CN110507678B - 菱角壳提取物在制备治疗高血脂症药物上的应用 - Google Patents
菱角壳提取物在制备治疗高血脂症药物上的应用 Download PDFInfo
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Abstract
本发明公开了菱角壳提取物在制备治疗高血脂症的药物或保健品上的新用途，其具有良好的降血脂作用，并可以治疗和逆转高血脂症引发的脂肪肝的病变，为治疗高血脂症提供了更为有效的药物基础。
Description
技术领域
本发明属于医药及保健食品领域，具体涉及一种天然提取物的新用途。
背景技术
高脂血症是指血浆中一类或几类脂蛋白水平过高的症状。高脂血症分为原发性高血脂症和继发性高脂血症。原发性与先天性和遗传有关，是由于单基因缺陷或多基因缺陷，使参与脂蛋白转运和代谢的受体、酶或载脂蛋白异常所致，或由于环境因素和通过未知的机制而致。继发性多发生于代谢性紊乱疾病，或与其他因素年龄、性别、季节、饮酒、吸烟、饮食、体力活动、精神紧张、情绪活动等有关。高血脂症可直接引起一些严重危害人体健康的疾病，如动脉粥样硬化、冠心病、胰腺炎等。
脂肪肝是指由于各种原因引起的肝细胞内脂肪堆积过多的病变，其中最常见的一种就是非酒精性脂肪肝(NAFLD)。现代社会随着人们生活水平的提高，饮食结构和生活行为方式的改变，脂肪肝的发病率明显上升。非酒精性脂肪肝病是一种无过量饮酒史，以肝实质细胞脂肪变性和脂肪贮积为特征的临床病理综合征。它可引起脂肪性肝炎、肝纤维化、肝硬化、肝功能衰竭等病变。
酚类化合物是一类芳烃的含羟基衍生物，广泛存在于自然界中，由于其羟基取代的高反应性和吞噬自由基的能力而有很好的生理活性。研究表明酚类化合物具有抗衰老、抗炎、保护心脑血管、抗肿瘤等作用。
菱角是菱科(Trapaceae)、菱属(Trapa L.)植物果实。菱角采收后除少量以鲜果食用直接上市外，大部分去壳以菱角仁加工成各种产品。加工过程中产生的菱角果壳由于缺乏利用价值而被大量丢弃，既浪费了资源又会产生环境污染。
发明内容
本发明的目的是为了开发菱角壳的新用途、有效进行废物利用，同时提供一种新的高血脂症治疗药物。
为了达到上述目的，本发明提供了菱角壳提取物在制备治疗高血脂症的药物或保健品上的应用。
进一步的，菱角壳提取物在制备治疗高血脂症并发症的药物或保健品上的应用。
更为具体的，菱角壳提取物在制备治疗脂肪肝的药物或保健品上的应用。
或，菱角壳提取物在制备治疗肥胖症的药物或保健品上的应用。
上述菱角壳提取物通过以下方法制备：取菱角壳干燥粉末醇提水沉，经大孔树脂分离，洗脱液浓缩干燥，即得所述菱角壳提取物。
进一步的，上述菱角壳提取物通过以下方法制备：将菱角果壳干燥粉碎，得菱角果壳粉末，取浓度为80％的乙醇为溶剂，渗滤提取2次，每次15天，每次80％乙醇加入量为每1kg菱角壳加入8L，合并提取液；将提取液浓缩至浸膏，取浸膏重量10倍的10％乙醇溶解，离心除去不溶物，得到上样溶液；取 LS-300B型大孔树脂，将上样溶液上样，采用水洗脱，弃去洗脱液，再采用40％乙醇进行洗脱，收集40％乙醇洗脱液，将40％乙醇洗脱液减压浓缩干燥，即得所述菱角壳提取物。。
本发明相比现有技术具有以下优点：
本发明提供了菱角壳提取物在治疗高血脂症上的新用途，其具有良好的降血脂作用，并可以治疗和逆转高血脂症引发的脂肪肝的病变，为治疗高血脂症提供了更为有效的药物基础。
附图说明
图1为不同处理组对高脂小鼠体重的影响对比；
图2为不同处理组对高脂小鼠白色脂肪体重比的影响对比；
