CN114832005A - 毛蕊花糖苷的新用途 - Google Patents
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Abstract
本发明提供了毛蕊花糖苷在制备预防和/或治疗高血脂以及动脉粥样硬化药物中的应用，开拓了毛蕊花糖苷的应用前景，为抗动脉粥样硬化的新药开发提供了理论依据与指导。经验证，毛蕊花糖苷在体外能够显著降低氧化低密度脂蛋白诱导的巨噬细胞的泡沫化程度，降低胆固醇水平，同时可以显著缓解西方饮食诱导的动脉粥样硬化动物模型中动脉斑块的形成；毛蕊花糖苷可以通过调节肝脏中甘油磷脂代谢途径减轻肝脏中的脂质沉积，调节脂代谢紊乱，降低血脂水平，进而起到抗动脉粥样硬化的作用。
Description
技术领域
本发明涉及医药技术领域，尤其是毛蕊花糖苷的新用途。
背景技术
动脉粥样硬化(AS)是一种由脂肪、胆固醇、钙和血液中的其他物质组成的粥样斑块在血管壁沉积并造成动脉狭窄的疾病。近年来，由于人们生活水平的提高，过量摄入不饱和脂肪酸、反式脂肪酸、碳酸饮料以及吸烟喝酒等不健康的生活习惯导致人体内脂质代谢失调，增加了动脉粥样硬化的风险。目前以他汀类为代表的降脂药被广泛用于临床动脉粥样硬化的治疗，但其剂量依赖性与时间依赖性产生的肌痛、肌炎等不良反应为广大患者带来困扰。
毛蕊花糖苷是苯乙醇苷类成分，其广泛分布在列当科、玄参科、木兰科、唇形科等多种药用植物中，目前列当科植物肉苁蓉为主要的获取途径。毛蕊花糖苷在神经保护、抗肿瘤、抗抑郁、抗炎等方面有积极的作用，另有研究显示肉苁蓉总苷具有降糖降脂的效果，但毛蕊花糖苷本身在抗动脉粥样硬化的作用未见研究报道。
发明内容
本发明所要解决的技术问题在于提供毛蕊花糖苷的新用途。
本发明采用的技术方案是：
毛蕊花糖苷在制备预防和/或治疗高血脂的产品中的应用，所
述毛蕊花糖苷的结构式如式(1)所示：
优选的，毛蕊花糖苷在制备预防和/或治疗动脉粥样硬化产品的应用。
优选的，毛蕊花糖苷在制备预防和/或治疗肝脏脂质沉积的产品中的应用。
优选的，毛蕊花糖苷在制备预防和/或治疗肝脏脂代谢紊乱的产品中的应用。
优选的，所述产品包括药物、食品或保健品。
优选的，所述药物为含本发明所述的毛蕊花糖苷的药物组合物，所述药物组合物在制备时包括药学上可接受的载体或辅料。
优选的，所述药物或保健品的剂型为片剂、胶囊剂、粉剂、糖浆、液剂、悬浮剂或针剂。
优选的，所述产品含有有效剂量的毛蕊花糖苷。
本发明的有益效果是：
本发明提供毛蕊花糖苷在制备预防和/或治疗高血脂、动脉粥样硬化的产品中的应用，毛蕊花糖苷在体外能够显著降低氧化低密度脂蛋白诱导的巨噬细胞的泡沫化程度，在体内可以通过调节肝脏中甘油磷脂代谢途径减轻肝脏中的脂质沉积，调节脂代谢紊乱，降低血脂水平，进而起到抗动脉粥样硬化的作用。所述毛蕊花糖苷在抗动脉粥样硬化方面的活性研究未见有论文期刊报道，开拓了毛蕊花糖苷的应用前景，为抗动脉粥样硬化的新药开发提供了理论依据与指导。
附图说明
图1为细胞油红O染色照片与染色面积柱状图，**P＜0.01vs.模型组；
图2为细胞总胆固醇含量测定结果柱状图，***P＜0.001vs.空白组；###P＜0.001vs.模型组；
图3为主动脉根部油红O染色照片与斑块面积柱状图，***P＜0.001vs.空白组；#P＜0.05vs.模型组；##P＜0.01vs.模型组；###P＜0.001vs.模型组；
图4为血浆中生化指标测定结果柱状图，***P＜0.001vs.空白组；#P＜0.05vs.模型组；##P＜0.01vs.模型组；###P＜0.001vs.模型组。
图5为肝脏中甘油磷脂代谢通路及相关脂质代谢物含量柱状图，*P＜0.05vs.模型组；**P＜0.01vs.模型组；***P＜0.001vs.空白组；#P＜0.05vs.模型组；##P＜0.01vs.模型组；###P＜0.001vs.模型组。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合附图及具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
