚萃取物、乙酸乙酯萃取物、正丁醇萃取物;第二步,基于构建的2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)的损伤模型,评价第一步中所得石油醚萃取物、乙酸乙酯萃取物、正丁醇萃取物的保护活性,发现乙酸乙酯萃取物具有最佳的保护活性。
作为本发明制备方法的一种具体实施方式,可采用蒲公英(干)7kg,粉碎,用45%乙醇渗漏提取48小时,合并减压浓缩提取液,得浸膏;总浸膏用适量水混悬,依次用石油醚、乙酸乙酯、正丁醇进行萃取,将各萃取液浓缩后分别得石油醚萃取物,乙酸乙酯萃取物,正丁醇萃取物;构建的2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)的损伤模型,评价石油醚萃取物,乙酸乙酯萃取物,正丁醇萃取物保护活性;将具有最佳保护活性的乙酸乙酯萃取物通过硅胶(200-300目)柱层析分离,采用石油醚-乙酸乙酯混合溶剂梯度洗脱,得到馏分Fr.1-7;基于前述构建的2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)的损伤模型,评价Fr.1-7保护活性;将具有最佳保护活性的Fr.4先后采用Sephadex LH-20凝胶柱(MeOH-CDCl3)、ODS反向柱层析(MeOH-H2O)以及制备型HPLC(MeOH/MeCN-H2O)分离纯化得蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3。
在本发明中,蒲公英二萜类化合物可以从蒲公英中基于活性追踪法分离提取得到,为其制备提供了一个新的途径。
再一方面,为了实现上述的发明目的,本发明还提供了一种用于抗炎、舒缓、止痒的蒲公英二萜的组合物,该组合物包括前述式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3中的至少一种。
优选地,在本发明的蒲公英二萜的组合物中,式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3的质量比为1:(1-100):(1-100)。
更优选地,在本发明的蒲公英二萜的组合物中,式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3的质量比为1:(1-10):(1-10)。
进一步优选地,在本发明的蒲公英二萜的组合物中,式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3的质量比大致为1:1:1,但此处并非是严格的比例。
经过试验,本申请的发明人发现,蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3分别具有很好的抗炎、舒缓、止痒的活性,而包括这三种化合物的组合物,则显示出比单独的蒲公英二萜化合物更为出色的抗炎、舒缓、止痒的活性。
又一方面,为了实现上述的发明目的,本发明还提供了上述蒲公英二萜或其组合物在制备消炎、舒缓、止痒化妆品或药品中的应用。
在本发明的应用中,该应用可通过提高HaCaT细胞活力、抑制HaCaT细胞炎性细胞因子分泌、降低蛋白酶激活受体-2含量、和/或降低Th2介导的IgE和IgG1以及Th1介导的IgG2a的血清水平而得以实现。
在本发明上述的应用中,化妆品包括护肤品,此类化妆品和护肤品可以为乳、霜、水剂等形式。蒲公英二萜或其组合物可以作为化妆品或护肤品的添加剂,加入至化妆品或护肤品中,作为舒缓、抗炎、止痒的有效成分。
在本发明上述的应用中,所涉及的炎症可以是指皮炎、湿疹、皮肤瘙痒等皮肤病的炎症,特别是皮肤瘙痒症。
相对于现有技术,本发明至少具有如下的有益效果:
(1)本发明所提供的蒲公英二萜类化合物及其组合物,细胞实验结果表明蒲公英二萜类化合物及其组合物能抑制2,4-二硝基氯苯诱导的人永生化角质形成细胞(HaCaT细胞)相关炎性因子分泌,发挥抗炎、舒缓的活性;
