CN114432294A - 一种5-去甲川陈皮素及其制备方法与应用 - Google Patents
一种5-去甲川陈皮素及其制备方法与应用 Download PDFInfo
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- CN114432294A CN114432294A CN202210154168.2A CN202210154168A CN114432294A CN 114432294 A CN114432294 A CN 114432294A CN 202210154168 A CN202210154168 A CN 202210154168A CN 114432294 A CN114432294 A CN 114432294A
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- demethylnobiletin
- nobiletin
- polymethoxyflavone
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Abstract
本发明提供了一种5‑去甲川陈皮素及其制备方法与应用，属于医药技术领域。本发明提供了一种5‑去甲川陈皮素在制备防治溃疡性结肠炎产品中的应用，本发明首次提出5‑去甲川陈皮素对溃疡性结肠炎具有显著的防治作用，表现为可显著改善腹泻程度、结肠长度变短、肠充血水肿和溃疡、肠上皮损伤、肠通透性增加等状况。且高通量筛选与PT‑qPCR表明5‑去甲川陈皮素是通过上调肠黏膜上皮粘蛋白Muc2的表达，增强肠黏膜的屏障作用，达到防治溃疡性结肠炎的目的。另外，本发明采用酸催化和加热方法来加速多甲氧基黄酮川陈皮素的去甲基化，成功实现了由多甲氧基黄酮川陈皮素到5‑去甲川陈皮素的转化，且得到的5‑去甲川陈皮素纯度可达97.5％。
Description
技术领域
本发明属于医药技术领域，尤其涉及一种5-去甲川陈皮素及其制备方法与应用。
背景技术
溃疡性结肠炎(Ulcerative colitis，UC)，是一种常见的、主要累及结直肠的慢性非特异性炎性疾病。该病为发达国家的常见病，其发病率近年来仍在递增，该病在我国原为低发病，但随着国人饮食结构西化，其发病率亦呈显著递增趋势。该病病程漫长，易反复，约15％的患者呈急性、灾难性的暴发过程，且伴有肠穿孔、大出血、息肉、甚至癌变等风险。对于UC的治疗，传统药物如氨基酸水杨酸制剂、糖皮质激素和免疫抑制剂等疗效有限，且存在不良反应多、复发率高、无法长期预防等弊端。新型生物制剂如TNF-α单克隆抗体虽被证实能够缓解UC，但只对约50％的患者有效，且价格昂贵。到目前为止，尚没有可将UC完全治愈的药物上市，UC亦被WHO列为现代难治病之一。因此，UC治疗的新思路、新手段亟待提出。
陈皮(CitriReticulataePericarpium)为芸香科柑桔属植物橘(CitrusreticulataBlanco)及其栽培变种的干燥成熟果皮。陈皮具有良好的抗癌、抗氧化等功效。5-去甲川陈皮素(5-demethylnobiletin,5-DN)，是多甲氧基黄酮川陈皮素(nobiletin，NBT)的5-去甲基对应物，二者共同存在于陈皮中，其化学结构见图1。黄酮类与挥发油类是存在于新鲜橘皮中的两大类活性成分，但随着储藏年限的延长，橘皮中精油成分逐渐挥发，而剩余的主要是包括5-DN与NBT在内的多甲氧基黄酮(见图1)。陈皮中NBT的含量要远高于5-DN，如储藏6年的市售新宝堂陈皮中，NBT含量约为7.634mg/g，5-DN含量约为0.608mg/g。现有技术并未有5-DN与溃疡性结肠炎相关性的有关研究，而且现有技术从陈皮中提取5-DN的方法存在提取率低、分离纯化工艺复杂等缺陷，并不适用于工业生产。
发明内容
有鉴于此，本发明的目的在于提供一种5-去甲川陈皮素在制备防治溃疡性结肠炎产品中的应用，对溃疡性结肠炎具有显著的防护作用。
