CN115607528B - D-阿拉伯糖醇在降脂保肝中的应用 - Google Patents
D-阿拉伯糖醇在降脂保肝中的应用 Download PDFInfo
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Abstract
本发明公开了D‑阿拉伯糖醇在降脂保肝中的应用。血脂或肝脏脂肪异常指血液或肝脏中脂质的量和质的异常，通常指胆固醇和/或甘油三酯升高。血脂和肝脏脂肪异常会导致动脉粥样硬化，增加心脑血管病的发病率和死亡率，还会导致肝脏损伤。本发明发现，D‑阿拉伯糖醇具有优异的降脂保肝作用，具有开发成降脂保肝的药品或保健品或食品的前景。
Description
技术领域
本发明涉及已知化合物的新用途，具体涉及D-阿拉伯糖醇在降脂保肝中的应用。
背景技术
血脂或肝脏脂肪异常指血液或肝脏中脂质的量和质的异常，通常指胆固醇和/或甘油三酯升高。血脂和肝脏脂肪异常会导致动脉粥样硬化，增加心脑血管病的发病率和死亡率，还会导致肝脏损伤。
D-阿拉伯糖醇作为一种功能性五碳糖醇已应用于一些行业。在食品行业中，阿拉伯糖醇不仅作为高档甜味剂，还可作为调制糖浆基质来改善酒精饮料品质；在医药领域，D-阿拉伯糖醇可作为阿糖腺苷、阿糖胞苷和α-葡萄糖苷酶抑制剂等药物的中间体，同时还可作为运输介质以通过血脑屏障；而在化工方面，D-阿拉伯糖醇是颗粒性固体或亲水涂层的促溶剂，可增强铝电容器在高温下的可靠性并提高电解质溶液的黏度，此外，还可作为合成高分子发泡材料的激活剂及显影材料稳定剂；在生物方面，还能促进植物生长。
目前未见D-阿拉伯糖醇在降脂保肝方面的报道。
发明内容
本发明的目的在于提供D-阿拉伯糖醇在降脂和保肝中的应用。
本发明上述目的通过如下技术方案实现：
D-阿拉伯糖醇在制备降脂保肝的药品或保健品或食品中的应用。
一种降脂保肝的药品或保健品或食品，该药品或保健品或食品以D-阿拉伯糖醇为活性成分，辅以药品或保健品或食品中可以接受的辅料。
有益效果：
本发明发现，D-阿拉伯糖醇具有优异的降脂保肝作用，具有开发成降脂保肝的药品或保健品或食品的前景。
附图说明
图1为各组小鼠体重比率变化(n＝8)；与正常饮食组相比，***P<0.001，与高脂饮食组相比，##P<0.01；
图2为各组小鼠血脂水平比较(n＝6)，其中：A：血清总甘油三酯含量；B：血清低密度脂蛋白胆固醇含量；C：血清高密度脂蛋白胆固醇含量；与高脂饮食组相比，*P<0.05，**P<0.01，***P<0.001；
图3为各组小鼠肝脏总胆固醇水平比较(n＝6)；与高脂饮食组相比，***P<0.001；
图4为各组小鼠肝组织HE染色；
图5为各组小鼠血清谷丙转氨酶水平(n＝6)；与高脂饮食组相比，***P<0.001。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
一、实验材料
1、仪器
JJ-12J型脱水机，JB-P5型包埋机，JB-L5型冻台(武汉俊杰电子有限公司)，RM2016型病理切片机，LEICA 819型切片刀(上海徕卡仪器有限公司)，KD-P型组织摊片机(浙江省金华市科迪仪器设备有限公司)，GFL-230型烤箱(天津市莱玻瑞仪器设备有限公司)，Eclipse E100型正置光学显微镜(日本尼康株式会社)，Revco UXF型超低温冰箱(美国Thermo Fisher Scientific公司)，M200型酶标仪(美国TECAN公司)，MinSpin型高速离心机(德国Eppendorf公司)，MB100-4P型恒温振荡仪(杭州奥盛仪器有限公司)，CPA225D型电子天平(德国Sartorius公司)，MM400型冷冻混合研磨仪(德国Retsch公司)。
2、试剂与材料