图3为不同处理组对高脂小鼠肝脏体重比的影响对比；
图4为不同处理组对高脂小鼠总胆固醇的影响对比
图5为不同处理组对高脂小鼠甘油三酯的影响对比；
图6为不同处理组对高脂小鼠高密度脂蛋白的影响对比；
图7为不同处理组对高脂小鼠低密度脂蛋白的影响对比；
图8为不同处理组对高脂小鼠超氧化物歧化酶水平的影响对比；
图9为不同处理组对高脂小鼠丙二醛的影响对比；
图10为不同处理组对高脂小鼠丙氨酸转氨酶的影响对比；
图11为不同处理组对高脂小鼠天冬氨酸转氨酶的影响对比；
图12为不同处理组对高脂小鼠肝脏外观的影响对比；
图13为不同处理组对高脂小鼠肝组织组织学分析的对比(H&E，200×放大)。
图1至3中，所有结果以均数±SEM表示(n＝8)。与对照组相比，#P<0.05，###P<0.001；与HFD组比较，*P<0.05，***P<0.001；
图4至7中，所有结果以均数±SEM表示(n＝8)。与对照组相比，#P<0.05，###P<0.001；与HFD组比较，*P<0.05，***P<0.001；
图8至11中，所有结果以均数±SEM表示(n＝8)。与对照组比较，###P< 0.001；与HFD组比较，***P<0.001。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
1、仪器与设备：Mettler EL204电子天平，瑞士梅特勒-托利多公司； MolecularDevices SpectraMax Plus 384型酶标仪，美国Molecular Devices公司；ThermoFinnpipette精密单通道加样器，赛默飞世尔科技公司； Transferpette-8型精密八通道移液排枪，德国普兰德公司。
2、化学试剂：没食子酸对照品(中国生物药品检定所)；Folin-Ciocalteu’sphenol试剂(Sigma-Aldrich公司)；
甘油三酯(TG)测定试剂盒、总胆固醇(TC)测定试剂盒、高密度脂蛋白胆固醇(HDL-C)测定试剂盒、低密度脂蛋白胆固醇(LDL-C)测定试剂盒、丙氨酸氨基转移酶(谷丙转氨酶/ALT/GPT)测试盒、天门冬氨酸氨基转移酶(谷草转氨酶/AST/GOT)测试盒(南京建成生物工程有限公司)、总超氧化物歧化酶 (SOD)测定试剂盒(WST-1法)(南京建成生物工程有限公司)、丙二醛(MDA) 测定试剂盒(TBA法)(均购自南京建成生物工程有限公司)，其余试剂均为分析纯购自国药集团化学试剂有限公司。
3、实验动物
SPF(Specific Pathogen Free)级ICR小鼠，雄性，体重18-22g。
4、含量测定方法：(紫外分光光度法)
标准曲线建立：
精密称取没食子酸对照品至棕色容量瓶中，用水溶解，配制成浓度为 0.1118mg/mL的标准品溶液。在96孔板中依次加入没食子酸标准品溶液0，5， 10，20，30，40，50μL。各样品中分别加入50μL10％Folin-Ciocalteu’s试剂，振荡3min后加入50μL 10％Na2CO3溶液充分混匀，以水溶液补足溶剂至150μL，在室温下放置1h后，将96孔板放入酶标仪中在760nm波长处测定各样品的吸光值，每个检测做3个重复，取其平均值。以吸光值(y)和没食子酸含量(x)绘制总酚含量标准曲线：y＝0.1995x+0.0788，R＝0.9993，没食子酸在0～5.59μg范围内呈良好的线性关系。
样品含量测定：
