CN112315953B - 一种姜黄素酯在改善急性肾损伤制品中的应用 - Google Patents
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Abstract
本发明属于活性物质筛选技术领域，具体涉及一种姜黄素酯在改善急性肾损伤制品中的应用。本发明首次将N‑3多不饱和脂肪酸和姜黄素合成为了富含N‑3多不饱和脂肪酸的姜黄素酯，其具有良好的水溶性，克服胃肠道反应，且综合了两者的优点，且首次证实了富含n‑3多不饱和脂肪酸的姜黄素酯均能明显改善急性肾损伤小鼠的肾损伤程度，说明了富含n‑3多不饱和脂肪酸的姜黄素酯能有效预防、改善或治疗急性肾损伤。
Description
技术领域：
本发明属于活性物质筛选技术领域，具体涉及一种姜黄素酯在改善急性肾损伤制品中的应用，特别是一种富含n-3多不饱和脂肪酸的姜黄素酯的制备方法，以及其在预防、改善或治疗急性肾损伤制品中的应用。
背景技术：
急性肾损伤(acute kidney injury,AKI)是一种以肾小球滤过率在短期内迅速降低为特点的常见临床综合征，主要表现为肾功能的快速下降和代谢废物的蓄积。多种病理生理状态(如血容量减少、低血压)和药物(如顺铂、造影剂等)都可导致肾脏血流减少，引起肾脏广泛或局部缺血，最终导致AKI。目前已有的研究表明，AKI的主要发病机制包括线粒体破坏、炎症反应、氧化应激反应及肾小管上皮细胞坏死和凋亡等。由于AKI有着十分复杂的发病机制，且目前仍缺乏有效的治疗手段，故通过膳食补充剂或者功能性食品预防肾脏疾病已经受到越来越多人的关注。
姜黄素是姜黄根茎中分离出的姜黄成分，是重要的天然多酚之一，因其副作用小、成本低、含量丰富而受到重视。二十多年的研究揭示了这种分子生物学效应的多效性。多篇文章揭示了姜黄素的各个方面，包括其调节脂质代谢、抗氧化、降血糖、抗炎和抗癌活性，但研究发现姜黄素在体内的活性偏低、体内吸少、代谢过快和生物利用度低，极大地限制了它的应用。N-3多不饱和脂肪酸具有改善脂质代谢、促进视觉和神经系统发育、预防和改善糖尿病、抗炎、抗癌、肾脏疾病、增强免疫力等生理活性，但其易氧化问题严重影响着产品品质。因此，本研究在姜黄素的基础上，合成了一种富含n-3多不饱和脂肪酸的姜黄素酯化合物，综合了两者各自的优点，但其生理活性尚未有研究报道。目前研究发现其他姜黄素酯类化合物具有改善动脉粥样硬化，脑损伤，癌症等疾病，但其是否可以改善肾脏疾病，目前尚未有研究报道，因此富含n-3多不饱和脂肪酸的姜黄素酯可能作为一种改善急性肾损伤的新型脂质保健产品。
发明内容：
本发明要解决的技术问题是由于AKI有着十分复杂的发病机制，且目前仍缺乏有效的治疗手段；而姜黄素在体内的活性偏低、体内吸少、代谢过快和生物利用度低，限制了其进一步的临床运用，N-3多不饱和脂肪酸又因其易氧化问题严重影响着产品品质。
为解决上述问题，本发明首次将N-3多不饱和脂肪酸和姜黄素合成为了富含N-3多不饱和脂肪酸的姜黄素酯，且综合了两者的优点。
为实现上述目的，本发明具体通过以下技术方案实现：
一种富含n-3多不饱和脂肪酸的姜黄素酯在改善急性肾损伤制品中的应用。
进一步的，所述姜黄素酯，其n-3多不饱和脂肪酸含量为30-60％。
进一步的，所述姜黄素酯为姜黄素单酯和姜黄素双酯中的一种或一种以上的混合物。