(2)本发明所提供的蒲公英二萜组合物,动物实验结果表明蒲公英二萜组合物能明显延长皮肤瘙痒模型小鼠瘙痒潜伏搔抓时间,减轻皮肤瘙痒小鼠搔抓次数。蒲公英二萜组合物治疗后,各用药组小鼠血清炎性因子含量较皮肤瘙痒模型组降低,说明蒲公英二萜组合物具有抗炎、缓解皮肤瘙痒的作用;
(3)本发明的蒲公英二萜化合物及其组合物可从蒲公英中提取、分离、组合得到,来源丰富;且蒲公英二萜化合物及其组合物制备工艺简单、操作方便,有利于在抗炎、舒缓、止痒类药品、化妆品中应用。
下面将结合具体实施方式和附图对本发明技术方案进行清楚、完整描述。本领域技术人员可以理解的是,此处所描述的具体实施方式仅仅是本发明一部分的实施方式,而不是全部的实施方式。基于本发明的精神,本领域的普通技术人员可以在不作出创造性劳动的前提下进行相应的替换、变换、改变或改进,但这些替换、变换、改变或改进,仍属于本发明的保护范围。
附图说明
图1是蒲公英二萜-1的HR-ESI-MS谱图;
图2是蒲公英二萜-1的1HNMR谱图;
图3是蒲公英二萜-1的13CNMR谱图;
图4是蒲公英二萜-2的HR-ESI-MS谱图;
图5是蒲公英二萜-2的1HNMR谱图;
图6是蒲公英二萜-2的13CNMR谱图;
图7是蒲公英二萜-3的HR-ESI-MS谱图;
图8是蒲公英二萜-3的1HNMR谱图;
图9是蒲公英二萜-3的13CNMR谱图;
图10显示了蒲公英二萜、其组合物抑制2,4-二硝基氯苯诱导的HaCaT细胞活力下降;
图11显示了蒲公英二萜、其组合物抑制2,4-二硝基氯苯诱导的HaCaT细胞炎性细胞因子分泌;
图12显示了蒲公英二萜、其组合物抑制2,4-二硝基氯苯诱导的细胞CCR3、MCP-1、CCR4分泌增多;
图13显示了蒲公英二萜、其组合物调控2,4-二硝基氯苯诱导的小鼠血清Ig变化。
具体实施方式
本发明具体实施方式中所采用的主要试验仪器和主要材料来源为:化合物的核磁检测用Bruker AV-500或Bruker AV-400MHz核磁共振仪测定核磁(NMR),并以TMS为内标(德国Bruker公司);用Agilent 6210LC/MSD TOF型质谱仪测定高分辨质谱;用ThermoFinnigan LCQ Advantage MAX质谱仪(美国Thermo公司)测定质谱(ESI-MS);HPLC采用Dionex型高效液相色谱仪(美国Dionex公司);PHPLC采用Varian制备型高效液相色谱仪(美国Varian公司)和Agilent 1100LC/MSD型高校色谱仪(美国Agilent公司);CosmosilC-1(8250mm×4.6mm,5μm)色谱柱。Sephadex LH-20层析填料购于Pharmacia公司;ODS柱色谱材料购于德国Merck公司;柱色谱用硅胶购于青岛海洋化工厂;核磁用氘代试剂购自美国CIL公司;所用试剂均为分析纯和色谱纯。
实施例1蒲公英二萜的分离、鉴定
下面所进行的实施方式是一具体的实施例,但分离制备的方法并不限于该实施例。
蒲公英(干)7kg,粉碎,用45%乙醇(140L)渗漏提取48小时,合并减压浓缩提取液,得浸膏。总浸膏用适量水混悬,依次用石油醚、乙酸乙酯、正丁醇进行萃取,将各萃取液浓缩后分别得石油醚萃取物,乙酸乙酯萃取物,正丁醇萃取物;
构建2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)损伤模型,评价石油醚萃取物、乙酸乙酯萃取物、正丁醇萃取物的保护活性;
将具有最佳保护活性的乙酸乙酯萃取物通过硅胶(200-300目)柱层析分离,采用石油醚-乙酸乙酯混合溶剂(100:10→10:100)梯度洗脱,得到馏分Fr.1-7;
基于前述构建的2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)损伤模型,评价Fr.1-7保护活性;