为了实现上述发明目的，本发明提供了以下技术方案：
本发明提供了一种5-去甲川陈皮素在制备防治溃疡性结肠炎产品中的应用。
优选的，所述5-去甲川陈皮素通过上调肠黏膜上皮Muc2蛋白的表达，增强肠黏膜的屏障作用，达到防治溃疡性结肠炎的目的。
优选的，所述产品包括药物。
优选的，所述5-去甲川陈皮素的制备方法，包括如下步骤：将从陈皮中提取获得的多甲氧基黄酮川陈皮素粉末与浓盐酸-无水乙醇溶液混合，加热回流反应，得反应液，将反应液减压浓缩，浓缩物溶于乙酸乙酯，水洗，再减压浓缩，即得5-去甲川陈皮素。
优选的，所述无水乙醇与浓盐酸的体积比为9:1。
优选的，所述多甲氧基黄酮川陈皮素粉末与浓盐酸-无水乙醇溶液的料液比为1:1。
优选的，所述加热回流反应的时间为24h。
优选的，所述从陈皮中提取获得的多甲氧基黄酮川陈皮素粉末的方法，包括如下步骤：将陈皮粉和无水乙醇混合，浸泡、过滤、浓缩，得浓缩物，将浓缩物与氯仿-水溶液混合萃取，取氯仿层，采用硅胶柱层析法对氯仿层进行分离纯化，得多甲氧基黄酮川陈皮素粉末。
优选的，所述采用硅胶柱层析法对氯仿层进行分离纯化时，洗脱方法为乙酸乙酯和石油醚按照1:9-1:3进行梯度洗脱。
优选的，所述陈皮粉和无水乙醇的料液比为1:10。
本发明的有益效果：
本发明首次采用酸催化和加热方法来加速多甲氧基黄酮川陈皮素的去甲基化，成功实现了由多甲氧基黄酮川陈皮素到5-去甲川陈皮素的转化，大大提高了5-去甲川陈皮素的生产效率，而且制备方法简单、收率高、产品纯度高，得到的5-去甲川陈皮素纯度可达97.5％。
本发明首次提出5-去甲川陈皮素对溃疡性结肠炎具有显著的防护作用，具体为可改善体重减轻状况、腹泻程度；肠绒毛损伤与变短现象缓解、肠上皮细胞凋亡率降低、肠上皮完整性增加、肠通透性增加状况改善；肠道炎症因子表达水平降低。
附图说明
图1为新鲜橘皮与陈皮主要有效成分及其变化规律；
图2为5-DN检测结果图，其中图A为液相色谱图，图B为质谱图；
图3为不同组别的DAI评分结果；
图4为不同组别小鼠粪便情况图；
图5为不同组别小鼠结肠解剖外观图；
图6为不同组别小鼠结肠长度比较结果；
图7为5-DN的细胞毒性实验结果；
图8为不同组别TER测定结果图；
图9为不同组别血清中FITC-dextran浓度检测结果；
图10为不同组别小鼠结肠样本高通量测序结果；
图11为RT-qPCR检测不同组别小鼠Muc2 mRNA水平。
具体实施方式
本发明提供了一种5-去甲川陈皮素在制备防治溃疡性结肠炎产品中的应用。
在本发明中，所述5-去甲川陈皮素优选的通过上调肠黏膜上皮Muc2蛋白的表达，增强肠黏膜的屏障作用，达到防治溃疡性结肠炎的目的。本发明对于所述产品的类型没有特殊限定，包括药物等。
在本发明中，所述5-去甲川陈皮素优选的为按照如下制备方法制备所得，具体包括如下步骤：将多甲氧基黄酮川陈皮素与浓盐酸-无水乙醇溶液混合，加热回流反应，得反应液，将反应液减压浓缩，浓缩物溶于乙酸乙酯，水洗，再减压浓缩，即得5-去甲川陈皮素。
在本发明中，所述多甲氧基黄酮川陈皮素优选的是从陈皮中提取获得，所述提取方法优选的包括如下步骤：将陈皮粉和无水乙醇混合，浸泡、过滤、浓缩，得浓缩物，将浓缩物与氯仿-水溶液混合萃取，取氯仿层，采用硅胶柱层析法对氯仿层进行分离纯化，得多甲氧基黄酮川陈皮素粉末。
本发明对于陈皮的具体来源没有特殊限定，采用本领域常规市售产品均可，本发明对于将陈皮粉碎成粉的具体操作没有特殊限定，采用本领域常规粉碎方式即可。在本发明具体实施例中，所述粉碎选择的是采用药物粉碎机进行粉碎，粉碎后过筛即得，所述过筛的目数优选为20-80目，更优选的为40目。获得陈皮粉后，将陈皮粉和无水乙醇混合，所述陈皮粉和无水乙醇的料液比优选为1:10。在本发明中，所述浸泡的时间优选为48h。本发明对于过滤浓缩的具体方式没有特殊限定，采用本领域常规过滤浓缩方式均可。获得浓缩物后，将浓缩物与氯仿-水溶液混合萃取，所述浓缩物与氯仿-水溶液的体积比优选为1:1，在本发明中，将浓缩物与氯仿-水溶液混合后，优选的为搅拌萃取，所得氯仿层即为黄酮混合物。获得黄酮混合物后，采用硅胶柱层析法对氯仿层进行分离纯化。本发明对于硅胶的具体来源没有特殊限定，采用本领域常规市售硅胶产品均可，在本发明中，优选的采用乙酸乙酯和石油醚作为洗脱剂进行洗脱，所述乙酸乙酯和石油醚的体积比优选为1:9-1:3。获得洗脱液后，优选的需将洗脱液制备液相进一步分离纯化得多甲氧基黄酮川陈皮素。