精密称取样品粉末，用纯水溶解，配制成1.0mg/mL的溶液。分别精密移取5μL样品溶液于96孔平板中，按标准曲线项下方法，加入显色剂反应，以样品溶液不加显示剂为空白，测定吸光值，根据没食子标准曲线求得各样品的总多酚含量(总多酚以没食子酸计)。
实施例1
1、菱角壳提取物制备：
菱角果壳干燥粉碎，称取菱角果壳粉末，浓度为80％的乙醇，渗滤提取2 次，每次加入体积为8倍于菱角壳质量(即体积质量比为8L/kg)的80％乙醇，每次15天，合并提取液。提取液浓缩至浸膏，浸膏用浸膏重量10倍的10％乙醇溶解，离心除去不溶物，得到上样溶液。取LS-300B型大孔树脂(弱极性大孔树脂柱)，将上样溶液上样，采用水洗脱，弃去洗脱液，再采用40％乙醇进行洗脱，收集乙醇洗脱液。40％乙醇洗脱液减压浓缩干燥，得菱角果壳多酚提取物。该提取物采用紫外分光光度法测得提取物多酚含量为94.7％。
2、高脂小鼠模型的建立
取18-22g SPF级ICR小鼠，自由饮食一周适应动物房环境后，随机分出正常组(NC)9只喂食小鼠全价营养颗粒饲料，其余小鼠喂食高脂饲料8周。
3、动物分组和给药
取菱角壳提取物，以0.5％CMC-Na分别溶剂配置成试药溶液。选取高脂小鼠随机分组，共3组，每组8只。分别为模型组(HFD)，菱角壳提取物低剂量组(HFD+TQPE 15，15mg·kg-1·d-1)，高剂量组(HFD+TQPE 30，30mg·kg-1·d-1)。模型组给予等体积的0.5％CMC-Na。空白对照组(CON)给予小鼠全价营养颗粒饲料，高脂小鼠继续给予高脂饲料。造模成功后灌胃给药4周。
4、基础指标观测及标本采集
小鼠给药4周后，第10周禁食不禁水12h，末次给药2h后，小鼠称重，尾静脉取血，以血糖仪测定小鼠空腹血糖(FBG)。小鼠摘眼球取血，收集于EP 管中，室温放置1h，3000转离心10分钟分离血清，分装后置于-20℃保存。测定血糖、胰岛素、TC、TG、HDL-C、LDL-C、ALT、AST含量。解剖小鼠取出腹股沟、附睾两侧白色脂肪记录重量，取出肝脏，记录重量并冻存于-80℃中待用。
5、肝脏病理学观测
取部分肝脏组织以10％福尔马林固定18-24小时，经流水冲洗6-12小时，再经脱水、透明、浸蜡、包埋、切片、脱蜡、HE染色、脱水、封片后，在100 倍显微镜下观察。
6、统计学方法
数据使用GraphPad Prism软件处理，两组间比较采用独立样本的t检验，多组间比较采用单因素方差分析(ONE-WAYANOVA)方法，结果以mean±SEM 表示。
7、实验结果
(1)菱角壳提取物(TQPE)对高脂小鼠体重、肝脏体重比、脂肪体重比的影响
由图1至图3所示，与空白组(CON)相比，高脂小鼠的体重(P<0.001)、肝脏体重比(P<0.001)和脂肪体重比(P<0.05)明显升高；与模型组(HFD) 相比，菱角壳提取物能够显著降低高脂小鼠的体重(P<0.001)、肝脏体重比 (P<0.05)和脂肪体重比(P<0.05)。
由此可以看出，菱角壳提取物能够有效降低高脂小鼠的体重和脂肪比重，可考虑用于治疗肥胖症。
(2)菱角壳提取物(TQPE)对高脂小鼠血脂的影响
由图4至图7可知：高脂模型组(HFD)小鼠血清中总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)含量显著高于空白组(CON) (P<0.001)，而高密度脂蛋白明显低于空白组(P<0.05)。菱角壳提取物给药4 周后，与模型组(HFD)比较，菱角壳组(HFD+TQPE15及HFD+TQPE 30) 显著降低高脂小鼠的TC(P<0.001)、TG(P<0.001)、LDL-c(P<0.001)，显著升高高脂小鼠的HDL-c(P<0.001)。