毛蕊花糖苷在体外具有抗动脉粥样硬化活性的研究。
实验方法
1.细胞培养：取RAW264.7巨噬细胞加入到含有10％胎牛血清的DMEM高糖培养基中，将细胞置于37℃，5％CO2的培养箱中进行培养。
2.油红O染色鉴定毛蕊花糖苷对巨噬细胞泡沫化的影响
2.1取上述对数生长期的RAW264.7细胞以每孔8000个细胞接种于96孔板中，将细胞在培养箱中培养24小时后分为空白组、模型组和毛蕊花糖苷给药组，每组5个复孔。模型组给予浓度为50μg/mL氧化低密度脂蛋白(Ox-LDL)的无血清培养基继续培养，毛蕊花糖苷给药组给予浓度为50μg/mL Ox-LDL加10μM实施例1中所得毛蕊花糖苷的无血清培养基共同培养，每孔100μL。
2.2药物作用24小时后，弃去旧培养基，再用适量PBS清洗2次后弃液，加入多聚甲醛固定液，常温固定20min，弃去；使用PBS清洗后弃液，加入60％异丙醇浸洗5min，弃去；加入油红O试剂进行染色，弃去染色液，加入蒸馏水清洗数次至无多余染料。蒸馏水覆盖细胞，于光学显微镜下观察、采集图像，使用Image-Pro Plus 6.0软件对染色结果进行分析。
3.毛蕊花糖苷对巨噬细胞总胆固醇的调节作用
3.1取对数生长期的RAW264.7细胞以每孔1.2×106个细胞接种于6孔板中，将细胞在培养箱中培养24小时后分为空白组、模型组和毛蕊花糖苷给药组，每组3个复孔。模型组给予浓度为50μg/mL Ox-LDL的无血清培养基继续培养，毛蕊花糖苷给药组给予浓度为50μg/mL Ox-LDL加10μM药物的无血清培养基共同培养，每孔2mL。
3.2药物作用24小时后，弃上清，加入PBS清洗两次，加入RIPA裂解液后，将6孔板置于4℃冰箱裂解细胞30-40min，用细胞刮刀将裂解好的细胞刮下并分别置于1.5mL离心管中，静置半小时待测。总胆固醇含量测定严格按照试剂盒说明进行操作。
实验结果
1.毛蕊花糖苷对Ox-LDL诱导的巨噬细胞泡沫化具有抑制作用
油红O染色结果及软件对染色面积分析结果如图1所示，空白组细胞形态正常，没有被染液染色，细胞呈透明状；模型组细胞体积胀大，胞浆呈疏松状态，且胞质内存在大量脂质颗粒而被染成红色；与模型组相比，毛蕊花糖苷给药组中红色脂滴的面积则大幅减少(P＜0.05)，说明毛蕊花糖苷对Ox-LDL诱导的巨噬细胞泡沫化具有明显的抑制作用。
2.毛蕊花糖苷对细胞总胆固醇含量具有下调作用
细胞总胆固醇含量测定结果如图2显示，与对照组相比，模型组细胞内总胆固醇含量明显升高(P＜0.001)，毛蕊花糖苷给药组则可以显著降低细胞中总胆固醇的含量(P＜0.001)。
实施例2
毛蕊花糖苷在体内具有抗动脉粥样硬化活性的研究。
实验方法
1.动物分组及给药：将10只8周龄雄性C57BL/6J小鼠作为对照组(i.g.生理盐水)，将50只8周龄雄性Apo E-/-基因敲除小鼠随机分为模型组(i.g.生理盐水)、辛伐他汀阳性药组(i.g.20mg/kg/天)、毛蕊花糖苷低剂量组(i.g.15mg/kg/天)、毛蕊花糖苷中剂量组(i.g.30mg/kg/天)、毛蕊花糖苷高剂量组(i.g.60mg/kg/天)。对照组给予普通饲料，模型组及各给药组给予高脂饲料喂养16周。取小鼠主动脉使用10％多聚甲醛固定，取小鼠血浆、肝脏保存待测。
2.将主动脉根部进行冰冻切片，将切片于油红染液浸染10min，蒸馏水洗涤；60％异丙醇分化，蒸馏水进行洗涤；切片入苏木素染液染3min，蒸馏水洗；分化液分化，水洗，返蓝液返蓝，水洗。封片，镜检，拍照，使用Image-Pro Plus 6.0软件对染色结果进行分析。