获得多甲氧基黄酮川陈皮素后，将多甲氧基黄酮川陈皮素与浓盐酸-无水乙醇溶液混合，加热回流反应，所述多甲氧基黄酮川陈皮素与浓盐酸-无水乙醇溶液的质量体积比优选为1:1，所述加热回流反应的时间优选为24h。本发明对于浓盐酸-无水乙醇溶液的具体来源没有特殊限定，优选的需确保所述无水乙醇与浓盐酸的体积比为9:1即可。获得反应液后，将反应液减压浓缩，浓缩物溶于乙酸乙酯，水洗，再减压浓缩，即得5-去甲川陈皮素。本发明对于减压浓缩的具体操作没有特殊限定，采用本领域常规减压浓缩的方式均可。本发明对于乙酸乙酯的具体来源没有特殊限定，采用本领域常规市售产品均可。
下面结合实施例对本发明提供的技术方案进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
将市售陈皮清洗、烘干，通过药物粉碎机直接粉碎，过40目筛，得陈皮粉。将陈皮粉和无水乙醇按料液比1:10充分混合，浸泡48h后过滤、浓缩，得浓缩物。将浓缩物与氯仿-水溶液以体积比为1:1的比例混合溶解，搅拌萃取，取氯仿层浓缩，得黄酮混合物。
采用硅胶柱层析法对获得的黄酮混合物进行分离纯化，以乙酸乙酯:石油醚为1:9-1:3的比例进行梯度洗脱，洗脱液以制备液相进一步分离纯化得NBT(保留时间11.1min)，以GC-MS技术确认NBT的结构。
将获得的NBT与浓盐酸-无水乙醇溶液(无水乙醇与浓盐酸体积比9:1)按料液比1:1充分混合，加热回流反应24h。然后将反应液减压浓缩，浓缩物溶于乙酸乙酯，水洗，再减压浓缩，即可制得5-DN，经HPLC检测纯度高达97.5％，进一步采用核磁共振与质谱技术对得到的5-DN进行结构鉴定。结果如图2所示。
实施例2
选用8-10周雄性C57 BL/6小鼠，体重21.5-23.0g，购自北京华阜康生物科技股份有限公司。购买的所有的小鼠均置于中国医学科学院放射医学研究所动物实验中心，室温20±1℃饲养，光照周期为12h，相对湿度控制在50％-70％，昼夜明暗交替时间为12/12，噪音<60dB，氨浓度不超过20ppm。观察一周后，无任何病症后用于后续实验。所有动物实验均通过天津商业大学伦理委员会批准。
将小鼠随机分为五组，每组6只，即：空白对照组(灌胃混有少量DMSO的橄榄油(DMSO含量不高于0.6％))、葡聚糖硫酸钠(DSS)实验对照组(3％DSS饮用水+灌胃混有少量DMSO的橄榄油(DMSO含量不高于0.6％))、5-DN实验组又分为低、中、高组，3％DSS饮用水+分别对应按照5、10、20mg/kg的量灌胃5-DN(5-DN用混有少量DMSO的橄榄油(DMSO含量不高于0.6％)进行溶解)，连续灌胃7天，于7天后将小鼠处死。
(1)腹泻程度记录
采用腹泻评分法(DAI评分法)。0分表示为正常的粪便，1分表示已失去已有形状的粪便；2分表示明显的痢疾和伴有肛门附近明显的污秽；3分表示血便或者严重的痢疾，尾部和肛门处伴有大量的污秽。在DSS作用后的第三天后，开始出现腹泻的症状，在DSS后的4到7天的时间中，是腹泻的高发期，每天进行两次腹泻评分，保证对粪便评价的准确和一致性。结果如图3-4所示。由图3可以看出，在DSS作用后的第三天，DSS组开始出现小鼠粪便不成形的情况。在DSS作用后的第四天，是DSS组腹泻的高发期，出现便溏甚至血便的现象，而5-DN低、中、高实验组均可明显减轻DSS小鼠腹泻程度。由图4可以看出，空白对照组没有任何一只小鼠出现腹泻或者血便等异常情况。
(2)结肠解剖外观记录