将具有最佳保护活性的Fr.4先后采用Sephadex LH-20凝胶柱(MeOH-CDCl3)、ODS反向柱层析(MeOH-H2O)、以及制备型HPLC(MeOH/MeCN-H2O)分离纯化得蒲公英二萜-1(623mg)、蒲公英二萜-2(1110mg)、蒲公英二萜-3(377mg)。
蒲公英二萜-1的结构鉴定:
请参见附图1-3。蒲公英二萜-1为无色油状物,HR-ESI-MS谱(图1)显示m/z301.2135[M+Na]+(C18H30NaO2,理论计算值为301.2138)。再结合该化合物的NMR谱,推断其ECL-1的分子式为C18H30O2,不饱和度为4。
1H NMR(400MHz,CDCl3)谱(图2)提示该化合物有2个烯氢质子信号[δH 6.82(1H,dd,J=15.7,10.5Hz),6.18(1H,d,J=15.7Hz)],而其13C NMR(100MHz,CDCl3)谱(图3)则提示该化合物含有1对双键碳信号(δC 144.9,135.6),结合其DEPT-135谱,可判断含有-CH=CH-。此外,1H NMR谱中还有5个甲基单峰质子信号[δH 2.25(3H,s),1.24(3H,s),0.97(3H,s),0.87(3H,s),0.80(3H,s)],而13C NMR谱结合DEPT-135谱可判断出还包含1个酮羰基碳信号(δC 197.8),以及1个连氧的季碳信号(δC72.6)。再结合不饱和度(4),除去1个酮羰基和1个双键,可知结构中含有2个环。综上所述,最终确定化合物结构,如式I所示,本发明中将该化合物命名为蒲公英二萜-1。
蒲公英二萜-2的结构鉴定:
请参见附图4-6。蒲公英二萜-2为无色油状物,HR-ESI-MS谱(图4)显示m/z317.2088[M+Na]+(C18H30NaO3,理论计算值为317.2087)。再结合该化合物的NMR谱,推断其分子式为C18H30O3,不饱和度为4。
1H NMR(400MHz,CDCl3)谱(图5)提示该化合物有2个烯氢质子信号[δH 6.82(1H,dd,J=15.8,10.3Hz),6.17(1H,d,J=15.8Hz)],13C NMR(100MHz,CDCl3)谱(图6)则提示该化合物含有1对双键碳信号(δC 143.3,135.8),结合其DEPT-135谱,可判断含有1个-CH=CH-。此外,1H NMR谱中还有5个甲基单峰质子信号[δH 2.26(3H,s),1.21(3H,s),0.97(3H,s),0.88(3H,s),0.82(3H,s)],而其13C NMR谱结合DEPT-135谱可判断出还包含1个酮羰基碳信号(δC 197.9),1个连氧的次甲基信号(δC79.7),以及1个连氧的季碳信号(δC 76.2)。再结合的不饱和度(4),除去1个酮羰基和1个双键,可知结构中含有2个环。综上所述,最终确定化合物结构,如式II所示,本发明中将该化合物命名为蒲公英二萜-2。
蒲公英二萜-3的结构鉴定:
请参见附图7-9。蒲公英二萜-3为无色油状物,HR-ESI-MS谱(图7)则显示m/z309.2436[M+H]+(C19H33O3,理论计算值为309.2424)。结合该化合物NMR谱,推断其分子式为C19H32O3不饱和度为4。
1H NMR(400MHz,CDCl3)谱(图8)显示该化合物有1个醛基质子信号[δH 9.34(1H,s)],13C NMR(100MHz,CDCl3)谱(图9)结合DEPT-135谱则提示该化合物含有1个醛羰基碳信号(δC195.7),可知含有-CHO。此外,1H NMR谱中还有1个烯氢质子信号[δH 6.59(1H,t,J=7.5Hz)],13C NMR谱则提示该化合物含有1对双键碳信号(δC 158.7,137.6),结合其DEPT-135谱,可判断含有1个-CH=C-。1H NMR谱中还有5个甲基单峰质子信号[δH 1.75(3H,s),1.14(3H,s),0.87(3H,s),0.86(3H,s),0.80(3H,s)],13C NMR谱结合DEPT-135谱可判断出中还包含1个连氧的次甲基信号(δC 80.7),以及1个连氧的季碳信号(δC 77.7)。再结合不饱和度(4),除去1个醛羰基和1个双键,可知结构中含有2个环。综上所述,最终确定化合物结构,如式III所示,本发明中将该化合物命名为蒲公英二萜-3。