无水乙醇、二甲苯、中性树胶、盐酸、氨水购自国药集团化学试剂有限公司；伊红染液、分化液、返蓝液、苏木素、甘油明胶购自武汉塞维尔生物科技有限公司；高密度脂蛋白胆固醇试剂盒(20191209)、低密度脂蛋白胆固醇试剂盒(20191223)、总胆固醇试剂盒(20191209)、总甘油三酯试剂盒(20191209)、丙氨酸氨基转移酶(谷丙转氨酶)测试盒(20191227)均购自南京建成生物工程研究所。D-阿拉伯糖醇(E34RF-MV)购于梯希爱(上海)化成工业发展公司，L-阿拉伯糖醇(A1921101)购于上海阿拉丁生化科技公司，L-阿拉伯糖(LG30S37)和D-阿拉伯糖(LM50S07)购于北京百灵威科技有限公司，木糖醇(C11954123)购于上海麦克林生化科技有限公司。高脂饲料(D12492)购自美国Research Diets公司，常规饲料(SWS9102)购自江苏协同医药生物工程有限公司。
二、实验方法
1、药物配制
用无菌蒸馏水分别将D-阿拉伯糖醇、L-阿拉伯糖醇、L-阿拉伯糖、D-阿拉伯糖和D-木糖醇配制为50g/L或20g/L的溶液备用。
2、动物与分组
SPF级8周龄C57 BL/6J雄性小鼠共64只，在具备独立送风笼(IVC)的屏障设施内用正常饲料适应性饲养3天后，测定初始体重，并被随机分为8组。第四天分别给予8组小鼠正常饲料或高脂饲料，并将给药组小鼠的饮水替换为含有药物的水。每只小鼠都可以自由饮食饮水，每周记录体重。分组、饮食和给药如下：
(1)正常饮食组：正常饲料+无菌蒸馏水；
(2)高脂饮食组：高脂饲料+无菌蒸馏水；
(3)50g/L的L-阿拉伯糖醇组：高脂饲料+50g/L的L-阿拉伯糖醇；
(4)20g/L的D-阿拉伯糖醇组：高脂饲料+20g/L的D-阿拉伯糖醇；
(5)50g/L的D-阿拉伯糖醇组：高脂饲料+50g/L的D-阿拉伯糖醇；
(6)50g/L的L-阿拉伯糖组：高脂饲料+50g/L的L-阿拉伯糖；
(7)50g/L的D-阿拉伯糖组：高脂饲料+50g/L的D-阿拉伯糖；
(8)50g/L的木糖醇组：高脂饲料+50g/L的木糖醇。
3、样本采集
小鼠终末采血，腹腔注射50mg/kg戊巴比妥钠溶液(5mg/mL)，给药体积0.1mL/10g，麻醉后进行眼眶采血，脱脊椎处死，取出肝脏，生理盐水漂洗后用滤纸控干水分；取一片肝叶，置多聚甲醛中固定，剩余部分液氮速冻，-80℃保存；血液静置30min后3500rpm离心10min取上清，-80℃保存。
4、组织病理学检测
切取已经用4％多聚甲醛固定的肝组织，在脱水机内梯度脱水：75％乙醇4h，85％乙醇2h，90％乙醇2h，95％乙醇1h，无水乙醇I 30min，无水乙醇II 30min；完全脱水后的组织用无水乙醇-二甲苯等体积混合液透明1次后，再用纯二甲苯透明2次，每次约5～10min；透明好的组织样本用纯石蜡浸泡3次，每次1h，而后在包埋机上用融化的石蜡进行包埋，-20℃冻台冷却凝固；对冷却的石蜡包块进行固着、修整后，用病理切片机进行切片；让切片漂浮于摊片机40℃温水上，并将组织展平，用载玻片将组织捞起，并放入60℃烘箱内烤片。待水烤干、蜡烤化后取出常温保存备用。
染色前先对石蜡切片进行脱蜡复水：将切片用纯二甲苯处理2次，每次20min；再用100％、90％、75％的乙醇依次梯度处理5min并用水清洗。脱蜡复水后的切片先放入苏木素染液染浸泡3～5min，用水清洗后，放入分化液中分化，再次用水清洗，而后放入返蓝液中返蓝，并用流水冲洗；苏木素染色结束后，将切片依次放入85％、95％的乙醇梯度脱水，每次5min，再放入伊红染液中染色5min。染色完成后，用无水乙醇和二甲苯分别处理处理切片3次和2次，每次5min，最后用中性树胶封片。
在显微镜下进行镜检，肝组织中细胞核呈蓝色，细胞质呈红色，脂肪滴则为白色空泡。
5、生化指标检测
对于血清样本，将其置于4℃解冻后，照试剂盒说明书的方法测定血清高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-c)、总甘油三酯(TG)、谷丙转氨酶(ALT)和谷草转氨酶(AST)。