进一步的，所述化合物其结构式如图1所示，将n-3多不饱和脂肪酸基团引入姜黄素类化合物中，姜黄素中的酚羟基酯化后，稳定性增加从而形成一种新型的姜黄素酯衍生物，改善了n-3多不饱和脂肪酸易氧化的情况；并且单独补充姜黄素和n-3多不饱和脂肪酸时，二者会在进入体内的过程中被排泄掉很大一部分，只有少部分可以进入体内继续发挥生理作用，本发明的化合物以酯的形式可以将更多姜黄素和n-3多不饱和脂肪酸带入体内脏器，然后在体内再分解为姜黄素和n-3多不饱和脂肪酸起效，解决了姜黄素在体内的活性偏低、体内吸少、代谢过快和生物利用度低的问题。所以本发明的化合物既能发挥姜黄素的抗炎、抗氧化的作用，又发挥n-3多不饱和脂肪酸高生物利用度、抗炎、改善肾脏疾能的作用，且避免了姜黄素在体内活性偏低、吸收少、代谢过快和生物利用度低以及n-3多不饱和脂肪酸易氧化等缺点。
进一步的，所述制品包括功能性食品或药品，及相关制品，如乳剂等。
进一步的，所述改善急性肾损伤的制品优选为特医食品，保健品，药品或者生物制剂。
进一步的，所述制品包含有药理有效浓度(1％-100％)的所述的权利要求1所述的姜黄素酯。
一种上述姜黄素酯的制备方法，包括以下步骤：
1)称取姜黄素和n-3多不饱和脂肪酸(或富含n-3多不饱和脂肪酸的鱼油)，加入二氯甲烷，DMAP，EDCI后25℃、充氮、磁力搅拌；反应12h后将反应混合物转移到烧杯中，加入二氯甲烷，再用盐酸溶液(1mol/L)、饱和碳酸氢钠溶液、饱和氯化钠溶液依次清洗；回收有机相，减压旋蒸至无二氯甲烷后得到富含n-3多不饱和脂肪酸的姜黄素酯粗产物；
2)将硅胶经活化装柱后，用氯仿平衡硅胶柱；再将步骤2)得到的粗产物用正己烷溶解后，缓慢倒入硅胶柱中，依次用正己烷、正己烷-丙酮混合液和丙酮进行洗脱，收集洗脱液，洗脱液进行薄层硅胶板层析；其中，收集正己烷-丙酮的洗脱液为姜黄素双酯；收集丙酮的洗脱液为姜黄素单酯。
本发明的有益效果如下：
(1)本发明以姜黄素和富含n-3多不饱和脂肪酸的鱼油为原料制备富含n-3多不饱和脂肪酸的姜黄素酯，进一步分离和转化，制得的纯度均在90％以上。
(2)本发明提供的制备方法成本低，步骤简单，使用的有机溶剂量少，对环境产生的有机溶剂污染小。
(3)通过动物实验验证，急性肾损伤小鼠仅补充干预200-500mg/kg的n-3多不饱和脂肪酸的姜黄素酯，就明显提高了肾损伤小鼠的生存时间，以及降低了小鼠的肾脏组织损伤程度；说明本发明制得的富含n-3多不饱和脂肪酸的姜黄素酯能够极大地延长了急性肾损伤小鼠的生存时间，并且能明显减缓小鼠肾脏组织病变速度，即富含n-3多不饱和脂肪酸的姜黄素酯均能明显改善急性肾损伤小鼠的肾损伤程度，说明了富含n-3多不饱和脂肪酸的姜黄素酯能有效预防、改善或治疗急性肾损伤。
附图说明
图1为本发明实施例2中富含n-3多不饱和脂肪酸的姜黄素酯结构；
图2为本发明实施例2中富含n-3多不饱和脂肪酸的姜黄素酯对急性肾损伤小鼠肾脏组织病理学影响的结果图；
图3为本发明实施例2中富含不同小鼠肾脏组织病理学评分的结果图。
具体实施方式：
为使本发明实施例的目的、技术方案和优点更加清楚，下面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。
实施例1：富含n-3多不饱和脂肪酸的姜黄素酯的制备
(1)称取1mmol姜黄素和2mmol鱼油，加入10mL二氯甲烷，100mg DMAP，300mg EDCI后25℃、充氮、磁力搅拌。反应12h后将反应混合物转移到烧杯中，加入50mL二氯甲烷，再用盐酸溶液(1mol/L)、饱和碳酸氢钠溶液、饱和氯化钠溶液依次清洗。回收有机相，减压旋蒸至无二氯甲烷后得到富含n-3多不饱和脂肪酸的姜黄素酯粗产物；