实施例2:本发明蒲公英二萜、其组合物的保护活性(细胞试验)
HaCaT细胞接种于96孔板,密度为5×104细胞/孔,培养24h。加入2,4-二硝基氯苯(5μM)处理细胞12h,然后,收集细胞,冷PBS清洗2遍,加入新的培养基并加入终浓度为20μg/mL的蒲公英二萜-1或蒲公英二萜-1或蒲公英二萜-3或蒲公英二萜组合物(蒲公英二萜-1,蒲公英二萜-2与蒲公英二萜-3质量比为1:1:1)。室温条件下共培育24h后,分离细胞及上清液备用。本实验部分,蒲公英二萜-1组标记为PET-1,蒲公英二萜-2组标记为PET-2,蒲公英二萜-3组标记为PET-3,空白组标记为CON,2,4-二硝基氯苯组标记为DCNB,蒲公英二萜组合物组标记为PETT。
图10所示的实验结果显示,相比于空白对照组(细胞活力,100%),2,4-二硝基氯苯暴露使HaCaT细胞活力显著降低(20.0%),而蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物处理后,细胞活力显著提高;相比于DCNB组。进一步分析实验结果发现,PETT组细胞活力高于PET-1组、PET-2组及PET-3组。
图11所示的ELISA实验结果显示,2,4-二硝基氯苯暴露使HaCaT细胞炎性细胞因子分泌显著增加,我们推测2,4-二硝基氯苯暴露显著诱导HaCaT细胞炎性损伤。而蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物处理后,细胞炎性因子过度分泌被抑制。进一步的分析实验结果发现,相比于蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3组,PETT组细胞炎性因子过度分泌被抑制效果更为显著,我们推测,蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3可能是通过发挥协同作用进而发挥抗炎活性的。
实验例3本发明之蒲公英二萜、其组合物的生物活性(动物试验)
昆明种小鼠,SPF级,雄性,体重(30±2)g,恒温环境饲养,温度(20±2)℃,湿度50%,饲养环境为光照节律12h:12h,自由进食进水,适应性喂养1周。将小鼠随机分为6组,每组8只,分别为正常组;皮肤瘙痒模型组;蒲公英二萜-1组;蒲公英二萜-2组;蒲公英二萜-3组;蒲公英二萜组合物组。实验开始后,除正常组外,其余各组小鼠颈背部皮下注射D-半乳糖注射液125/mg·kg,连续3周(正常组予同等剂量生理盐水)。第4周开始,各用药组小鼠按0.5mg/cm2涂抹给药,于每日傍晚给药1次,连续7d(正常组、皮肤瘙痒模型组每日给予同等剂量蒸馏水)。实验过程中,小鼠颈背部剪刀剃毛,保持颈背部无毛。
于第7天涂药1h后,静脉注射0.025%低分子右旋糖酐-40注射液,30min后,摄像机记录小鼠搔抓表现。摘眼球取血,3000r/min离心10min,取血清,酶联免疫吸附法检测血清MCP-1、CCR3、CCR4及CCL11、IgE、IgG1、IgG2a含量。
从表1数据中可以看出,与正常组比较,皮肤瘙痒模型组瘙痒潜伏时间缩短,瘙痒次数增多。而用药后各用药组瘙痒潜伏时间显著延长,瘙痒次数显著减少,其中蒲公英二萜组合物组瘙痒潜伏时间最长,瘙痒次数减少最显著。
表1蒲公英二萜组合物对小鼠瘙痒潜伏时间及瘙痒次数的影响
与皮肤瘙痒模型组比较*p<0.05,**p<0.01.