对于肝组织样本，将其置于4℃解冻后称取适量，加入9倍(v/m)无水乙醇，在冷冻混合研磨仪中研磨5min，匀浆液2500rpm离心10min，取匀浆液照试剂盒说明书的方法测定肝组织的总胆固醇(TC)。
6、数据处理及统计分析
小鼠体重比率：第n周体重(g)×100％/初始体重(g)。用GraphpadPrism v9.0对数据进行统计学检验，对于体重数据，采用two-wayANOVA及Tukey’s多重比较检验；对于其它数据，采用one-wayANOVA及Dunnett’s多重比较检验。
三、实验结果
1、体重
各组小鼠体重变化趋势见图1。高脂饮食小鼠体重增长显著快于正常饮食小鼠，从第三周开始体重比率开始出现显著差异(P<0.05)，第十二周差异极显著(P<0.001)。而相比模型组小鼠，给予50g/L的D-阿拉伯糖醇从第四周开始显著降低高脂小鼠的体重比率(P<0.05)，第十二周时P＝0.0058；而20g/L的D-阿拉伯糖醇从第八周开始显示出显著降低高脂小鼠体重比率的作用(P<0.05)，第十二周P＝0.0060。这表明D-阿拉伯糖醇可以浓度依赖性减轻高脂小鼠的体重增长。而给予50g/L的L-阿拉伯糖醇、50g/L的L-阿拉伯糖、50g/L的D-阿拉伯糖和50g/L木糖醇则没有显著降低小鼠体重比率的作用。
2、血脂
由图2中A可知，对比正常饮食组，高脂饮食组小鼠血清总甘油三酯显著升高(P<0.001)，除了给予50g/L的D-阿拉伯糖醇的高脂饮食小鼠血清中总甘油三酯显著下降(P<0.001)，其他组均无显著变化。如图2中B、C显示，高脂饮食组小鼠的低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平相较正常饮食组显著升高(P<0.001)，给予50g/L或20g/L的D-阿拉伯糖醇均可显著降低高脂小鼠血清中这两种血脂的浓度(P<0.05)，而其他组均无显著变化。这表明D-阿拉伯糖醇对高脂饮食小鼠的血脂具有显著改善作用，且存在一定浓度依赖性。
3、肝脂质
如图3显示，高脂喂养十二周的小鼠肝脏中总胆固醇水平明显增加(P<0.001)。给予20g/L或50g/L的D-阿拉伯糖醇可显著降低高脂饮食小鼠肝脏内总胆固醇的蓄积(P＜0.01)，而其他组均无显著变化。这表明D-阿拉伯糖醇对高脂饮食小鼠的肝脂蓄积具有显著改善作用，且存在一定浓度依赖性。
4、肝组织病理学
如图4，高脂饮食小鼠肝组织相较于正常饮食小鼠，存在大量白色圆形空泡，表明脂滴大量积累，而给予50g/L或20g/L的D-阿拉伯糖醇的高脂饮食小鼠，肝组织内没有明显的白色空泡；给予50g/L的L-阿拉伯糖醇的高脂饮食小鼠虽无显著白色空泡，但其肝脏细胞结构消失，暗示肝脏出现损伤，因此L-阿拉伯糖醇总体改善效果不及相同剂量的D-阿拉伯糖醇。综上，D-阿拉伯糖醇可以缓解高脂饮食诱导的小鼠肝组织脂肪变性及肝脏损伤。
5、转氨酶
如图5显示，高脂喂养十二周的小鼠血清中谷丙转氨酶水平明显增加(P<0.001)。20g/L的D-阿拉伯糖醇(P<0.001)、50g/L的D-阿拉伯糖醇(P<0.001)可显著减轻高脂饮食小鼠血清谷丙转氨酶浓度，其他组均无显著变化。本领域技术人员知道，谷丙转氨酶主要存在于肝脏细胞内，肝脏受损时会大量释放至血液中，其在血液中的含量水平是肝细胞损害的敏感标志，是评价肝脏功能损伤的重要指标。由此可见，D-阿拉伯糖醇对高脂饮食小鼠肝功能具有优异的保护作用，且呈现一定的剂量依赖性。
综合上述实验可以确定D-阿拉伯糖醇具有优异的降脂保肝作用，具有开发成降脂保肝的药品或保健品或食品的前景。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (1)
1.D-阿拉伯糖醇作为唯一活性成分在制备降脂保肝的药物中的应用。
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