实验结束后，解剖各组小鼠，获得各组小鼠的结肠解剖外观图(图5)，DSS模型组出现严重充血水肿、肠壁增厚和溃疡，结肠内还有血便的累积，而5-DN中处理组小鼠较模型组虽也含有血便，但充血水肿等现象得到改善。测量各组小鼠结肠的长度，结果如图6所示，5-DN低、中、高实验组均可明显减轻DSS小鼠结肠变短情况。
实施例3
在体外实验中，通常以检测跨上皮电阻以及细胞单层通透性方式来模拟肠道屏障的完整性。Caco2细胞系是人的结肠癌细胞，结构和功能类似于分化的小肠上皮细胞。与小肠上皮细胞在形态学上相似，具有相同的极性及紧密连接，因此，在本次研究中采用Caco2细胞作为体外肠屏障模型。经细胞毒性实验检测显示(图7)，5-DN在2-50μM浓度范围内对Caco2细胞不产生毒性。
紧密连接模型的建立：将细胞以8×104/小室的密度接种于孔径为0.4μm，膜面积为0.33cm2的Transwell培养板上，小室外BL层加入600μL的DMEM培养基，小室内AP层加入细胞悬浮液100μL，接种后第一周隔日换液，第二周开始每日换液持续到21天。当细胞分化21天建立细胞紧密连接模型后，无血清培养24h，在Transwell小室AP层加入10μM的5-DN预处理6h后，再加入10μg/mL的脂多糖(LPS)处理，分别在处理2h，4h，8h，12h，24h，48h后测量小室的电阻值变化。测量前，将电极浸入75％的酒精中浸泡15min，然后放在已灭完菌的PBS中备用。测量时，先将培养板放入超净台内平衡半小时以保证数值得稳定性，再测定培养板三个不同方向的电阻值取其平均值乘以膜面积，因为Transwell的空白膜也有一定的电阻值，所以实际的电阻值应减去空白膜的电阻值。
计算公式：TER＝(R-R空白)*A(Ω*cm2)
(注：R为实际测量电阻值，R空白为未添加细胞的空白膜电阻值，A为膜面积，空白对照组不进行任何处理。结果如图8所示。由图8可以看出，5-DN处理组LPS诱导的结肠炎小鼠的肠道完整性损伤明显减轻。
实施例4
测量荧光标记大分子物质FITC-葡聚糖(FITC-dextran)通过单层细胞的通过率，用来评价单层细胞的通透性。Caco2细胞分化21天后，用预温为37℃的PBS溶液缓慢冲洗Transwell小室2次，然后在Transwell小室的AP层加入0.1mg/mL的FITC 100μL，BL层则加入600μLPBS缓冲液，将细胞培养板放于CO2培养箱内孵育1h后，分别于Transwell的BL侧及AP侧各取100μL的液体，利用多功能酶标仪计算荧光吸光度(其中激发波长设定在480nm，发射波长设定在520nm)，并计算FITC的通透率及跨膜转运表观渗透系数(Papp)。
计算公式：计算公式：Papp＝ΔQ/(Δt*A*Co)(cm*s-1)
其中ΔQ为Δt的转运量，A为膜面积，Co为Caco2细胞AP侧的初始浓度。
细胞单层透过率是另一个测量体外屏障模型是否遭到破坏的重要因素。在本实验中，Caco2细胞进行培养21天形成致密的单层膜屏障后无血清培养24h，提前加入5-DN预处理6h后，再加入10μg/mL的LPS处理2h，模型组直接加入LPS处理2h。2h后在基底层加入提前预热到37℃的PBS缓冲液600μL，上层加入用PBS缓冲液稀释到1mg/mL的FITC-dextran，培养1h后分别从基底层及上层吸取100mL的培养液加入全黑的96孔板上按要求测其吸光度。
结果如图9所示，由图9可以看出加入LPS刺激细胞可使细胞的通透率增高，而5-DN预处理6h可显著抑制细胞的通透率增加(p＜0.05)。提示5-DN可保护细胞单层膜屏障遭到破坏，对体外膜屏障具有一定的保护作用。
实施例5
模型构建同实施例2，设置三组实验：空白对照组(灌胃混有少量DMSO的橄榄油(DMSO含量不高于0.6％))、葡聚糖硫酸钠(DSS)实验对照组(3％DSS饮用水+灌胃混有少量DMSO的橄榄油(DMSO含量不高于0.6％))、5-DN实验组(3％DSS饮用水+10mg/kg的量灌胃5-DN，其中5-DN用混有少量DMSO的橄榄油(DMSO含量不高于0.6％)进行溶解)，连续灌胃7天，于7天后将小鼠处死。