从表2数据中可以看出,与正常组比较,皮肤瘙痒模型组炎性细胞因子IL-1β含量显著性升高,说明模型组小鼠受到严重的炎性损伤。而与皮肤瘙痒模型组比较,用药后各用药组炎性细胞因子IL-1β含量降低,说明蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物均具有抑制炎症的活性,我们推测,蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物缓解小鼠皮肤瘙痒可能是通过缓解炎症发挥作用的。
表2蒲公英二萜组合物对小鼠IL-1β的影响
注:与正常组比较#p<0.05,##p<0.01;与皮肤瘙痒模型组比较*p<0.05,**p<0.01.
蛋白酶激活受体(Protease activated receptors,PARs)属于G-蛋白耦联受体家族,其中PAR-2是胰蛋白酶的细胞表面受体。PAR-2在许多的细胞表面表达并在激活后发挥多种作用。研究显示PAR-2的激活导致了血管的舒张、血管渗透性的增加、水肿、组织完整性的破坏等特征性的炎症反应,PAR-2在炎症时起保护或者损害作用主要依靠疾病的状态和被激活的细胞类型。
进一步的分析数据,从表3中可以看出,与正常组比较,皮肤瘙痒模型组PAR-2含量显著性升高。而蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物用药后,与皮肤瘙痒模型组比较,各用药组PAR-2含量显著降低。
表3蒲公英二萜组合物对小鼠血清PAR-2的影响
注:与正常组比较#p<0.05,##p<0.01;与皮肤瘙痒模型组比较*p<0.05,**p<0.01.
Th1和Th2细胞分别表达不同的趋化因子受体并与不同的趋化因子结合其中Th1细胞优势性表达CXCR3、CCR5。Th2细胞优势性表达CCR3,从而调控Th1和Th2细胞活化与极化。为了研究公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物对Th1型或Th2型细胞因子水平的影响,我们用ELISA试剂盒检测小鼠CCR3、MCP-1、CCR4的水平。
从图12中可以看出,与正常组比较,皮肤瘙痒模型组CCR3、MCP-1、CCR4含量显著性升高。而蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物用药后,与皮肤瘙痒模型组比较,各用药组CCR3、MCP-1、CCR4含量显著降低。
小鼠在皮炎发作后表现出血清中IgE水平升高,因此,我们测试了蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物是否能够控制Th2介导的IgE和IgG1以及Th1介导的IgG2a的血清水平。从图13中可以看出,与正常组比较,皮肤瘙痒模型组IgE、IgG1、IgG2a含量显著性升高。而蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3及蒲公英二萜组合物用药后,与皮肤瘙痒模型组比较,各用药组IgE、IgG1、IgG2a含量显著降低。其中,与蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3组相比,蒲公英二萜组合物组IgE、IgG1、IgG2a含量更低,我们推测,在相同浓度条件下,蒲公英二萜-1、蒲公英二萜-2、蒲公英二萜-3可能发挥协同作用,具有更优的保护活性。
Claims (2)
1.一种由干蒲公英通过活性追踪法制备蒲公英二萜类化合物的方法,该方法包括如下的过程制备:
(1)将干蒲公英粉碎;
(2)粉碎后的蒲公英用含乙醇30%-75%的乙醇-水进行渗漉提取;
(3)合并减压浓缩步骤(2)所得的提取液,得到浸膏;
(4)用水混悬步骤(3)所得的浸膏,得到混悬液;
(5)步骤(4)所得的混悬液用乙酸乙酯进行萃取,萃取液浓缩后得乙酸乙酯萃取物;
(6)将乙酸乙酯萃取物通过硅胶柱层析分离,采用石油醚-乙酸乙酯混合溶剂进行梯度洗脱,得到若干馏分;
(7)构建2,4-二硝基氯苯暴露人永生化角质形成细胞(HaCaT)的损伤模型,评价步骤(6)所得各馏分的活性;
(8)将步骤(7)中具有最佳保护活性的馏分先后采用凝胶柱、ODS反向柱层析、以及制备型HPLC分离纯化得如式I所示的蒲公英二萜-1、式II所示的蒲公英二萜-2和式III所示的蒲公英二萜-3:
2.如权利要求1所述的制备方法,其中,步骤(2)中所采用的乙醇-水为40%-60%的乙醇。
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