3.使用全自动生化分析仪检测血浆样本中总胆固醇、甘油三酯、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平。
4.称取新鲜肝脏样本100mg于2mL离心管中，加入435μL超纯水，使用自动匀浆器冰上匀浆。于离心管中加入1.5mL二氯甲烷/甲醇(2:1,v：v)，漩涡震荡，静置10min后离心，离心10分钟(3000r/min)，液体分层，取下层液体0.5mL，转移到新的1.5mL离心管中，氮气下吹干。用200μL异丙醇/甲醇(1:1,v：v)复溶，涡旋混合，转移到进样瓶中使用LC-MS/MS质谱进行非靶向脂质组学分析。
实验结果
1.各组小鼠主动脉根部病理切片结果与软件分析主动脉根部中斑块占血管腔横切面积百分比如图3显示。空白组主动脉根部油红O染色未见脂质堆积，与空白组相比，模型组结果显示主动脉根部斑块内有大量脂质堆积，可见明显斑块。辛伐他汀阳性药组、毛蕊花糖苷中剂量组与高剂量组均能使得主动脉根部脂滴堆积减少(P＜0.05)。
2.图4显示了生化仪检测各组小鼠血浆中总胆固醇、甘油三酯、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平。辛伐他汀阳性药和毛蕊花糖苷低、中、高剂量组中总胆固醇、甘油三酯下调显著(P＜0.05)，辛伐他汀阳性药和毛蕊花糖苷中、高剂量组中低密度脂蛋白胆固醇下调显著(P＜0.05)，各给药组中高密度脂蛋白胆固醇相比模型组则有回调的趋势。
3.差异脂质主要通过有监督的正交偏最小二乘判别分析法进行筛选，卡foldchange值大于2以及P小于0.05。筛选结果显示：毛蕊花糖苷可以显著将肝脏心磷脂(CL)、乙醚连接磷脂酰胆碱(ether PC)、溶血磷脂酰胆碱(LPC)、磷脂酰胆碱(PC)、氧化磷脂酰胆碱(OxPC)、氧化磷脂酰乙醇胺(OxPE)、三酰甘油(TG)和鞘磷脂(SM)的异常代谢恢复至正常水平，毛蕊花糖苷调节的脂质代谢途径如图5所示，这些脂质的通路富集分析结果显示毛蕊花糖苷对甘油磷脂代谢有显著影响。
结论
综上，本发明提供了毛蕊花糖苷在制备预防和/或治疗高血脂、动脉粥样硬化的产品中的应用，其可以在体外抑制氧化低密度脂蛋白诱导巨噬细胞分化为泡沫细胞的进程，可以显著降低小鼠动脉斑块的形成，下调血脂水平，同时肝脏非靶向脂质组学结果显示毛蕊花糖苷通过调节甘油磷脂代谢通路对肝脏脂代谢紊乱起到恢复作用，进而起到抗动脉粥样硬化的作用。本发明开拓了毛蕊花糖苷的应用前景，为新药的开发提供了理论依据与指导。
以上所述实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通工程技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明的权利要求书确定的保护范围内。
Claims (8)
1.毛蕊花糖苷在制备预防和/或治疗高血脂的产品中的应用。
2.根据权利要求1所述的应用，其特征在于：毛蕊花糖苷在制备预防和/或治疗动脉粥样硬化的产品中的应用。
3.根据权利要求1所述的应用，其特征在于，毛蕊花糖苷在制备预防和/或治疗肝脏脂质沉积的产品中的应用。
4.根据权利要求1所述的应用，其特征在于，毛蕊花糖苷在制备预防和/或治疗肝脏脂代谢紊乱的产品中的应用。
5.根据权利要求1-4任一项所述的应用，其特征在于，所述产品包括药物、食品或保健品。
6.根据权利要求5所述的应用，其特征在于，所述产品为药物，所述药物在制备时包括药学上可接受的载体或辅料。
7.根据权利要求5所述的应用，其特征在于，所述药物或保健品的剂型为片剂、胶囊剂、粉剂、糖浆、液剂、悬浮剂或针剂。
8.根据权利要求1-4任一项所述的应用，其特征在于，所述产品含有有效剂量的毛蕊花糖苷。
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