高通量测序技术检测基因表达谱变化。取以上三组的结肠样本送检，通过全基因组表达谱芯片技术检测上述处理后基因表达谱的变化，从而得到相对全面的在小鼠结肠炎前后相关蛋白mRNA表达水平的变化。测试结果结合聚类分析寻找与小鼠结肠炎相关的差异表达基因。结果如图10所示(由于原图太长，只截取了其中的关键部分)，其中，每个处理组送检样本均为三个独立样本。从该结果可以看出，在5-DN处理前后，Gene ID:17831的基因表达出现显著性差异，查阅NCBI Gene数据库(https://www.ncbi.nlm.nih.gov/gene/)发现基因Gene ID:17831编码的蛋白正是肠黏膜上皮黏蛋白Muc2(Mucin2)。表明5-DN对DSS诱导的小鼠结肠炎的防治功能与其上调肠道Muc2的表达有关。
RT-qPCR验证测序结果。表达谱芯片是一种高通量的分析工具，其分析得到的结果难免存在误差，需要通过RT-qPCR方法对芯片结果加以验证。以GAPDH作为内参基因。结果如图11所示，DSS单独处理组Muc2 mRNA表达水平显著降低，而联合5-DN处理组Muc2 mRNA水平与空白对照相比虽然也有降低，但降低幅度明显减小，且DSS与5-DN+DSS两个处理组的两独立样本t检验结果显示，5-DN处理后Muc2 mRNA水平明显升高。RT-qPCR结果与高通量测序结果一致，进一步显示5-DN对DSS诱导的小鼠结肠炎的防治功能与其上调肠上皮Muc2表达有关。最终，高通量测序与RT-qPCR结果一致显示Muc2上调表达参与了5-DN防治结肠炎的过程。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种5-去甲川陈皮素在制备防治溃疡性结肠炎产品中的应用。
2.根据权利要求1所述的应用，其特征在于，所述5-去甲川陈皮素通过上调肠黏膜上皮Muc2蛋白的表达，增强肠黏膜的屏障作用，达到防治溃疡性结肠炎的目的。
3.根据权利要求1所述的应用，其特征在于，所述产品包括药物。
4.根据权利要求1-3任意一项所述的应用，其特征在于，所述5-去甲川陈皮素的制备方法，包括如下步骤：将从陈皮中提取获得的多甲氧基黄酮川陈皮素粉末与浓盐酸-无水乙醇溶液混合，加热回流反应，得反应液，将反应液减压浓缩，浓缩物溶于乙酸乙酯，水洗，再减压浓缩，即得5-去甲川陈皮素。
5.根据权利要求4所述的应用，其特征在于，所述无水乙醇与浓盐酸的体积比为9:1。
6.根据权利要求4所述的应用，其特征在于，所述多甲氧基黄酮川陈皮素粉末与浓盐酸-无水乙醇溶液的料液比为1:1。
7.根据权利要求4所述的应用，其特征在于，所述加热回流反应的时间为24h。
8.根据权利要求4所述的应用，其特征在于，所述从陈皮中提取获得的多甲氧基黄酮川陈皮素粉末的方法，包括如下步骤：将陈皮粉和无水乙醇混合，浸泡、过滤、浓缩，得浓缩物，将浓缩物与氯仿-水溶液混合萃取，取氯仿层，采用硅胶柱层析法对氯仿层进行分离纯化，得多甲氧基黄酮川陈皮素粉末。
9.根据权利要求8所述的应用，其特征在于，所述采用硅胶柱层析法对氯仿层进行分离纯化时，洗脱方法为乙酸乙酯和石油醚按照1:9-1:3进行梯度洗脱。
10.根据权利要求8所述的应用，其特征在于，所述陈皮粉和无水乙醇的料液比为1:10。
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| CN114890972A (zh) * | 2022-05-26 | 2022-08-12 | 华南理工大学 | 一种微波协同深共溶试剂降解川陈皮素制备去甲基川陈皮素的方法 |
| CN114890972B (zh) * | 2022-05-26 | 2023-11-10 | 华南理工大学 | 一种微波协同深共溶试剂降解川陈皮素制备去甲基川陈皮素的方法 |
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