(2)将硅胶经活化装柱后，用氯仿平衡硅胶柱；再将步骤2)得到的粗产物用正己烷溶解后，缓慢倒入硅胶柱中，依次用正己烷、正己烷-丙酮混合液和丙酮进行洗脱，收集洗脱液，洗脱液进行薄层硅胶板层析，；其中,收集正己烷-丙酮的洗脱液为姜黄素双酯；收集丙酮的洗脱液为姜黄素单酯。
实施例2：动物实验
2.1.材料和方法
(1)动物喂养和行为学分析
实验动物采用Balb/c小鼠，雄性，体重20-22g，购自北京维通利华实验动物技术有限公司。动物房湿度65±15％，室温23±2℃，12h:12h明暗交替，小鼠可自由摄食和饮水。小鼠在适应性喂养一周后，将小鼠分为8组：正常对照组、模型对照组、姜黄素、DHA、姜黄素-DHA单酯、姜黄素-DHA双酯、姜黄素+DHA(1:1)、姜黄素+DHA(1:2)每组8只，分别喂食相应的饲料。饲料参照AIN-93G啮齿动物饲料配方并加以改良，记录和统计摄食量，每隔一天称量记录体重变化，连续喂养1周。除正常组外，其余七组每日腹腔注射盐酸顺铂((15mg/kg.bw/day)，姜黄素的灌胃剂量为300mg/kg.bw/day，模型对照组组灌胃等量的生理盐水。注射顺铂三日后，每组小鼠禁食过夜处死，收集血液和肾组织样本，用于生化指标检测。
(2)统计学处理
ˉ
实验数据以x±SEM表示，采用SPSS 18.0软件进行Student’s t test and Tukey’s test分析，以P＜0.05为有显著差异。
(3)实验结果
富含n-3多不饱和脂肪酸的姜黄素酯对急性肾损伤小鼠的肾脏组织的病理学苏木素-伊红染色结果如图2所示，与正常组小鼠相比，模型组小鼠注射顺铂会引起肾脏组织发生明显的变化：大面积坏死区域，近端小管严重扩张和管状上皮细胞大量脱落和坏死，出现典型的急性肾损伤病理表现。而富含n-3多不饱和脂肪酸的姜黄素酯明显的减轻肾损伤程度，肾小管萎缩程度明显减轻，坏死的肾小管上皮细胞明显减少，肾小球和肾小管结构逐渐趋于完整，且以双酯形式的姜黄素酯效果最为突出；单独补充姜黄素和DHA也可以改善肾脏病理损伤，但效果远远不如姜黄素酯。此外，对小鼠同时干预姜黄素和DHA也可以显著改善药物诱导的肾脏组织病理损伤，且效果略优于单独补充姜黄素和DHA，但改善程度低于姜黄素酯。图3结果则显示富含n-3多不饱和脂肪酸的姜黄素酯能明显的改善顺铂诱导的急性肾损伤小鼠的肾脏组织的病理改变。
以类似急性肾损伤作为实验对象，其病症产生机理较复杂，包括线粒体功能障碍介导的细胞凋亡，MAPK信号通路，炎症，肾脏内氧化应激和内质网应激等，实施例2中主要机制可能为肾脏内氧化应激导致的细胞凋亡造成的肾小管损伤，即说明了富含n-3多不饱和脂肪酸的姜黄素酯能显著的改善顺铂诱导的急性肾损伤。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (3)
1.一种富含n-3多不饱和脂肪酸的姜黄素酯在制备改善急性肾损伤制品中的应用；n-3多不饱和脂肪酸含量为30-60％；所述姜黄素酯为DHA-姜黄素双酯。
2.如权利要求1所述的应用，其特征在于：所述制品为药品。
3.如权利要求1所述的应用，其特征在于：所述制品包含1％-100％的药理有效浓度的姜黄素酯。
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