(3)菱角壳提取物(TQPE)对高脂小鼠谷丙转氨酶(ALT)和谷草转氨酶 (AST)活力及氧化应激相关酶的影响
从图8至图11可见，与空白组(CON)小鼠相比高脂小鼠(HFD)ALT和 AST活力显著升高(p<0.001)，给药菱角壳提取物后显著降低了ALT(丙氨酸转氨酶)和AST(天冬氨酸转氨酶)活力(P<0.001)，说明菱角壳提取物可以改善高脂小鼠肝细胞损伤。同时与正常组小鼠相比高脂小鼠血清SOD(超氧化物歧化酶)水平显著下降MDA(丙二醛)活力显著升高(P<0.001)，给药菱角壳提取物后高脂小鼠SOD水平显著回升，MDA水平显著下降，说明菱角壳提取物可以改善高脂小鼠失常的氧化应激水平。
(4)菱角壳提取物(TQPE)对高脂小鼠组织病理学影响
如图12所示，正常对照组肝脏外观呈深红色，组织光滑有弹性。相比之下，高脂小鼠肝脏增大，失去光泽，弹性，表面有黄色坏死病灶，表明产生了非酒精性脂肪肝的症状。菱角壳提取物(TQPE)高低剂量组可以改善肝脏外观。
肝组织切片见图13。正常对照组(即空白组，CON)肝组织结构正常，无脂肪堆积和炎症。与正常饮食处理小鼠相比HFD饲养小鼠肝脏切片肝小叶结构和肝细胞脂滴明显紊乱。经菱角壳提取物(TQPE)给药后，肝细胞肿胀、脂滴体积和数量均得到改善。尤其是菱角壳提取物(TQPE)高剂量组(HFD+TQPE 30) 小鼠肝小叶结构形态恢复到接近正常状态。
上述实验结果可知，菱角壳提取物能有效改善并治疗高脂饮食造成的小鼠非酒精性脂肪肝的症状，可考虑应用于治疗非酒精性脂肪肝药物。
Claims (5)
1.菱角壳提取物在制备治疗高血脂症的药物上的应用，所述菱角壳提取物通过以下方法制备：取菱角壳干燥粉末醇提水沉，经大孔树脂分离，洗脱液浓缩干燥，即得所述菱角壳提取物；所述醇提采用80%乙醇，所述大孔树脂采用弱极性大孔树脂，所述洗脱液采用40%乙醇。
2.菱角壳提取物在制备治疗高血脂症并发症的药物上的应用，所述菱角壳提取物通过以下方法制备：取菱角壳干燥粉末醇提水沉，经大孔树脂分离，洗脱液浓缩干燥，即得所述菱角壳提取物；所述醇提采用80%乙醇，所述大孔树脂采用弱极性大孔树脂，所述洗脱液采用40%乙醇。
3.菱角壳提取物在制备治疗非酒精性脂肪肝的药物上的应用，所述菱角壳提取物通过以下方法制备：取菱角壳干燥粉末醇提水沉，经大孔树脂分离，洗脱液浓缩干燥，即得所述菱角壳提取物；所述醇提采用80%乙醇，所述大孔树脂采用弱极性大孔树脂，所述洗脱液采用40%乙醇。
4.菱角壳提取物在制备治疗肥胖症的药物上的应用，所述菱角壳提取物通过以下方法制备：取菱角壳干燥粉末醇提水沉,经大孔树脂分离，洗脱液浓缩干燥，即得所述菱角壳提取物；所述醇提采用80%乙醇，所述大孔树脂采用弱极性大孔树脂，所述洗脱液采用40%乙醇。
5.根据权利要求1至4任一所述的应用，其特征在于，所述菱角壳提取物通过以下方法制备：将菱角果壳干燥粉碎，得菱角果壳粉末，取浓度为 80% 的乙醇为溶剂，渗滤提取 2次，每次 15 天，每次80%乙醇加入量为每1kg菱角壳加入8L，合并提取液；将提取液浓缩至浸膏，取浸膏重量 10 倍的 10% 乙醇溶解，离心除去不溶物，得到上样溶液；取LS-300B 型大孔树脂，将上样溶液上样，采用水洗脱，弃去洗脱液，再采用 40% 乙醇进行洗脱，收集40%乙醇洗脱液，将40% 乙醇洗脱液减压浓缩干燥，即得所述菱角壳提取物。
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